Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy
Scoliosis volume 6, Article number: 26 (2011)
Genetic factors are believed to play an important role in the etiology of adolescent idiopathic scoliosis (AIS). Discordant findings for monozygotic (MZ) twins with AIS show that environmental factors including different intrauterine environments are important in etiology, but what these environmental factors may be is unknown. Recent evidence for common chronic non-communicable diseases suggests epigenetic differences may underlie MZ twin discordance, and be the link between environmental factors and phenotypic differences. DNA methylation is one important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life. The word exposome refers to the totality of environmental exposures from conception onwards, comprising factors in external and internal environment s. The word exposome is used here also in relation to physiologic and etiopathogenetic factors that affect normal spinal growth and may induce the deformity of AIS. In normal postnatal spinal growth we propose a new term and concept, physiologic growth-plate exposome for the normal processes particularly of the internal environments that may have epigenetic effects on growth plates of vertebrae. In AIS, we propose a new term and concept pathophysiologic scoliogenic exposome for the abnormal processes in molecular pathways particularly of the internal environment currently expressed as etiopathogenetic hypotheses; these are suggested to have deforming effects on the growth plates of vertebrae at cell, tissue, structure and/or organ levels that are considered to be epigenetic. New research is required for chromatin modifications including DNA methylation in AIS subjects and vertebral growth plates excised at surgery. In addition, consideration is needed for a possible network approach to etiopathogenesis by constructing AIS diseasomes. These approaches may lead through screening, genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS. The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis.
The principal aim of this paper is to examine the etiopathogenesis of adolescent idiopathic scoliosis (AIS) from the standpoint of epigenetics. To our knowledge this has not previously been addressed. Epigenetics, a relatively recent field now vast and vigorous, evaluates factors concerned with gene expression in relation to environment, disease, normal development and aging, with a complex regulation across the genome during the first decade of life. Butcher and Beck  describe epigenetics as follows:
"Although environmental measures are logical covariants for genotype-phenotype investigations, another non-genetic intermediary exists: epigenetics. Epigenetics is the analysis of somatically-acquired and, in some cases, transgenerationally inherited epigenetic modifications that regulate gene expression, and offers to bridge the gap between genetics and environment to understand phenotype. The most widely studied epigenetic mark is DNA methylation. Aberrant methylation at gene promoters is strongly implicated in disease etiology, most notably cancer."
There is controversy relating to the definition of epigenetics which we outline. Taking the broad definition, a view of AIS etiopathogenesis and normal spinal development is presented from an epigenetic standpoint, predicated on a model for other diseases.
Research into the causation of adolescent idiopathic scoliosis (AIS) draws heavily from mechanical and biological disciplines, but still lacks an agreed theory of etiopathogenesis [2, 3]. Genetic factors are believed to play an important role in the etiology of AIS with considerable heterogeneity [2, 4, 5]. Hence treatment is empirical and not based on sufficient understanding of etiology to support the current mechanically-based therapy . The research problem is complicated by the suspicion that AIS may result not from one cause, but several that interact. Genetic, and now genomic, research on AIS has not yet provided the therapeutically-required etiologic understanding. In other diseases and particularly diseases of developmental origin [7–13] and late-onset chronic non-communcable diseases (NCDs) [14–22], research on the role of environmental factors and epigenetics after a slow start  has exploded in the last decade [1, 17, 18, 24–32]. Not so for AIS research where, except for monozygotic twin studies and very recent mentions on the net [33, 34], there are only sporadic reports suggesting that environmental factors are at work in etiology.
Genotype-environment (GxE, nature/nurture) interactions are being extensively researched in human growth [35–40], behavioural studies [41–43], early-life conditions [7–13, 44, 45], placentation  and gastrointestinal diseases [46–48]. The increasing incidence of idiopathic club foot in Denmark and Sweden has led to the speculation that factors associated with population density namely, environmental stress (traffic pollution, noise) and stress of urban living (misuse of tobacco, alcohol, drugs), could be reasons for this epidemiological change .
DNA methylation (DNAm) is an important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life . Recent data suggests that epigenetic responses including DNAm is involved not only in cellular differentiation but also in modulation of genome function in response to signals from the various environments . The window of developmental plasticity extends from preconception to early childhood and is exerted particularly during life-history phase transitions . Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental and behavioural strategies in response to local physical, biological and/or social conditions [13, 45, 51].
Epigenetics is now generally defined as information heritable during cell division but not contained within the DNA sequence itself . There are three major ways organisms alter their DNAs inherited messages: enzymes methylate DNA to modulate transcription; histone modifications and nucleosome positioning to induce or repress target sequences; and non-coding small RNAs (including microRNAs and short interfering RNAs) which attach themselves to messenger RNA to modify the expression of specific genes [10, 46, 52, 53]. DNA-cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease . According to Cropley et al  epigenetic mechanisms provide multicellular organisms with a system of normal gene regulation that silences portions of the genome and keeps them silent as tissues differentiate. Long-term silencing can be reprogrammed by demethylation of DNA which starts afresh in each generation in germ cells and early embryos through which effects on nutrition in utero may influence health in later life [56–58] (Appendix I).
Errors in this complex system termed epimutations arising from environmental and stochastic (random) events, can give rise to abnormal gene silencing, that may result in a great deal of phenotypic variation and common disease, At present, there are only a handful of clear examples; but importantly this can occur in the absence of any underlying genetic defect . Alterations in the epigenetic status can be directly modified by various environmental insults or maternal dietary factors [44, 60]. Epigenetics helps to explain the relationship between an individual's genetic background, environment, aging, and disease . Sex differences in epigenetic processes may alter the risk or resilience to develop a particular disorder . Increased understanding of epigenetic-disease mechanisms could lead to innovative diagnostic tests and disease-risk stratification to targeted intervention and therapies [16, 46].
The Human Epigenome Project (HE) and other epigenomic projects [62–66] are evaluating epigenetics in developmental origins of human disease [9, 11], and for musculoskeletal disorders in bone development [67–69] and dysmorphology .
Apart from the emerging role of epigenetic mechanisms in the etiology of neural tube defects , Prader-Willi syndrome [71, 72], and the recent theoretical interpretations of Burwell and colleagues [73–76] and McMaster , epigenetics does not figure in any causal analysis of postnatal normal spinal growth, or in the etiopathogenesis of AIS (Figure 1), This reflects current scientific opinion that genetic rather than environmental factors determine the etiology of AIS in accordance with the genetic variant hypothesis of disease[17, 78] (Appendix II).
In this paper we briefly evaluate postnatal normal spinal growth and the etiopathogenesis of AIS in relation to the epigenetic explosion and the terminologic disagreements; the latter arise from the different requirements of geneticists, molecular biologists, developmental biologists and pathogetieticists. Our interpretation for AIS attempts to overcome these difficulties. It is predicated on the premise that in all scolioses, idiopathic, and secondary, spinal deformity cannot occur without normal vertebral growth-plate function being compromised ultimately in three dimensions by abnormal processes. This focus on vertebral growth does not imply that asynchronous ribcage growth [79–83], intervertebral discs and vertebral bone may not contain factors in AIS pathogenesis. The tenets outlined here for AIS are applicable to other developmental growth disorders including infantile and juvenile idiopathic scoliosis.
The aims of this paper are:
To review sporadic reports suggesting that environmental factors are involved in AIS etiology.
To note that the risks of developing late-onset chronic non-communicable diseases (NCDs) including cancer, diabetes, cardiovascular disease, respiratory disease, obesity and schizophrenia, are attributed to genetic and environmental factors.
To discuss the meaning of the word exposome. Currently, it refers to the totality of environmental exposures, exogenous and endogenous from conception onwards, some of which lead to occupational health problems.
To use the word exposome also in relation to physiologic and etiopathogenetic factors that respectively affect normal spinal growth and may induce/promote the deformity of AIS.
To suggest that the harmful effects produced by exposome factors leading to dysfunction involve interference with normal cellular processes and molecular pathways in cells, tissues, structures and organs.
To define epigenetics, its origin and two current meanings, modification and interactions.
To outline epigenetics in relation to normal embryonic development, involving epigenetic modification and interactions.
To present a causal analysis of the normal postnatal normal spinal growth putatively involving epigenetic interactions and modification.
To apply a new collective term and concept, physiologic growth-plate exposome, to the mainly endogenous (internal) environmental processes that affect normal spinal growth.
To present a causal analysis of abnormal deforming postnatal spinal growth in AIS, putatively involving epigenetic interactions and modification.
To apply a new collective term and concept, pathophysiologic scoliogenic exposome to abnormal processes in developmental pathways particularly of the internal environment that have putative epigenetic deforming effects on the growth plates of vertebrae at cell, tissue, structure and organ levels, and currently expressed as etiopathogenetic hypotheses.
To consider that the pathogenesis of AIS may involve a one--hit to multi-hit model.
To suggest research on chromatin modification including DNA methylation (DNAm) which plays an important role in gene expression, using tissues from AIS subjects including vertebral growth plates excised at surgery
To touch on network medicine and consider a network approach to AIS etiopathogenesis by constructing AIS diseasomes.
Environmental risk factors for adolescent idiopathic scoliosis (AIS)
Thirty years ago Wynne-Davies  examining the etiology of some common skeletal deformities including infantile idiopathic scoliosis, concluded that all are likely to have a common multifactorial genetic background associated with differing intrauterine or postnatal environmental factors. Most authors state that genetics stipulates the course of adolescent idiopathic scoliosis (AIS). In the last 20 years, sporadic reports have suggested environmental factors are involved in the etiopathogenesis and phenotypic expression of AIS. The evidence is outlined here together with an interpretation of AIS pathogenesis and the environment by some workers [85–87].
Monozygotic (MZ) twins and spinal radiology in AIS
MZ twins have a significantly higher concordance for AIS than dizygotic twins, with scoliosis curves in MZ twins developing and progressing together. Based on these data, Kesling and Reinker  concluded there is strong evidence for a genetic etiology for AIS, and familial idiopathic scoliosis [89, 90].
MZ twins have been used to demonstrate the role of environmental factors in determining complex diseases and phenotypes, but the true nature of the phenotypic discordance remains poorly understood [24, 50]. In AIS, concordance rates in MZ twins are 0.73-0.92 [88, 91, 92] with lower figures of 0.13 and 0.10 reported respectively from the Danish Twin Registry  and Swedish Twin Registry . These findings are quite surprisingly different, and suggest that variation in diagnostic criteria is important in the results of these studies [Armour J personal communication]. The Swedish Twin Registry study revealed a unique environment effect of 0.60  suggesting environmental factors are important in the etiology of AIS from different intrauterine environments . In 32 MZ twins, van Rhijn et al  found several parameters - gender, direction of convexity, apical level and kyphotic angle - were determined more by genetic factors than the lateral Cobb angle, suggesting that curve severity may be affected by the environment. Mirroring of curves was found in each of two MZ twin sets with idiopathic scoliosis [88, 96]. In another MZ twin pair concordant for AIS, the twins had different apical levels, curve magnitudes, and age at detection which stress the importance of environmental (non-genetic) factors in etiopathogenesis .
Concordance rate of less than 100% in MZ twins for AIS may be explained not only from environmental influences but also by other factors including, uneven cytoplasmic cleavage of the fertilized egg - thought to cause the scoliosis mirroring of one twin pair, mutation after fertilization causing a genotype mosaic , differences in placentation, amniotic sac, and vascularization of separate cell masses . In MZ twins with congenital scoliosis, environmental factors are reported to play a leading role in the development of the condition .
According to Fraga et al epigenetic differences may underlie MZ twin discordance for common diseases, and represent the link between environmental factors and phenotypic differences. The patterns of epigenetic modification of twin pairs diverge as they become older and their lifestyles become distinct reflecting accumulated exposure to a wide range of external and internal factors including environmental factors such as physical (and perhaps mental) activity, diet, drink, smoking and other habits . They referred to the phenomenon as "epigenetic drift" and associated it with the aging process .
A food and growth connection?
A sudden increase in the incidence of idiopathic scoliosis in Jamaica after 1965 was evaluated by Golding . Attention was directed to endocrine additives used to promote the growth of livestock and the meat-to-food conversion in cattle and broilers. Taking Into consideration the 10-year delay in the onset of the idiopathic scoliosis, this fitted remarkably well with increase frequency of the scoliosis which occurred up to 1983 and its decline since.
Nutrition in the etiology of idiopathic scoliosis (IS)
A review of American and European articles from 1955-1990 evaluated nutrition as an environmental factor in the etiology of idiopathic scoliosis . These authors concluded:
"...there is at least an anecdotal association of IS with poor nutrition, there is strong evidence from an animal model and there is a partial understanding of the biochemical mechanisms explaining nutrition as an etiological factor. Given the fact that nutrition is an environmental factor which can easily be changed, further investigation of the link between nutrition and IS in humans is warranted."
Relative osteopenia and life-style factors
Studies on Chinese girls with AIS have revealed relative osteopenia [113, 114] suggesting a contribution from life-style factors including nutrition, diet, calcium, vitamin D intake and exercise level 
Good dietary practices and optimal nutritional status are known to promote growth and tissue development, as well as disease prevention [39, 53, 103, 104]. Nutritional epigenetics has emerged as a novel mechanism underlying gene-diet interactions  with the strongest evidence for transgenerational inheritance coming from the survivors of the Dutch Hunger Winter . Dietary modification can have a profound effect on DNAm and genomic imprinting [16, 106], with plant-derived microRNAs entering the bloodstream . A major focus of research on dietary influences on epigenetic status has been on nutrition in utero, because the epigenome is probably malleable particularly during this life-course window [60, 107, 108], and because epigenetic marking by early exposures is a compelling mechanism underlying effects on lifelong health [108, 109]. DNAm depends on dietary methionine and folate, both of which are affected by the nutritional state [14, 17, 110]. Ford et al  have published a Table summarizing specific dietary components with effects on DNAm; these include methyl donors, bioactive polyphenols, zinc, selenium,and vitamin A. In AIS, prevention by diet is discussed speculatively [111, 112], and on the net .
Physical activities of patients with AIS
McMaster et al [115, 116] reported AIS to be negatively associated with participation in dance, skating, gymnastics/karate and horse riding classes. They asked the question: Do children who develop AIS have a long-standing proprioception defect which makes them less likely to participate in sporting activities? If so, by encouraging sport and increasing proprioceptive abilities common to all joints  might make those at risk less likely to develop spinal asymmetry.
Geographic latitude and the prevalence of AIS
In a review of peer-reviewed published papers, Grivas et al  found that a later age at menarche is associated with a higher prevalence of AIS. The prevalence decreases as geographic latitude approaches the equator, suggesting a possible role for environmental factors in the pathogenesis of AIS in girls. A slight delay of menarcheal age in northern countries by lengthening the period of spine vulnerability to etiologic factors, was suggested as a pathogenetic mechanism.
Maternal age and socio-economic status
In a study of 404 children with idiopathic scoliosis predominantly from New York State there was an excess of propositi born to mothers at ages 30-39 years . Wynne-Davies [89, 120] reviewing 94 children with AIS found in girls and boys, maternal but not paternal age was significantly in excess of normal. In a Swedish study of perinatal and environmental aspects of 551 adolescent patients with thoracic idiopathic scoliosis, maternal age was higher, birth weight normal, scoliosis commoner in higher socioeconomic groups, and the illegitimacy rate half that expected . These findings from the USA, Scotland and Sweden are consistent and reveal increased maternal age as a risk factor for AIS, suggesting maternal factors can predispose to it. The intra-uterine environment is crucial in programming the fetus for various health and disease outcomes throughout life .
Heated indoor swimming pools infants and delayed epigenetic effects
In a case-control study in Scotland, McMaster et al [115, 116, 122] reported a statistically significant correlation between the introduction of infants to heated indoor swimming pools and the development of AIS. A neurogenic hypothesis was formulated to explain how toxins produced by chlorine in such pools may act on the infant's immature central nervous system; through vulnerability of the developing brain to circulating toxins and delayed epigenetic effects with the bony trunk deformity of AIS not becoming evident until adolescence . There may be many such environmental factors acting in the first year of life to initiate AIS and differing around the world, with one environmental factor involving heated indoor swimming pools being detected in Scotland . Whatever effects the neurotoxic products may have on the immature brain, the process of puberty with its increased growth velocity is suggested to play a role in the delayed phenotypic expression of AIS .
Non-surgical treatments for AIS
Publications on environmental effects induced in the spine by physical exercises and brace treatments will not be considered here.
Hypothesis of developmental instability for scoliosis
Speculation that genetic and environmental factors are involved the etiopathogenesis of idiopathic scoliosis [123, 124] was developed by Goldberg and colleagues [85–87] who suggested that scoliosis is caused by environmental stress causing developmental instability:
"....scoliosis is not a disease or group of diseases but a symptom or sign of environmental stress, significant enough to overwhelm the intrinsic stability of the morphological genome. As such, there is no specific etiology but a large number of precipitating stressors....".
Such environmental factors could be hormonal, nutritional, alcohol, smoking, viruses, drugs, medicaments, radiation, maternal reactivity to male-specific features of the fetus, hypoxia during birth , factors associated with population density , toxins in heated indoor swimming pool , and lack of physical activity. [115, 116].
The hypothesis of devevlopmental instability applied to scoliosis is contained within both the developmental origins of health and disease concept (DOHaD) [9, 12, 13] and the common disease genetic and epigenetic model for late-onset chronic non-communicable diseases (CDGE)[14, 17]. Both the DOHaD and CDGE models for disease invoke epigenetic mechanisms  (Appendix III).
Chronic diseases, external and internal environments, phnotypic plasticity, exposome
The risks of developing late-onset chronic non-communicable diseases (NCDs) including cancer, diabetes, cardiovascular disease, respiratory disease, obesity and schizophrenia, are attributed to both genetic and environmental factors; 70-90% of disease risks are thought to be due to differences in environments [19, 126]. Hanson et al  comment that progress in this field has been slow due to an excessive emphasis on fixed genomic variations (hard inheritance) as the major determinants of disease susceptibility. However, new evidence demonstrates the much greater importance of early-life developmental factors, involving epigenetic processes and 'soft' inheritance in modulating an individual's vulnerability to NCDs. According to Rappaport and Smith  epidemiologists increasingly use genome-wide association studies (GWAS) to investigate NCDs, and rely on questionnaires to characterize "environmental exposures". The risk factors for NCDs include smoking, unhealthy diet, lack of physical activity and alcohol abuse [21, 22].
The word exposome refers to the totality of environmental exposures from conception onwards that create dysfunction which in some individuals leads to occupational health problems . The exposome comprises exogenous and endogenous factors: exogenous factors in the external environment - chemicals (toxicants) entering the body from air, water and food, eg diet, food supplements, life style, drugs, chemicals; and endogenous factors in the internal environment - chemicals produced in the body eg, oxidative stress, lipid peroxidation [111, 112, 129], gut flora, and other natural processes, including biomarkers. Any harmful effects leading to dysfunction evidently interferes with normal cellular processes and molecular pathways in cells, tissues, structures and organs with the individual response to environmental factors being genetically influenced . There are likely to be critical periods of exposure in development with vulnerability to the exposome . Human evolution through natural selection has involved reduced exposure to challenges from external and internal environments .
Definitiions: epigenetics, origin and its recent double meaning in health and disease
Epigenesis in biology describes the morphogenesis and development of an organism with organ systems that are not preformed.
The word epigenetics was coined by Waddington  to link the two fields of developmental biology and genetics, hitherto considered as separate disciplines [132–134]. There are now several definitions of epigenetics[14, 18, 25, 135–140] (Appendix IV). Waddington's broad view of epigenetics fell out of favor in modern biology to be replaced with a much narrower one defining epigenetics as:
These changes result from chemical alterations to DNA or associated histone proteins termed epigenetic modification, occurring in health and disease from stochastic (random) and environmental factors modulating transcription from chromatin [29, 141]. The best known example of epigenetic modification is DNA methylation (DNAm). Cell type-specific DNAm patterns are established during mammalian development and maintained by tissue-specific gene expression in adult somatic cells . DNAm plays an important role in programming gene expression, including the regulation of changes in gene expression in response to aging and environmental signals [104, 143]. Loss of methylation, which may result from enzymic mechanisms will lead to heritable abnormalities in gene expression, and these may be important in oncogenesis and aging [104, 142–144].
Epigenotype refers to information in a cell that is maintained through mitosis and/or meiosis but does not involve DNA sequence itself .
Epigenome, is the sum total of all the epigenetic information in a cell; there are as many epigenomes as there are cell types . It has been likened to an archive of the prenatal environment . The epigenome parallels the word genome, and refers to the overall epigenetic state of a cell. Although all (nucleated) human cells effectively contain the same genome (and therefore the same genetic instruction sets), they contain very different epigenomes depending upon cell type, developmental stage, sex, age, environmental cues, various other parameters and maintain different terminal phenotypes [147, 148]. Epigenomics refers to the genome-scale analysis of epigenetic marks .
Epimutations and disease. According to Martin et al , epigenetic silencing is a pervasive mode of gene regulation in multicellular animals. Epigenetic silencing is not irreversible and requires active maintenance. This requirement for active maintenance of epigenetic states, creates the potential for errors on a large scale. When epigenetic errors - or epimutations - activate or inactivate a critical gene, they may cause disease. They define epigenetic disease as: "...one caused by stable alteration in the epigenetic state of a gene (epimutation) without any contributory genetic mutation."
Epigenetic modification and interactions. Very recently, some workers have returned to using Waddington's more inclusive definition to bridge more fully the gap between genotype and phenotype, introducing the term epigenetic interactions[138–140, 149]. This concept does not entirely accord with the view that an epigenetic system should be heritable, self-perpetuating and reversible . Whether or not the term epigenetics retains its original meaning or becomes restricted to chromatin modification remains to be seen . Taken together both terms, modification and interactions, enrich and broaden our view of development, evolution and disease .
How may these new epigenetic concepts of modification and interactions be related to normal development?
Epigenetics - relevance for normal development
Developmental biology and embryonic development. Figure 2 shows that in normal embryonic development, epigenetic changes may occur at each of cell, tissue, structure and organ levels. A cell's environment, location and surroundings provide epigenetic factors that influence the cell's identity and activities  as it rolls down Waddington's metaphorical epigenetic landscape . Francis  states that the fate of each cell is largely determined by its position in the embryo and the nature of its neighbour cells with which it chemically interacts; this is termed patterning in skull development [74, 75, 138, 139]. These intercellular interactions influence the environment within the cell, which in turn influences which genes are epigenetically activated or inactivated. At organ level, the growing brain influences the development of the skull presumably involving mechanical interaction (mechanotransduction) as an epigenetic interaction [137, 140].
Epigenetic modifications and regulation
Figure 3[152–154] shows predominant epigenetic modifications: DNA methylation (DNAm) modifications to histones, non-coding RNAs and parent-of-origin imprinting for placental development. (Appendix V)[155–172] [see Figure 2, reference  and [29, 46, 141, 153]].
Figure 4 shows epigenetic interactions for normal vertebral growth constructed mostly from the descriptions of Herring [136, 137] and Lieberman [138, 139], and for chemicals from other workers [173–175].(Appendices IV & VI).
How may epigenetic modification and interactions relate to normal postnatal spine growth?
Normal postnatal spine development - physiologic growth-plate exposome
Figure 5 shows factors that affect growth of the normal spine through vertebral growth plates. They are shown as three groups: genetic, internal environment, and external environment. Besides genetic control, the growth of normal vertebral growth plates is influenced by factors mainly within the internal environment; these include hormones [133, 136, 176, 177], growth factors  chemicals [173–175] and mechanical forces [133, 136, 137, 178, 179]; the latter are created by the vertebral growth force [136, 180], gravity (a weak force [181–183], upright posture and muscular contractions under central nervous system control acting against gravity. External environmental factors include gravity, nutrition and lifestyle.
We propose the term, physiologic growth-plate exposome for the mainly internal normal environmental processes that affect normal spinal growth. The effects of this physiologic exposome on vertebral growth plates is viewed as epigenetic. This will involve epigenetic interactions. How much epigenetic modification is involved is unknown.
Adolescent idiopathic scoliosis - pathophysiologic scoliogenic exposome
Figure 5 shows etiopathogenetic hypotheses for AIS which express abnormality(ies) in normal developmental pathways of one or more of the normal internal environmental processes. Whether one (one-hit model) or several (multi-hit model) abnormalities are involved in pathogeenesis for different individuals with AIS is unknown. We propose a new term and concept, pathophysiologic scoliogenic exposome be applied to abnormal processes in normal developmental pathways particularly of the internal environment that have putative epigenetic deforming effects on the growth plates of vertebrae [184–191] at cell, tissue, structure and organ levels, and currently expressed as etiopathogenetic hypotheses (Appendix VII) [192–242]. This will involve epigenetic interactions. How much epigenetic modification is involved is unknown.
Figure 6 shows etiopathogenetic hypotheses acting at cell, tissue, structure and organ levels linked to possible epigenetic mechanisms affecting vertebral growth plates, possibly in a diverse network of developmental pathways .
Trunk velocity of growth and asymmetric internal pressure as environmental stress
Trunk growth, hormonally stimulated, provides an important internal environment in which scoliosis curves progress . Likewise, asymmetric internal pressure of the intervertebral disc and vertebral growth plate in scoliosis suggests an abnorma l stress environment generates a positive feedback of cellular changes, resulting in curve progression due to a combination of factors [244, 245]. These will include cyclical loads and asymmetrical changes in disc fluid content which affect vertebral growth (deforming three joint complex) .
Pathogenic asymmetry inducing and exacerbating processes
AIS asymmetry-inducing processes [238, 240] - be they mechanical or biological - affecting vertebral growth plates, may render other factors including velocity of growth and hormones, abnormally increased or physiologic [3, 6], to exacerbate the scoliotic deformity . The etiologic, and potentially therapeutic, problem is to establish in each AIS girl, which process(es) in what pathway(s), is (are) abnormal, or exacerbating the deformity.
In a cohort of normal individuals born in the UK in 1946 and surveyed longitudinally to the present, research is in hand to analyse tens of thousands of possible methylation sites in the DNA looking for changes that could explain the link between birth weight and breast cancer risk . A similar study could evaluate AIS subjects.
Epigenetics at the epicenter of modern medicine
Feinberg  writes:
"Epigenetics, the study of non-DNA sequence-related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual's genetic background, the environment, aging, and disease..." (see Appendix II).
The therapeutic potential of epigenetics for preventing and treating common human illness is threefold .
The possibility of new therapies because epigenetic changes are by definition reversible, unlike sequence mutations in disease.
Using medication to target biochemical pathways that are disturbed epigenetically in disease.
To intervene at the junction between genome and environment, to modify the effects of deleterious genes, and to influence the effects of the environment on phenotypic plasticity - ie, cells' ability to change their behavior in response to internal or external environmental cues.
The potential of these therapeutic and epigenetic epidemiologic approaches to AIS is at present unknown, and is restricted by the absence of established environmental factors involved in its etiopathogenesis.
Network medicine and AIS
Barabasi  introduced the term network medicine which provides a network-based approach to human diseases by constructing diseasomes. According to Barabasi et al  given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. Interactome describes the complex biological systems and cellular networks within cells .
Barabasi  states that network analysis is poised to play its biggest role at the cellular level since most cellular components are connected to each other through intricate regulatory metabolic and protein-protein interactions with proteomic assessment where research is needed [3, 250]. The paradigm of network medicine is, "think globally, act locally"..
In AIS, consideration is needed for the possible creation of a network approach to etiopathogenesis by constructing AIS diseasomes.
Summary and Conclusions
Genetic factors are believed to play an important role in the etiology of AIS in accordance with the genetic variant hypothesis of disease.
Sporadic reports, particularly for monozygotic twins but also other findings, suggest environmental factors are involved in the etiopathogenesis and phenotypic expression of AIS.
Research on the role of environmental factors and epigenetics has exploded in the last decade but not so for AIS (Figure 1).
Apart from the emerging role of epigenetic mechanisms in the etiology of neural tube defects , the Prader-Willi syndrome [71, 72], and theoretical interpretations of Burwell and colleagues [73–76] and McMaster , epigenetics does not figure in any causal analysis of postnatal normal spinal growth, or in the etiopathogenesis of AIS (Figure 1).
There are three major ways organisms modify their DNAs inherited messages without changing DNA sequence: enzymes methylate DNA to modulate transcription; histone modifications and nucleosome positioning to induce or repress target sequences; and non-coding small RNAs to modify the expression of specific genes where there is therapeutic potential (Figure 3, Appendix V)
DNA methylation is an important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life
DNA methylation depends on dietary methionine and folate, both of which are affected by the nutritional state of the individual.
Epigenetic modification provides multicellular organisms with a system of normal gene regulation that silences portions of the genome and keeps them silent as tissues differentiate as epigenotypes (Figure 3).
Errors in this complex system from environmental and stochastic (random) events termed epimutations can give rise to abnormal gene silencing, that may result in a great deal of phenotypic variation and common disease.
Epigenetic interactions operating at cell, tissue, structure and organ levels, have been defined very recently by some workers in keeping with Waddington's inclusive definition of epigeneticss; the term is used to describe additional mechanisms for modulating cellular effects in response to changes in the internal and external environments without altering DNA sequence (Figure 4).
A molecular perspective encompassing epigenetic modification and interactions at vertebral growth plates for normal postnatal spinal growth and the etiopathogenesis of AIS is given.
The word exposome, means the totality of environmental exposures, external and internal, from conception onwards that create dysfunction leading in some individuals to occupational health problems,
The woed exposome is used here also in relation to physiologic and etiopathogenetic factors that respectively affect normal spinal growth and may induce the deformity of AIS namely, physiologic growth-plate exposome and pathophysiologic scoliogenic exposome (Figures 5 & 6).
The concept of a one-hit to multi-hit model for AIS pathogenesis is mentioned.
The potential of epigenetic-based medical therapy for AIS cannot be assessed at present. It must await new research derived from the evaluation of epigenetic concepts for spinal growth in health and deformity.
Consideration is needed for the creation of a network approach to AIS etiopathogenesis by constructing AIS diseasomes,
These approaches, epigenetic and network, may possibly lead through several approaches - screening, genetic [195, 198, 199, 251], epigenetic, biochemical [3, 173–175, 229, 230], metabolic phenotypes  and pharmacogenomic [5, 251], to the modulation of abnormal molecular pathways [108, 179, 252] by the development of novel preventive and curative measures based on diet, novel epigenetic drugs [13, 108] and other approaches .
The tenets outlined here for AIS etiopathogenesis are applicable to other musculoskeletal growth disorders, including infantile and juvenile idiopathic scoliosis.
Dual inheritance. Holliday  points out that genetic inheritance in higher organisms normally refers to the transmission of information from one generation to the next. Nevertheless, there is also inheritance in somatic cells, characterized by the phenotypic stability of differentiated cells that divide (such as fibroblasts and lymphocytes), and also mitosis of stem line cells, which gives rise to another stem line daughter cell, and one that will differentiate.
"Traditionally, the pathology of human disease has been focused on microscopic examination of affected tissues, chemical and biochemical analysis of biopsy samples, other available samples of convenience, such as blood, and noninvasive or invasive imaging of varying complexity, in order to classify disease and illuminate its mechanistic basis. The molecular age has complemented this armamentarium with gene expression arrays and selective analysis of individual genes. However, we are entering a new era of epigenomic profiling, i.e., genome-scale analysis of cell-heritable nonsequence genetic change, such as DNAm. The epigenome offers access to stable measurements of cellular state and to biobanked material for large-scale epidemiological studies. Some of these genome-scale technologies are beginning to be applied to create the new field of epigenetic epidemiology."
According to Feinberg  the new filed of epigenetic epidemiology will measure and catalog epigenetic variation within and across populations in genome-scale analyses to characterize the correlation properties of methylation, similar to the catalog of SNP/CNV and linkage disequilibrium (non-random association of alleles at different loci), already showing promise in neuropsychiatric disease.
Phenotypic plasticity, time dependency and the CDGE, model for chronic disease. A common theme to disease epigenetics is the disruption of phenotypic plasticity; this is the ability of cells to change their behavior in response to internal or external environmental cues over time [12, 14–16]. Feinberg and colleagues [14, 17, 18] suggested the hypothesis that epigenetics provides an added layer of variation that might mediate the relationship between genotype and internal and external environmental factors which they termed the common disease genetic and epigenetic hypothesis (CDGE). This conjectural model overlies the genetic hypothesis of disease with an epigenetic component interacting with it [17, 78]. The CDGE, model better explains the age degeneration of epigenetic patterns than does the genetic hypothesis.
Genetic variant hypothesis of disease and non-genomic factors. Butcher and Beck  write:
"A spate of high-powered genome-wide association studies (GWAS) have recently identified numerous single-nucleotide polymorphisms (SNPs) robustly linked with complex disease. Despite interrogating the majority of common human variation, these SNPs only account for a small proportion of the phenotypic variance, which suggests genetic factors are acting in concert with non-genetic factors. Although environmental measures are logical covariants for genotype-phenotype investigations, another non-genetic intermediary exists: epigenetics." [see ].
Haig  states that epigenetics has different meanings for different sciientists. Molecular biologists are familiar with the definition as:
"The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence.
In contrast, functional morphologists would be more familiar with the definition:
"... the entire series of interactions among cells and cell products which leads to morphogenesis and differentiation.". Herring continues, "Thus all cranial development is epigenetic... Among the numerous epigenetic factors influencing the vertebrate face is mechanical loading. Loading seems to be particularly significant for formation and growth of skeletal tissues... Epigenetic influences range from hormones and growth factors to ambient temperature and orientation in a gravitational field." [see [137–140]].
Feinberg  states that epigeneticss is at the heart of developmental biology, with the modern definition and Waddington's definition having converged. That is because "...the epigenetic state of an organism progresses from gamete to zygote to somatic tissue, all of which have profoundly different epigenomes, while the DNA is the same . This view does not accommodate the concept of epigenetic interactions[137–140].
A few scientists take a more relaxed, or stricter view, either including RNA modification or limiting to vertical (generational) transmission .
Epigenetics does not invoke inheritance of mutational changes. leaving open what kinds of mechanism are at work . An epigenetic system should be heritable, self-perpetuating and reversible . Bird  wishing to avoid the constraints imposed by stringently requiring heritability in the definition of epigenetics, suggested the following:
"...the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states."
DNA methylation ( DNAm). The predominant epigenetic mechanisms involve DNA methylation, modifications to chromatin, genomic imprinting [106, 155, 156], and non-coding RNAs [46, 52]. DNAm in mammals occurs almost exclusively as the covalent addition (or mark) of a methyl (CH3) group mainly to the nucleotide cytosine at cytosine-guanine dinucleotide sequences catalyzed by DNA methyltransferases (CpG islands, where 'p' indicates interstitial phosphate group between the DNA bases [10, 17, 26, 29, 63, 141]). Promoters are key targets for epigenetic modification . There are also covalent modifications of DNA-bound histones [157, 158], notably acetylation, phosphorylation, methylation and ubiquitination [1, 159–161]. Cytosine methylations of gene promoters which are reversible, are generally associated with silencing of genes, whereas histone acetylations are generally associated with activation of genes [26, 99]. Many groups have studied the genomic distribution of DNA cytosine methylation and other chemical modifications of histone proteins to the epigenome[145, 161]. Imprinting leads to the mono-allelic expression of certain genes depending on the parent origin of the allele controlled by imprinting control regions marked by DNA and histone methylation on one of the two parent alleles, perturbations of which induce diseases, including the Prader-Willi syndrome . Recently it has become appreciated that hydroxymethylation of cytosine is a minor, but prevalent, form of base modification in addition to 5-methylation .
DNAm and folic acid. The source of methyl groups for DNAm is methionine an essential amino acid that is converted to a biologically active methyl donor state, S-adenosylmethionine, through a pathway involving folic acid, both of which are affected by the nutritional state [17,108,110, see Figure 1 of ]. Findings in subjects with chronic kidney disease and uremia have established a link between the epigenetic control of gene expression and xenobiotic influences, such as folate therapy . Accoeding to Park et al  nutrients involved in one-carbon metabolism, namely folate, vitamin B12, vitamin B6, riboflavin, methionine, choline and betaine, are involved in DNA methylation by regulating levels of the universal methyl donor S-adenosylmethionine and methyltransferase inhibitor S-adenosylhomocysteine. Other nutrients and bioactive food components such as retinoic acid, resveratrol, curcumin, sulforaphane and tea polyphenols can modulate epigenetic patterns by altering the levels of S-adenosylmethionine and S-adenosylhomocysteine or directing the enzymes that catalyse DNA methylation and histone modifications.
MicroRNAs, short interfering RNAs and potential for therapy. MicroRNAs (miRNAs) are a class of short endogenous non-coding RNAs that act as post-transcriptional regulators of gene expression by attaching themselves to messenger RNA . MiRNAs play fundamental roles in the control of many biological processes such as growth, development, differentiation and cell, death by repressing their target genes, and in relation to cancer and some other diseases . Some miRNAs are regulated by epigenetic mechanisms, especially by methylation . Short interfering RNAs, are a class of double-strnded RNA (dsRNA) molecules, that can guide methylation to complementary DNA, were first elucidated in plants, to enable the precise targeting of gene action . Plant-derived miRNAs which enter the blood stream have been shown to muffle or amplify gene expression by binding to strands of messenger RNA with potential for therapy .
DNAmn and metals. Epigenetics may be the critical pathway by which metals produce their health effects [108, 165]. Copper [166–168], zinc  and selenium [168, 169] have each been linked to the pathogenesis of AIS. Other metals disrupt DNAm [170, 171].
DNAm in MZ twins, aging and epigenetic drift. Recent studies using mostly peripheral blood lymphocytes (also skin, muscle and fat) and a battery of powerful molecular genetic methodologies coupled with competitive chromosomal hybridizations, suggest that phenotypic discordance between MZ twins is to some extent due to epigenetic factors that change over the lifetime of a multicellular organism [24, 99]. It has been proposed that epigenetic drift during development can result from stochastic mechanisms (independent of environmental perturbations), or determined by such environmental perturbations [24, 99, 172]. Eckhardt et al  found no age-related DNAm change but did not report longitudinal data. In a longitudinal study, Bjornsson et al  found methylation changes over time with familial clustering suggesting that methylation maintenance may be under genetic control. In 46 MZ twin-pairs and 45 DZ twin-pairs Wong et al  found that DNAm differences are apparent already in early childhood, even between genetically identical individuals; and that individual differences in methylation are not stable over time. Unlike the primary DNA sequence, methylation status will depend on the tissue being analysed [Armour J personal communication]. Epigenetic mechanisms may be causal in the aging process and be influenced by diet providing opportunities to improve health in later life .
In connection with epigenetic interactions in normal development, Lieberman  writes:
"In normal development, " .... hormones and growth factors bind with specific receptors in the cell membrane or nucleus. Activated receptors then trigger a cellular response through mechanisms such as altering gene transcription, altering ion transport in and out of the cell, activating or inhibiting intracellular enzymes, stimulating protein synthesis, or inducing cellular proliferation."
"Regulation of local growth occurs through interactions between the genes that cause skeletogenic cells to synthesize, resorb, or otherwise modify skeletal tissue, and stimuli from other genes or cells. Such interaction between cells and their environment (which includes other cells) are generally categorized as epigenetic interactions... Additional categories of epigenetic interactions influencing morphogenesis include systemic hormones, growth factors, and the effects of mechanical loading."
"Bones do have a strong genetic component to their growth and development, but a set of complex and constrained interactions between bone cells and their mechanical environment can influence bone morphology, particularly while the skeleton is still growing." (see Herring  in Appendix IV]).
Body-spatial orientation concept .
Neurodevelopmental concept .
Deforming three joint complex hypothesis .
Collective and escalator models .
Butcher LM, Beck S: Future impact of integrated high-throughput methylome analyses on human health and disease. J Genet Genomics. 2008, 35 (7): 391-401.
Wang WJ, Yeung HY, Chu WC, Tang NL, Lee KM, Qiu Y, Burwell RG, Cheng JC: Top theories for the etiopathogenesis of adolescent idiopathic scoliosis. J Pediatr Orthop. 2011, 31 (1 Suppl): S14-27.
Lombardi G, Akoume MY, Colombini A, Moreau A, Banfi G: Biochemistry of adolescent idiopathic scoliosis. Adv Clin Chem. 2011, 54: 165-82.
Fendri K, Patten S, Zaouter C, Parent S, Kaufman G, Labelle H, Edery P, Moldovan F: Recent advances in the study of candidate genes for adolescent idiopathic scoliosis. Stud Health Technol Inform. 2010, 158: 3-7.
Edery P, Margaritte-Jeannin P, Biot B, Labalme A, Bernard JC, Chastang J, Kassai B, Plais MH, Moldovan F, Clerget-Darpoux : New disease gene location and high genetic heterogeneity in idiopathic scoliosis. Eur J Hum Genet. 2011, 19 (8): 865-9.
Burwell RG, Aujla RK, Grevitt MP, Dangerfield PH, Moulton A, Randell TL, Anderson SI: Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy. Scoliosis. 2009, 4: 24-
Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM: Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993, 36 (1): 62-7.
Barker DJ, Eriksson JG, Forsén T, Osmond C: Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol. 2002, 31 (6): 1235-9.
Gluckman PD, Hanson MA: The developmental origins of health and disease: an overview. Developmental mechanisms of health and disease. Edited by: Gluckman P, Hanson M. 2006, Cambridge: Cambridge University Press, 1: 1-5.
Gluckman PD, Hanson MA, Cooper C, Thornburg KL: Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008, 359 (1): 61-73.
Gluckman PD, Hanson MA, Mitchell MD: Developmental origins of health and disease: reducing the burden of chronic disease in the next generation. Genome Med. 2010, 24, 2 (2): 14-
Gluckman PD, Hanson MA, Beedle AS, Buklijas T, Low FM: Epigenetics of human disease. Epigenetics linking genotype and phenotype in development and evolution. Edited by: Hallgrimsson B, Hall BK. 2011, Berkeley: University of California Press, 22: 198-423.
Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC, Boileau P, Le Bouc Y, Deal CL, Lillycrop K, Scharfmann R, Sheppard A, Skinner M, Szyf M, Waterland RA, Waxman DJ, Whitelaw E, Ong K, Albertsson-Wikland K: Child health, developmental plasticity, and epigenetic programming. Endocr Rev. 2011, 32 (2): 159-224.
Bjornsson HT, Fallin MD, Feinberg AP: An integrated epigenetic and genetic approach to common human disease. Trends Genet. 2004, 20 (8): 350-8.
Bjornsson HT, Cui H, Gius D, Fallin MD, Feinberg AP: The new field of epigenomics: implications for cancer and other common disease research. Cold Spring Harb Symp Quant Biol. 2004, 69: 447-56.
Feinberg AP: Phenotypic plasticity and the epigenetics of human disease. Nature. 2007, 447 (7143): 433-40.
Feinberg AP: Epigenetics at the epicenter of modern medicine. JAMA. 2008, 299 (11): 1345-50.
Feinberg AP: Genome-scale approaches to the epigenetics of common human disease. Virchows Arch. 2010, 456 (1): 13-21.
Rappaport SM, Smith MT: Epidemiology. Environment and disease risks. Science. 2010, 330 (6003): 460-1.
Hanson MA, Low FM, Gluckman PD: Epigenetic epidemiology: the rebirth of soft inheritance. Ann Nutr Metab. 2011, 58 (Suppl 2): 8-15.
Reardon S: A world of chronic disease. Science. 2011, 333 (6042): 558-9.
Reardon S: U.N. Summit on noncommunicable diseases. Meeting brings attention but little action on chronic diseases. Science. 2011, 333 (6049): 1561-
Russo VEA, Martienssen RA, Riggs AD, (Eds): Epigenetic mechanisms of gene regulation. Monograph 32. 1996, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA, 692-
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M: Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005, 102 (30): 10604-9.
Bird A: Perceptions of epigenetics. Nature. 2007, 447 (7143): 396-8.
Suzuki MM, Bird A: DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008, 9 (6): 465-76.
Whitelaw E, Garrick D: Epigenetic mechanisms. Developmental mechanisms of health and disease. Edited by: Hallgrimsson B, Hall BK. 2006, Cambridge University Press, 5: 62-74.
Rivera RM, Bennett LB: Epigenetics in humans: an overview. Curr Opin Endocrinol Diabetes Obes. 2010, 7 (6): 493-9.
Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL: Epigenetics and the placenta. Hum Reprod Update. 2011, 17 (3): 397-417.
Lipps HJ, Postberg J, Jackson DA, (Eds.): Epigenetics, disease and behavior. Essays in Biochemistry. 2010, 48: 292-
Carey N: The epigenetics revolution. 2011, Icon Books: London, 339-
Francis RC: Epigenetics, the ultimate mystery of inheritance. 2011, New York: WW Norton & Company, 234-
Strauss A: Dietray recommendations for idiopathic scoliosis. www
Dovorany BT, Stitzel CJ: Scoliosis - treatment and epigenetics. www
Bogin B: Environmental factors influencing growth. Patterns of human growth. 1999, Cambridge: Cambridge: University Press, 6: 268-328. Second
Bogin B: The growth of humanity. 2001, New York, A John Wiley & Sons Inc.Publication, 19-
Dasgupta P, Hauspie R, (Eds): Perspectives in human growth, development and maturation. 2001, Dordrecht:Kluwer Academic publishers, 364-
Schell LM, Gallo MV, Ravenscroft J: Environmental influences on human growth and development: historical review and case study of contemporary influences. Ann Hum Biol. 2009, 36 (5): 459-77.
Bogin B, Varela-Silva MI: Leg length, body proportion, and health: a review with a note on beauty. Int J Environ Res Public Health. 2010, 7 (3): 1047-75.
Green J, Cairns BJ, Casabonne D, Wright FL, Reeves G, Beral V: Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. Lancet Oncol. 2011, 12 (8): 785-94.
Caspi A, Williams B, Kim-Cohen J, Craig IW, Milne BJ, Poulton R, Schalkwyk LC, Taylor A, Werts H, Moffitt TE: Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. Proc Natl Acad Sci USA. 2007, 104 (47): 18860-5.
Plomin R, DeFries JC, McClearn GE, McGuffin P: The interplay between genes and environment. Behavioral genetics. 2008, New York: Worth Publishers, 16: 305-333. Fifth
Lester BM, Tronick E, Nestler E, Abel T, Kosofsky B, Kuzawa CW, Marsit CJ, Maze I, Meaney MJ, Monteggia LM, Reul JM, Skuse DH, Sweatt JD, Wood MA: Behavioral epigenetics. Ann N Y Acad Sci. 2011, 226: 14-33.
Heijmans BT, Tobi EW, Lumey LH, Slagboom PE: The epigenome: archive of the prenatal environment. Epigenetics. 2009, 4 (8): 526-31.
Szyf M: The early life social environment and DNA methylation; DNA methylation mediating the long-term impact of social environments early in life. Epigenetics. 2011,
Hamilton JP: Epigenetics: principles and practice. Dig Dis. 2011, 9 (2): 130-5.
Maloy KJ, Powrie F: Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011, 474 (7351): 298-306.
Waterland RA: Epigenetic mechanisms and gastrointestinal development. J Pediatr. 2006, 149 (5 Suppl): S137-42.
Engesaeter LB: Increasing incidence of club foot: changes in the genes or the environment?. Acta Orthop. 2006, 77 (6): 837-838.
Wong CC, Caspi A, Williams B, Craig IW, Houts R, Ambler A, Moffitt TE, Mill J: A longitudinal study of epigenetic variation in twins. Epigenetics. 2010, 5 (6): 516-26.
Csaba G: The biological basis and clinical significance of hormonal imprinting, an epigenetic process. Clin Epigenetics. 2011, 2: 187-196.
Silahtaroglu A, Stenvang J: MicroRNAs, epigenetics and disease. Essays Biochem. 2010, 48 (1): 165-85.
Jabr E: Eating genes alters genes. New Sci. 2011, 211 (2832): 10-11.
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR: Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009, 462 (7271): 315-22.
Cropley JE, Martin DI, Suter CM: Germline epimutation in humans. Pharmacogenomics. 2008, 9 (12): 1861-8.
Reik W: Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007, 447 (7143): 425-32.
Feng S, Jacobsen SE, Reik W: Epigenetic reprogramming in plant and animal development. Science. 2010, 330 (6004): 622-7.
Holliday R: Dual inheritance. Curr Top Microbiol Immunol. 2006, 301: 243-56.
Martin DI, Cropley JE, Suter CM: Epigenetics in disease: leader or follower?. Epigenetics. 2011, 6 (7): 843-8.
Greene ND, Stanier P, Moore GE: The emerging role of epigenetic mechanisms in the etiology of neural tube defects. Epigenetics. 2011, 6 (7): 875-83.
Jessen HM, Auger AP: Sex differences in epigenetic mechanisms may underlie risk and resilience for mental health disorders. Epigenetics. 2011, 6 (7): 857-61.
Bradbury J: Human Epigenome Project--up and running. PLoS Biol. 2003, 1 (3): e82.-
Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, Burton J, Cox TV, Davies R, Down TA, Haefliger C, Horton R, Howe K, Jackson DK, Kunde J, Koenig C, Liddle J, Niblett D, Otto T, Pettett R, Seemann S, Thompson C, West T, Rogers J, Olek A, Berlin K, Beck S: DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet. 2006, 8 (12): 1378-85.
American Association for Cancer Research Human Epigenome Task Force, European Union, Network of Excellence, Scientific Advisory Board: Moving AHEAD with an international human epigenome project. Nature. 2008, 454 (7205): 711-5.
Annotation: Time for the epigenome. Nature. 2010, 463 (7281): 587-
Ptashne M, Hobert O, Davidson E: Questions over the scientific basis of epigenome project. Nature. 2010, 464 (7288): 487-
Franz-Odendaal TA: Epigenetics in bone and cartilage development. Epigenetics linking genotype and phenotype in development and evolution. Edited by: Hallgrimsson B, Hall BK. 2011, Berkeley: University of California Press, 12: 195-220.
Herring SW: Muscle-bone interactions and the development of skeletal phenotype. Epigenetics linking genotype and phenotype in development and evolution. Edited by: Hallgrimsson B, Hall BK. 20110, Berkeley: University of California Press, 13: 221-237.
O'Connor RD, Schanan NC: Genetic and epigenetic aspects of bone development. Bone and Development. Edited by: Bronner F, MCFarach-Carson, HI Roach. 2010, Springer London, Topics in Bone Biology, 6: 1-23. Chapter 1
Percival C, Richtsmeier JT: The epigenetics of dysmorphology. Epigenetics linking genotype and phenotype in development and evolution. Edited by: Hallgrimsson B, Hall BK. 2010, Berkeley: University of California Press, 21: 377-397.
Cassidy SB, Schwartz S, Miller JL, Driscoll DJ: Prader-Willi syndrome. Genet Med. 2011,
Carey N: The battle of the sexes, when imprinting goes bad. The epigenetics revolution. Edited by: Carey N. 2011, London: Icon Books, 8: 136-139.
Burwell RG, Aujla RK, Cole AA, Randell TL, Dangerfield PH, Moulton A: Length asymmetries in upper limbs of right- and left-handed healthy girls age 5-18 years: proximo-distal reciprocal linear growth asynchronies, genetics, handedness and epigenetics [abstract]. Clin Anat. 2011, 24 (4): 529-530.
Burwell RG, Aujla RK, Randell TL, Dangerfield PH, Moulton A, Anderson SI: Regional skeletal sizes of healthy girls relative to size attained at 10 years as the comparator: percentage size trajectories reveal effects of differential growth consistent with intrinsic growth-plate programs involving time-tally patterning, genetically- and epigenetically-determined [abstract]. Proceedings of the Summer Meeting of the British Association of Clinical Anatomists, Padua, Italy, 29th June to 1st. 2011, , July . Clin Anat
Burwell RG, Aujla RK, Randell TL, Dangerfield PH, Moulton A, Anderson SI: Regional skeletal sizes of healthy boys relative to size attained at 10 years as the comparator: percentage size trajectories reveal effects of differential growth consistent with intrinsic growth-plate programs involving time-tally patterning, genetically- and epigenetically- determined [abstract]. Proceedings of the Summer Meeting of the British Association of Clinical Anatomists, Padua, Italy, 29th June to 1st. 2011, , July ; Clin Anat
Burwell RG, Grevitt MP, Aujla RK, Randell TL, Dangerfield PH, Aujla RK, Cole AA, Pratt RK, Webb JK, Moulton A, Anderson SI: Abnormal bilateral skeletal asymmetries and their putative genetic and epigenetic origins in enantiomorphic growth plates of girls with adolescent idiopathic scoliosis (AIS) [abstract]. Proceedings of the Summer Meeting of the British Association of Clinical Anatomists, Padua, Italy, 29th June to 1st. 2011, , July ; Clin Anat
McMaster ME: Heated indoor swimming pools, infants, and the pathogenesis of adolescent idiopathic scoliosis: a neurogenic hypothesis. Environ Health.
Frazer KA, Murray SS, Schork NJ, Topol EJ: Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009, 10 (4): 241-51.
Sevastik J: The "thoracospinal" concept of the early development of idiopathic scoliosis. Experimental and clinical considerations. International Symposium on 3-D Scoliotic Deformities joined with the VIIth International Symposium on Spinal Deformity and Surface Topography. Edited by: Dansereau J. 1992, Ēdition de l'Ēcole Polytechnique de Montrēal:Gustav Fischer Verlag, 193-7.
Sevastik B, Xiong B, Lundberg A, Sevastik JA: In vitro opto-electronic analysis of 3-D segmental vertebral movements during gradual rib lengthening in the pig. Acta Orthop Belg. 1995, 61 (3): 218-25.
Sevastik JA: The thoracospinal concept of the etiopathogenesis of idiopathic scoliosis. Etiology of Adolescent Idiopathic Scoliosis: Current Trends and Relevance to New Treatment Approaches. Edited by: Burwell RG, Dangerfield PH, Lowe TG, Margulies JY. 2000, State of the Art Reviews: Spine, 14 (2): 391-400.
Sevastik JA: Dysfunction of the autonomic nerve system (ANS) in the aetiopathogenesis of adolescent idiopathic scoliosis. Stud Health Technol Inform. 2002, 88: 20-3.
Sevastik J, Burwell RG, Dangerfield PH: A new concept for the etiopathogenesis of the thoracospinal deformity of idiopathic scoliosis: summary of an electronic focus group debate of the IBSE. Eur Spine J. 2003, 12: 440-50.
Wynne-Davies R, Littlejohn A, Gormley J: Aetiology and interrelationship of some common skeletal deformities. (Talipes equinovarus and calcaneovalgus, metatarsus varus, congenital dislocation of the hip, and infantile idiopathic scoliosis). J Med Genet. 1982, 19 (5): 321-8.
Goldberg CJ, Dowling FE, Fogarty EE, Moore DP: Adolescent idiopathic scoliosis as developmental instability. Genetica. 1995, 96 (3): 247-55.
Goldberg CJ, Fogarty EE, Moore DP, Dowling FE: Scoliosis and developmental theory: adolescent idiopathic scoliosis. Spine. 1997, 22 (19): 2228-37.
Goldberg CJ: Symmetry control. Etiology of Adolescent Idiopathic Scoliosis: Current Trends and Relevance to New Treatment Approaches, State of the Art Reviews: Spine. Edited by: Burwell RG, Dangerfield PH, Lowe TG, Margulies JY. 2000, Philadelphia, Hanley & Belfus Inc, 14 (2): 327-8.
Kesling KL, Reinker KA: Scoliosis in twins. A meta-analysis of the literature and report of six cases. Spine (Phila Pa 1976). 1997, 22 (17): 2009-14. discussion 2015
Wynne-Davies R: Familial (idiopathic) scoliosis. A family survey. J Bone Joint Surg Br. 1968, 50 (1): 24-30.
Sales de Gauzy J, Ballouhey Q, Arnaud C, Grandjean H, Accadbled F: Concordance for curve type in familial idiopathic scoliosis: a survey of one hundred families. Spine (Phila Pa 1976). 2010, 35 (17): 1602-6.
Inoue M, Minami S, Kitahara H, Otsuka Y, Nakata Y, Takaso M, Moriya H: Idiopathic scoliosis in twins studied by DNA fingerprinting: the incidence and type of scoliosis. J Bone Joint Surg Br. 1998, 80 (2): 212-7.
Miller NH: Genetics of familial idiopathic scoliosis. Clin Orthop Rel Res. 2007, 462: 6-10.
Andersen MO, Thomsen K, Kyvik KO: Adolescent idiopathic scoliosis in twins: a population-based survey. Spine (Phila Pa 1976). 2007, 32 (8): 927-30.
Grauers A, Rahman I, Gerdhem P: Heritability of scoliosis in the Swedish Twin Registry. Stud Health Technol Inform. 2010, 158: 194-
van Rhijn LW, Jansen EJ, Plasmans CM, Veraart BE: Curve characteristics in monozygotic twins with adolescent idiopathic scoliosis: 3 new twin pairs and a review of the literature. Acta Orthop Scand. 2001, 72 (6): 621-5.
Smyrnis T, Antoniou D, Valavanis J, Zachariou C: Idiopathic scoliosis: characteristics and epidemiology. Orthopedics. 1987, 10 (6): 921-6.
Hermus JP, van Rhijn LW, van Ooij A: Non-genetic expression of adolescent idiopathic scoliosis: a case report and review of the literature. Eur Spine J. 2007, 16 (Suppl 3): 338-41.
Kaspiris A, Grivas TB, Weiss HR: Congenital scoliosis in monozygotic twins: case report and review of possible factors contributing to its development. Scoliosis. 2008, 18;3: 17-
Martin GM: Epigenetic drift in aging identical twins. Proc Natl Acad Sci USA. 2005, 102 (30): 10413-4.
Day JJ, Sweatt JD: Epigenetic mechanisms in cognition. Neuron. 2011, 70 (5): 813-29.
Golding J: Observations on idiopathic scoliosis: aetiology and natural history in Jamaica - a food and growth connection. Cajanus. 1991, 24 (1): 31-38.
Worthington V, Shambaugh P: Nutrition as an environmental factor in the etiology of idiopathic scoliosis. J Manipulative Physiol Ther. 1993, 16 (3): 169-73.
Enwonwu CO, Sanders C: Nutrition: impact on oral and systemic health. Compend Contin Educ Dent. 2001, 22 (3 Spec No): 12-8.
Park LK, Friso S, Choi SW: Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc. 2011,
Carey N: The sins of the fathers. The epigenetics revolution. Edited by: Carey N. 2011, London: Icon Books, 6: 97-114.
Feil R: Epigenetics: Ready for the marks. Nature. 2009, 461 (7262): 359-60.
Kaati G, Bygren LO, Pembrey M, Sjöström M: Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet. 2007, 15 (7): 784-90.
Ford D, Ions LJ, Alatawi F, Wakeling LA: The potential role of epigenetic responses to diet in ageing. Proc Nutr Soc. 2011, 70 (3): 374-84.
Francis RC: A grandmother effect. Epigenetics, the ultimate mystery of inheritance. 2011, New York: WW Norton & Company, 1: 1-8.
Van den Veyver IB: Genetic effects of methylation diets. Annu Rev Nutr. 2002, 22: 255-82.
Burwell RG: Aetiology of idiopathic scoliosis: current concepts. Pediatr Rehabil. 2003, 6 (3-4): 137-70.
Burwell RG, Dangerfield PH: Hypotheses on the pathogenesis of adolescent idiopathic scoliosis (AIS): a neurodevelopmental concept involving neuronal lipid peroidation and possible prevention by diet. International Research Society of Spinal Deformities Symposium. Edited by: Bonita J Sawatzky, Vancouver. 2004, 34-38.
Hung VWY, Qin L, Cheung CSK, Lam TP, Ng BKW, Tse YK, Go X, Lee KM, Cheng JCY: Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis. J Bone Joint Surg Am. 2005, 87-A: 2709-2716.
Lam TP, Hung VW, Yeung HY, Tse YK, Chu WC, Ng BK, Lee KM, Qin L, Cheng JC: Abnormal bone quality in adolescent idiopathic scoliosis: a case-control study on 635 subjects and 269 normal controls with bone densitometry and quantitative ultrasound. Spine (Phila Pa 1976). 2011, 36 (15): 1211-7.
McMaster M, Lee AJ, Burwell RG: Physical activities of patients with adolescent idiopathic scoliosis (AIS) compared with a control group: implications for etiology and possible prevention. International Research Society of Spinal Deformities Symposium. Edited by: Bonita J Sawatzky, Vancouver. 2004, 68-71.
McMaster M, Lee AJ, Burwell RG: Physical activities of patients with adolescent idiopathic scoliosis (AIS) compared with a control group: implications for etiology and possible prevention [abstract]. J Bone Joint Surg Br. 2006, 88-B (Supp II): 225-
Bagnall KM: Ligaments and muscles in adolescent idiopathic scoliosis. Etiology of Adolescent Idiopathic Scoliosis: Current Trends and Relevance to New Treatment Approaches, State of the Art Reviews: Spine. Edited by: Burwell RG, Dangerfield PH, Lowe TG, Margulies JY. 2000, Philadelphia, Hanley & Belfus Inc, 14 (2): 447-57.
Grivas TB, Vasiliadis E, Mouzakis V, Mihas C, Koufopoulos G: Association between adolescent idiopathic scoliosis prevalence and age at menarche in different geographic latitudes. Scoliosis. 2006, 23: 1:9
De George FV, Fisher RL: Idiopathic scoliosis: genetic and environmental aspects. J Med Genet. 1967, 4 (4): 251-7.
James JIP, Wynne-Davies R: Genetic factors in Orthopaedics. Recent Advances in Orthopaedics. Edited by: Apley AG. 1969, London; J & A Churchill Ltd, 1: 1-35.
Ryan MD, Nachemson A: Thoracic adolescent idiopathic scoliosis: perinatal and environmental aspects in a Swedish population and their relationship to curve severity. J Pediatr Orthop. 1987, 7 (1): 72-7.
McMaster M, Lee AJ, Burwell RG: Indoor heated swimming pools: vulnerability of some infants to develop spinal asymmetries years later. Stud Health Technol Inform. 2006, 123: 151-155.
Burwell RG, Dangerfield PH, Vernon CL: Anthropometry and scoliosis. Scoliosis, Proceedings of a Fifth Symposium. Edited by: Zorab PA. 1977, London: Academic Press, 123-163.
Burwell RG, Dangerfield PH, James NJ, Johnson F, Webb JK, Wilson YG: Anthropometric studies of normal and scoliotic children: axial and appendicular skeletal asymmetry, sexual dimorphisms and age-related changes. Pathogenesis of idiopathic scoliosis. Proceedings of an international conference. Edited by: Jacobs RR. 1984, Chicago: Scoliosis Research Society, 27-44.
Goldstein DB: Growth of genome screening needs debate. Nature. 2011, 476 (7358): 27-8.
Hamzelou J: Welcome to the exposome. New Sci. 2011, 208 (2792/2793): 6-7.
Wild CP: Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev. 2005, 14 (8): 1847-50.
Faisandier L, Bonneterre V, De Gaudemaris R, Bicout DJ: Occupational exposome: A network-based approach for characterizing Occupational Health Problems. J Biomed Inform. 2011, 44 (4): 545-52.
Krzywanski DM, Moellering DR, Fetterman JL, Dunham-Snary KJ, Sammy MJ, Ballinger SW: The mitochondrial paradigm for cardiovascular disease susceptibility and cellular function: a complementary concept to Mendelian genetics. Lab Invest. 2011, 91 (8): 1122-35.
Dunn R: The wild life of our bodies: predators, parasites, and partners that shape who we are today. 2010, New York: Harper Collins Publishers, 290-
Waddington CH: The epigenotype. Endeavour. 1942, 1: 18-20.
Nanney DL: Epigenetic control systems. Proc Natl Acad Sci USA. 1958, 44 (7): 712-7.
Haig D: The (dual) origin of epigenetics. Cold Spring Harb Symp Quant Biol. 2004, 69: 67-70.
Holliday R: Epigenetics: a historical overview. Epigenetics. 2006, 1 (2): 76-80.
Riggs AD, Martienssen RA, Russo VEA: Introduction. Epigenetic mechanisms of gene regulation, Monograph 32. Edited by: Russo VEA, Martienssen RA, Riggs AD. 1996, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA, 1-4.
Herring SW: Formation of the vertebrate face; epigenetic and functional influences. Amer Zoo. 1993, 33: 472-483.
Herring SW: Muscle-bone interactions and the development of the skeletal phenotype: jaw muscles and the skull. Epigenetics linking genotype and phenotype in development and evolution. Edited by: B Hallgrimsson B, Hall BK. 2011, Berkeley: University of California Press, 13: 221-237.
Lieberman DE: The skeletal tissues of the head. The evolution of the human head. 2011, Cambridge Massachusetts: The Belknap Press of Harvard University Press, 2: 18-55.
Lieberman DE: Epigenetic integration, complexity, and evolvability of the head. Epigenetics linking genotype and phenotype in development and evolution. Edited by: Hallgrimsson B, Hall BK. 2011, Berkeley: University of California Press, 16: 271-289.
Jamniczky HA, Boughner JC, Rolian C, Gonzalez PN, Powell CD, Schmidt EJ, Parsons TE, Bookstein FL, Hallgrímsson B: Rediscovering Waddington in the post-genomic age: Operationalising Waddington's epigenetics reveals new ways to investigate the generation and modulation of phenotypic variation. Bioessays. 2010, 32 (7): 553-8.
Bonasio R, Tu S, Reinberg D: Molecular signals of epigenetic states. Science. 2010, 330 (6004): 612-6.
Chen ZX, Riggs AD: DNA methylation and demethylation in mammals. J Biol Chem. 2011, 286 (21): 18347-53.
Tajerian M, Alvarado S, Millecamps M, Dashwood T, Anderson KM, Haglund L, Ouellet J, Szyf M, Stone LS: DNA methylation of SPARC and chronic low back pain. Mol Pain. 2011, 7 (1): 65-
Holliday R: The inheritance of epigenetic defects. Science. 1987, 238 (4824): 163-70.
Katsnelson A: Epigenome effort makes its mark. Nature. 2010, 467 (7316): 646-
Jeltsch A: Molecular biology. Phylogeny of methylomes. Science. 2010, 328 (5980): 837-8.
Murrell A, Rakyan VK, Beck S: From genome to epigenome. Hum Mol Genet. 2005, 14 Spec No 1: R3-R10.
Riddihough G, Zahn LM: Epigenetics. What is epigenetics? Introduction. Science. 2010, 330 (6004): 611-
Hallgrimsson B, Hall BK: Epigenetics: the context of development. Epigenetics linking genotype and phenotype in development and evolution. Edited by: B Hallgrimsson B, Hall BK. 2011, Berkeley: University of California Press, 23: 424-438.
Waddington CH: Organisers and genes. 1940, Cambridge: University Press, 160-
Francis RC: Sea urchins are not just to eat. Epigenetics, the ultimate mystery of inheritance. 2011, New York: WW Norton & Company, 10: 119-137.
Burwell RG, Dangerfield PH: Hypotheses on the pathogenesis of adolescent idiopathic scoliosis (AIS): X-chromosome mosaicism and microchimerism - need for appraisal in AIS?. International Research Society of Spinal Deformities Symposium. Edited by: Bonita J Sawatzky, Vancouver. 2004, 345-8.
Basu R, Zhang LF: X chromosome inactivation: A silence that needs to be broken. Genesis. 2011,
Moreira de Mello JC, de Araújo ES, Stabellini R, Fraga AM, de Souza JE, Sumita DR, Camargo AA, Pereira LV: Random X inactivation and extensive mosaicism in human placenta revealed by analysis of allele-specific gene expression along the X chromosome. PLoS One. 2010, e10947-6
Henckel A, Nakabayashi K, Sanz LA, Feil R, Hata K, Arnaud P: Histone methylation is mechanistically linked to DNA methylation at imprinting control regions in mammals. Hum Mol Genet. 2009, 18 (18): 3375-83.
Hirasawa R, Feil R: Genomic imprinting and human disease. Essays Biochem. 2010, 8 (1): 187-200.
Kouzarides T: Chromatin modifications and their function. Cell. 2007, 128 (4): 693-705.
Bannister AJ, Kouzarides T: Regulation of chromatin by histone modifications. Cell Res. 2011, 21 (3): 381-95.
Putiri EL, Robertson KD: Epigenetic mechanisms and genome stability. Clin Epigenetics. 2011, 2 (2): 299-314.
Venkitaraman AR: Cancer: Let sleeping DNA lie. Nature. 2011, 477 (7363): 169-70.
Schübeler D: Epigenomics: Methylation matters. Nature. 2009, 462 (7271): 296-7.
Kinney SM, Chin HG, Vaisvila R, Bitinaite J, Zheng Y, Estève PO, Feng S, Stroud H, Jacobsen SE, Pradhan S: Tissue-specific distribution and dynamic changes of 5-hydroxymethylcytosine in mammalian genomes. J Biol Chem. 2011, 286 (28): 24685-93.
Ingrosso D, Perna AF: Epigenetics in hyperhomocysteinemic states. A special focus on uremia. Biochim Biophys Acta. 2009, 790 (9): 892-9.
Waterland RA: Does nutrition during infancy and early childhood contribute to later obesity via metabolic imprinting of epigenetic gene regulatory mechanisms?. Nestle Nutr Workshop Ser Pediatr Program. 200, 56: 157-71. discussion 171-4
Wrobel K, Wrobel K, Caruso JA: Epigenetics: an important challenge for ICP-MS in metallomics studies. Anal Bioanal Chem. 2009, 393 (2): 481-6.
Pratt WB, Phippen WG: Elevated hair copper level in idiopathic scoliosis: preliminary observations. Spine (Phila Pa 1976). 1980, 5 (3): 230-3.
Pratt WB, Schader JB, Phippen WG: Elevation of hair copper in idiopathic scoliosis. A follow-up report. Spine (Phila Pa 1976). 1984, 9 (5): 540-
Dastych M, Cienciala J, Krbec M: Changes of selenium, copper, and zinc content in hair and serum of patients with idiopathic scoliosis. J Orthop Res. 2008, 26 (9): 1279-82.
Yang Z, Xie Y, Chen J, Zhang D, Yang C, Li M: High selenium may be a risk factor of adolescent idiopathic scoliosis. Med Hypotheses. 2010, 75 (1): 126-7.
Poirier LA, Vlasova TI: The prospective role of abnormal methyl metabolism in cadmium toxicity. Environ Health Perspect. 2002, 110 (Suppl 5): 793-5.
Sutherland JE, Costa M: Epigenetics and the environment. Ann N Y Acad Sci. 2003, 983: 151-60.
Poulsen P, Esteller M, Vaag A, Fraga MF: The epigenetic basis of twin discordance in age-related diseases. Pediatr Res. 2007, 61 (5 Pt 2): 38R-42R.
Azeddine B, Franco A, Rompré PH, Roy-Gagnon M-H, Turgeon I, Boiro MS, Blain S, Boulanger H, Wang DS, Bagnall KM, Poitras B, Labelle HLL, Rivard C-H, Grimard G, Ouellet J, Parent S, Moreau A: High circulating levels of osteopontin are associated with idiopathic scoliosis onset and spinal deform.ity progression. Proceedings of Pediatric Orthopaedic Society of North America 25th Anniversary 2009 Annual Meeting Boston, Massachusetts. 2009, Boston Marriott Copley Place, 128-In Scoliosis Research Society 44 th Annual Meeting and Course, San Antonio, Texas, USA, September 23-26, 200;109, and Stud Health Technol Inform. 2010, 158:207
Moreau A, Akoumé Ndong MY, Azeddine B, Franco A, Rompré PH, Roy-Gagnon MH, Turgeon I, Wang D, Bagnall KM, Poitras B, Labelle H, Rivard CH, Grimard G, Ouellet J, Parent S, Moldovan F: Molecular and genetic aspects of idiopathic scoliosis: Blood test for idiopathic scoliosis. Orthopade. 2009, 38 (2): 114-21. (German)
Fendri K, Moldovan F: Potential role of COMP as a biomarker for adolescent idiopathic scoliosis. Med Hypotheses. 2011, 76 (5): 762-3.
Anderson HC, Shapiro L: The epiphyseal growth plate. Bone and Development. Edited by: Bronner F, MCFarach-Carson, Roach HI. 2010, Springer London, Topics in Bone Biology, 6: 39-64. Chapter 3
Azeddine B, Letellier K, Wang DS, Moldovan F, Moreau A: Molecular determinants of melatonin signaling dysfunction in adolescent idiopathic scoliosis. Clin Orthop Rel Res. 2007, 462: 45-52.
Hofman BD, Grashoff C, Schwartz MA: Dynamic molecular processes mediate cellular mechanotransduction. Nature. 2011, 475 (7356): 316-23.
Villemure I, Stokes IA: Growth plate mechanics and mechanobiology. A survey of present understanding. J Biomech. 2009, 42 (12): 1793-803.
Rajasekaran S, Natarajan RN, Babu JN, Kanna PR, Shetty AP, Andersson GB: Lumbar Vertebral Growth is governed by 'Chondral Growth Force Response Curve' rather than 'Hueter-Volkmann Law': A Clinico-Biomechanical Study of Growth Modulation Changes in Childhood Spinal Tuberculosis. Spine (Phila Pa 1976). 2011
Stokes IAF, Burwell RG, Dangerfield PH: Biomechanical spinal growth modulation and progressive adolescent scoliosis - a test of the 'vicious cycle' pathogenetic hypothesis: Summary of an electronic focus group debate of the IBSE. Scoliosis. 2006, 1: 16-
Stokes IAF: Analysis and simulation of progressive adolescent scoliosis by biomechanical growth modulation. Eur Spine J. 2007, 16: 1621-8.
Rizzo-Sierra CV, Leon-Sarmiento FE: Pathophysiology of movement disorders due to gravity transitions: the channelopathy linkage in human balance and locomotion. Med Hypotheses. 2011, 77 (1): 97-100.
Xiong B, Sevastik B, Sevastik J, Hedlund R: Early three dimensional changes in scoliosis. International Symposium on 3-D Scoliotic Deformities joined with the VIIth International Symposium on Spinal Deformity and Surface Topography. Edited by: Dansereau J. 1992, Ēdition de l'Ēcole Polytechnique de Montrēal:Gustav Fischer Verlag, 498-504.
Taylor TFK, Melrose J: The role of the intervertebral disc in adolescent idiopathic scoliosis. Etiology of Adolescent Idiopathic Scoliosis: Current Trends and Relevance to New Treatment Approaches, State of the Art Reviews: Spine. Edited by: Burwell RG, Dangerfield PH, Lowe TG, Margulies JY. 2000, Philadelphia, Hanley & Belfus Inc, 14 (2): 359-369.
Roberts S, Caterson B, Urban JPG: Structure and composition of the cartilage end plate and intervertebral disc in scoliosis. Etiology of Adolescent Idiopathic Scoliosis: Current Trends and Relevance to New Treatment Approaches, State of the Art Reviews: Spine. Edited by: Burwell RG, Dangerfield PH, Lowe TG, Margulies JY. 2000, Philadelphia, Hanley & Belfus Inc, 14 (2): 371-381.
Wang S, Qiu Y, Zhu Z, Ma Z, Xia C, Zhu F: Histomorphological study of the spinal growth plates from the convex side and the concave side in adolescent idiopathic scoliosis. J Orthop Surg. 2007, 19-2
Day G, Frawley K, Phillips B, McPhee TB, Labrom R, Askin G, Mueller P: The vertebral body growth plate in scoliosis: a primary disturbance in growth?. Scoliosis. 2008, 3: 3-
Antoniou J, Arlet V, Goswami T, Aebi M, Alini M: Elevated synthetic activity in the convex side of scoliotic intervertebral discs and endplates compared with normal tissues. Spine. 2001, 26 (10): E198-206.
Will RE, Stokes IA, Qiu X, Walker MR, Sanders JO: Cobb angle progression in adolescent scoliosis begins at the intervertebral disc. Spine (Phila Pa 1976). 2009, 34 (25): 2782-6.
Wang S, Qiu Y, Ma Z, Xia C, Zhu F, Zhu Z: Expression of Runx2 and type X collagen in vertebral growth plate of patients with adolescent idiopathic scoliosis. Connect Tissue Res. 2010, 51 (3): 188-96.
Burwell RG, Dangerfield PH, Freeman BJC: Concepts on the pathogenesis of adolescent idiopathic scoliosis. Bone growth and mass, vertebral column, spinal cord, brain, skull, extra-spinal left-right skeletal length asymmetries, disproportions and molecular pathogenesis. Stud Health Technol Inform. 2008, 135: 3-52.
Cheng JC, Tang NL, Yeung HY, Miller N: Genetic association of complex traits: using idiopathic scoliosis as an example. Clin Orthop Relat Res. 2007, 462: 38-44.
Gao X, Gordon D, Zhang D, Browne R, Helms C, Gillum J, Weber S, Devroy S, Swaney S, Dobbs M, Morcuende J, Sheffield V, Lovett M, Bowcock A, Herring J, Wise C: CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis. Am J Hum Genet. 2007, 80 (5): 957-65.
Ward K, Ogilvie JW, Singleton MV, Chettier R, Engler G, Nelson LM: Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2010, 35 (25): E1455-64.
Miller NH: Idiopathic scoliosis: cracking the genetic code and what does it mean?. J Pediatr Orthop. 2011, 31 (1 Suppl): S49-52.
Sharma S, Gao X, Londono D, Devroy SE, Mauldin KN, Frankel JT, Brandon JM, Zhang D, Li QZ, Dobbs MB, Gurnett CA, Grant SF, Hakonarson H, Dormans JP, Herring JA, Gordon D, Wise CA: Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet. 2011, 20 (7): 1456-66.
Ogilvie J: Adolescent idiopathic scoliosis and genetic testing. Curr Opin Pediatr. 2010, 22 (1): 67-70.
Ogilvie JW: Update on prognostic genetic testing in adolescent idiopathic scoliosis (AIS). J Pediatr Orthop. 2011, 31 (1 Suppl): S46-8.
Guo X, Chau W-W, Chan Y-L, Cheng J-Y-C: Relative anterior spinal overgrowth in adolescent idiopathic scoliosis. Results of disproportionate endochondral-membranous bone growth. J Bone Joint Surg Br. 2003, 85-B: 1026-31.
Guo X, Chau W-W, Chan YL, Cheng J-C-Y, Burwell RG, Dangerfield PH: Relative anterior spinal overgrowth in adolescent idiopathic scoliosis - result of disproportionate endochondral-membranous bone growth? Summary of an electronic focus group debate of the IBSE. Eur Spine J. 2005, 14: 862-73.
Gu SX, Wang CF, Zhao YC, Zhu XD, Li M: Abnormal ossification as a cause the progression of adolescent idiopathic scoliosis. Med Hypotheses. 2009, 72 (4): 416-7.
Yang Z, Xie Y, Li M: Three-dimensional spring model: a new hypothesis of pathogenesis of adolescent idiopathic scoliosis. Med Hypotheses. 2009, 73 (5): 709-13.
Castelein RM, van Dieën JH, Smit TH: The role of dorsal shear forces in the pathogenesis of adolescent idiopathic scoliosis - a hypothesis. Med Hypotheses. 2005, 65: 501-508.
Janssen MM, Kouwenhoven JW, Castelein RM: The role of posteriorly directed shear loads acting on a pre-rotated growing spine: a hypothesis on the pathogenesis of idiopathic scoliosis. Stud Health Technol Inform. 2010, 158: 112-7.
Roth M: Idiopathic scoliosis from the point of view of the neuroradiologist. Neuroradiol. 1981, 21: 133-138.
Porter RW: The pathogenesis of idiopathic scoliosis: uncoupled neuro-osseous growth?. Eur Spine J. 200, 10: 473-481.
Chu WCW, Man GCW, Lam WWM, Yeung BHY, Chau WW, Ng BKW, Lam T-p, Lee K-m, Cheng JCY: Morphological and functional electrophysiological evidence of relative spinal cord tethering in adolescent idiopathic scoliosis. Spine. 2008, 31: 673-80.
Chu WCW, Lam WWM, Ng BKW, Lam T-p, Lee K-m, Guo X, Cheng JCY, Burwell RG, Dangerfield PH, Jaspan T: Relative shortening and functional tethering of spinal cord in adolescent scoliosis - Result of asynchronous neuro-osseous growth? Summary of an electronic focus group debate of the IBSE. Scoliosis. 2008, 3: 8-
Chu WC, Rasalkar DD, Cheng JC: Asynchronous neuro-osseous growth in adolescent idiopathic scoliosis-MRI-based research. Pediatr Radiol. 2011, 41 (9): 1100-11.
Lao LF, Shen JX, Chen ZG, Wang YP, Wen XS, Qiu GX: Uncoupled neuro-osseous growth in adolescent idiopathic scoliosis? A preliminary study of 90 adolescents with whole-spine three-dimensional magnetic resonance imaging. Eur Spine J. 2011, 20 (7): 1081-6.
Shi L, Wang D, Chu WC, Burwell GR, Wong TT, Heng PA, Cheng JC: Automatic MRI segmentation and morphoanatomy analysis of the vestibular system in adolescent idiopathic scoliosis. Neuroimage. 2011, 54 (Suppl 1): S180-8.
Wang D, Shi L, Chu WC, Burwell RG, Cheng JC, Ahuja AT: Abnormal cerebral cortical thinning pattern in adolescent girls with idiopathic scoliosis. Neuroimage. 2011,
Herman R, Mixon J, Fisher A, Maulucci R, Stuyck J: Idiopathic scoliosis and the central nervous system: a motor control problem. The Harrington Lecture, 1983. Scoliosis Research Society. Spine. 1985, 10 (1): 1-14.
Doménech J, Tormos JM, Barrios C, Pascual-Leone A: Motor cortical hyperexcitability in idiopathic scoliosis: could focal dystonia be a subclinical etiological factor?. Eur Spine J. 2010, 19 (2): 223-30.
Domenech J, García-Martí G, Martí-Bonmatí L, Barrios C, Tormos JM, Pascual-Leone A: Abnormal activation of the motor cortical network in idiopathic scoliosis demonstrated by functional MRI. Eur Spine J. 2011, 20 (7): 1069-78.
Burwell RG, Aujla RK, Grevitt MP, Randell TL, Dangerfield PH, Moulton A, Anderson SI: Is scoliosis curve initiation and progression contributed to by dysfunction of somatosensory, somatomotor, and/or sympathetic mechanisms? New observation and interpretation for the pathogenesis of right thoracic adolescent idiopathic scoliosis [abstract]. Clin Anat. 2011, 24 (3): 384-5.
Veldhuizen AG, Wever DJ, Webb PJ: The aetiology of idiopathic scoliosis: biomechanical and neuromuscular factors. Eur Spine J. 2000, 9 (3): 178-84.
Burwell RG, Freeman BJC, Dangerfield PH, Aujla RK, Cole AA, Kirby AS, Polak F, Pratt RK, Webb JK, Moulton A: Etiologic theories of idiopathic scoliosis: neurodevelopmental concept of maturational delay of the CNS body schema ("body-in-the-brain"). Stud Health Technol Inform. 2006, 123: 72-9. and J Bone Joint Surg Br 2008, 90-B:Supp II, 434
Qiu Y, Sun GQ, Zhu F, Wang WJ, Zhu ZZ: Rib length discrepancy in patients with adolescent idiopathic scoliosis. Stud Health Technol Inform. 2010, 158: 63-6.
Zhu F, Chu WC, Sun G, Zhu ZZ, Wang WJ, Cheng JC, Qiu Y: Rib length asymmetry in thoracic adolescent idiopathic scoliosis: is it primary or secondary?. Eur Spine J. 2011, 20 (2): 254-9.
Grivas TB, Vasiliadis ES, Triantafyllopolous G, Kaspiris A: A comprehensive model of idiopathic scoliosis (IS) progression, based on the patho-biomechanics of the deforming "three joint complex". Scoliosis. 2009, 4 (Suppl2): O10-
Machida M, Dubousset J, Imamura Y, Miyashita Y, Yamada T, Kimura J: Melatonin. A possible role in pathogenesis of adolescent idiopathic scoliosis. Spine. 1996, 21 (10): 1147-52.
Machida M: Cause of idiopathic scoliosis. Spine. 1999, 24 (24): 2576-2583.
Dubousset J, Machida M: Possible role of the pineal gland in pathogenesis of idiopathic scoliosis: experimental and clinical studies. Bull de l'Acad Nat de Méd. 2010, 185: 593-602. discussion 602-604.(French)
Girardo M, Bettini N, Dema E, Cervellati S: The role of melatonin in the pathogenesis of adolescent idiopathic scoliosis (AIS). Eur Spine J. 2011, S68-74. Suppl 1
Moreau A, Wang DS, Forget S, Azeddine B, Angeloni D, Fraschini F, Labelle H, Poitras B, Rivard C-H, Grimard G: Melatonin signaling dysfunction in adolescent idiopathic scoliosis. Spine. 2004, 29 (16): 1772-1781.
Letellier K, Azeddine B, Blain S, Turgeon I, Wang da S, Boiro MS, Moldovan F, Labelle H, Poitras B, Rivard CH, Grimard G, Parent S, Ouellet J, Lacroix G, Moreau A: Etiopathogenesis of adolescent idiopathic scoliosis and new molecular concepts. Med Sci (Paris). 2007, 23 (11): 910-6.
Moreau A, Turgeon I, Samba Boiro M, Azeddine B, Franco A, Labelle H, Poitras B, Rivard CH, Grimard G, Ouellet J, Parent S, Cheng JC, Brayda-Bruno M: Clinical validation of a biochemical test for adolescent idiopathic scoliosis: an International Collaborative 19. Consortium [Abstract]. Eur Spine J. 2008, 17: 768-769.
Akoume MY, Azeddine B, Turgeon I, Franco A, Labelle H, Poitras B, Rivard CH, Grimard G, Ouellet J, Parent S, Moreau A: Cell-based screening test for idiopathic scoliosis using cellular dielectric spectroscopy. Spine (Phila Pa 1976). 2010, 35 (13): E601-8.
Szalay EA, Bosch P, Schwend RM, Buggie B, Tandberg D, Sherman F: Adolescents with idiopathic scoliosis are not osteoporotic. Spine. 2008, 33 (7): 802-6.
Zhuang Q, Li J, Wu Z, Zhang J, Sun W, Li T, Yan Y, Jiang Y, Zhao RC, Qiu G: Differential proteome analysis of bone marrow mesenchymal stem cells from adolescent idiopathic scoliosis patients. PLoS One. 2011, 6 (4): e18834-
Kindsfater K, Lowe T, Lawellin D, Weinstein D, Akmakjian J: Levels of platelet calmodulin for the prediction of progression and severity of adolescent idiopathic scoliosis. J Bone Joint Surg Am. 1994, 76 (8): 1186-92.
Lowe TG, Lawellin D, Smith D, Price C, Haher T, Merola A, O'Brien M: Platelet calmodulin levels in adolescent idiopathic scoliosis. Do the levels correlate with curve progression and severity?. Spine. 2002, 27 (7): 768-775.
Lowe TG, Burwell RG, Dangerfield PH: Platelet calmodulin levels in adolescent idiopathic scoliosis: can they predict curve progression and severity? Summary of an electronic focus group debate of the IBSE. Eur Spine J. 2004, 13: 257-265.
Burwell RG, Dangerfield PH: Pathogenesis of progressive adolescent idiopathic scoliosis. Platelet activation and vascular biology in immature vertebrae: an alternative molecular hypothesis. Acta Orthop Belg. 2006, 72: 247-260.
Burwell RG, Freeman BJ, Dangerfield PH, Aujla RK, Cole AA, Kirby AS, Pratt RK, Webb JK, Moulton A: Etiologic theories of idiopathic scoliosis: enantiomorph disorder concept of bilateral symmetry, physeally-created growth conflicts and possible prevention. Stud Health Technol Inform. 2006, 123: 391-7.
Burwell RG, Aujla RK, Grevitt MP, Randell TL, Dangerfield PH, Cole AA, Kirby AS, Polak FJ, Pratt RK, Webb JK, Moulton A: Upper arm length model suggests a transient asymmetry process in the pathogenesis of right thoracic adolescent idiopathic scoliosis (RT-AIS) in girls [abstract]. Clin Anat. 2011, 24 (3): 384-
Burwell RG, Aujla RK, Grevitt MP, Randell TL, Dangerfield PH, Cole AA, Kirby AS, Polak FJ, Pratt RK, Webb JK, Moulton A: Right thoracic adolescent idiopathic scoliosis (RT-AIS) in girls: Abnormal bilateral asymmetry of upper limb lengths involves forearm-with-hands as well as upper arms [abstract]. Clin Anat. 2011, 24 (4): 530-
Burwell RG, Aujla RK, Grevitt MP, Randell TL, Dangerfield PH, Cole AA, Kirby AS, Polak FJ, Pratt RK, Webb JK, Moulton A: A transient, or resolving, bilateral asymmetry process in the pathogenesis of right thoracic adolescent idiopathic scoliosis in girls, suggested by findings of upper arm length asymmetry related to age, curve severity, and years after estimated menarcheal age [abstract]. 12th International Phillip Zorab Symposium, Royal College of Surgeons, London. 2011, 60-
Burwell RG, Grevitt MP, Randell TL, Dangerfield PH, Aujla RK, Cole AA, Pratt RK, Webb JK, Moulton A, Anderson SI: Abnormal bilateral skeletal asymmetries and their putative genetic and epigenetic origins in enantiomorphic growth plates of girls with adolescent idiopathic scoliosis (AIS) [abstract]. Ckin Anatt.
Liu Z, Tam EM, Sun GQ, Lam TP, Zhu ZZ, Sun X, Lee KM, Ng TB, Qiu Y, Cheng JC, Yeung HY: Abnormal Leptin Bioavailability in Adolescent Idiopathic Scoliosis - an Important New Finding. Spine (Phila Pa 1976). 2011,
Burwell RG, Aujla RK, Grevitt MP, Randell TL, Dangerfield PH, Moulton A, Anderson SI: A new approach to the pathogenesis of adolescent idiopathic scoliosis: interaction between risk factors involving a diverse network of causal developmental pathways [abstract]. Clin Anat. 2011, 24 (3): 384-
Bibby SR, Meir A, Fairbank JC, Urban JP: Cell viability and the physical environment in the scoliotic intervertebral disc. Stud Health Technol Inform. 2002, 91: 419-21.
Meir A, McNally DS, Fairbank JC, Jones D, Urban JP: The internal pressure and stress environment of the scoliotic intervertebral disc--a review. Proc Inst Mech Eng H. 2008, 222 (2): 209-19.
Pearson H: Epidemiology: Study of a lifetime. Nature. 2011, 471 (7336): 20-4.
Barabási AL: Network medicine--from obesity to the "diseasome". N Engl J Med. 2007, 357 (4): 404-7.
Barabasi AL, Gulbahce N, Loscalzo J: Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011, 12 (1): 56-68.
Vidal M, Cusick ME, Barabási AL: Interactome networks and human disease. Cell. 2011, 144 (6): 986-98.
Bonetta L: Protein-protein interactions: Interactome under construction. Nature. 2010, 468 (7325): 851-4.
Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wägele B, Altmaier E, CARDIoGRAM, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmüller G, Köttgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes HW, Milburn MV, Prehn C, Raffler J, Ried JS, Römisch-Margl W, Samani NJ, Small KS, Wichmann HE, Zhai G: Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011, 31;477 (7362): 54-60.
Blakemore C: Why the gene revolution has been postponed. The Times. 2011, 33-
Dr Ruth Wynne-Davies helped to initiate this review at, and subsequent to, the 12th International Phillip Zorab Symposium in London on 16-18 March 2011. We are grateful to Professor J Armour, Professor of Human Genetics and Head, School of Biology, University of Nottingham, UK, for reading the text and making suggestions. Discussions with Mrs M E McMaster about her research provoked our early interest in epigenetics and we thank her for allowing us to quote from her recent paper , for reading the text and making suggestions. We thank Dr SS Upadhyay for reading the text and for suggestions, and Mr Lyndon Cochrane for the art work.
The authors declare that they have no competing interests.
GB with TG, PD and AM initiated this review at the time of presentations in London  and Padua . GB wrote the text and conceived the novel concepts relating to the exposome and spinal development in health and AIS. PD and TG helped GB in finding and obtaining references. All authors contributed their professional skills to the ensuing discussions as the text and Figures progressed. All authors have read and approved the final manuscript.
Authors’ original submitted files for images
About this article
Cite this article
Burwell, R.G., Dangerfield, P.H., Moulton, A. et al. Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy. Scoliosis 6, 26 (2011). https://doi.org/10.1186/1748-7161-6-26
- Adolescent Idiopathic Scoliosis
- Epigenetic Modification
- Idiopathic Scoliosis
- Spinal Growth
- Juvenile Idiopathic Scoliosis