Journal of Child Psychology and Psychiatry 55:10 (2014), pp 1065–1067
doi:10.1111/jcpp.12323
Editorial: Translational genetics of child psychopathology: a distant dream? For decades now twin, family and adoption studies have pointed to a substantial role for genetic factors in risk for psychiatric disorder. Behaviour genetic studies are not, of course, designed to tell us about the ‘genetic architecture’ of disorders – the number of risk variants involved, their frequency, or their effects sizes – but their findings clearly suggest that given the high levels of heritability detected, identifying the gene variants involved could provide important pointers to aetiology, and might well have implications for treatment. In and of themselves, heritability findings have little practical value as a basis for a translational genetics of psychiatric disorders. They cannot help us identify pathophysiological pathways that need to be targeted through therapeutic innovation or inform the sort of tailoring of treatments to individual biological ‘types’ to promote personalized medicine. To do these things we need to move from estimating heritability to identifying specific genetic markers implicating specific neuro-biological systems. The initial pioneering work in the mid-to-late 1990s using candidate gene approaches produced a great sense of optimism that practical benefits of genetic science would follow relatively quickly. The reality, however, has been that the more we have discovered about the complexity and heterogeneity of the genetic underpinnings of psychiatric disorders, the less sanguine we have become and the further away into the future any possible practical benefits of genetic enquiry appear to move. Progress in identifying the relevant DNA variants has been slow, and much more challenging than expected. Candidate gene studies came up with few replicated findings, and the move to genome-wide association studies (GWAS), designed to identify key variants in a hypothesis-free way, also initially produced few significant hits in the psychiatric domain. What they did tell us, however (as Wray and colleagues1 put it in this issue’s Research Review), is that ‘. . .common variants of large effect are not part of nature’s repertoire’. Instead, it seems that psychiatric disorders and related traits are truly polygenic, and associated with many gene variants of extremely small effect. As a result, extremely large studies (often only achievable via international collaborations) will be needed to detect them. The Wray et al. review provides overview of the polygenic methods now being used in the new generation of studies of this kind, and summarizes progress to date. Their review is timely: this summer has seen the publication of two widely-publicized reports of this
kind, one identifying over 100 common loci where variation is associated with schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014), the second suggesting that common variation, as well as rare variants, is likely to While a translational be important in risk for science of child autism (Gaugler et al., psychiatric genetics may be currently no 2014). From the perspective more than a distant of our understanding of dream, it is essential the ‘genetic architecture’ that practitioners of these disorders, such remain informed about findings are clearly of progress in this vital major importance. But field. what do they mean for clinicians, and for developmental and other researchers keen to include markers of genetic variants in their studies? What is likely to be the value of identifying genome-wide effects of individual genes, if their effects are so very tiny? Can current approaches really help us in the search for the biological mechanisms that underlie disorder; or in identifying new targets for treatments; or in the quest for personalized medicine? In the short term, the answer is probably that we shouldn’t hold our breath. In the schizophrenia study, for example, the associations identified were enriched in genes involved in glutamatergic neurotransmission, and also those expressed in tissues with roles in immunity. Investigating the biological basis of such associations will undoubtedly be complex, and far more difficult than in the case of rare variants with larger effects. In the longer term, however, Wray et al. argue that there should be grounds for optimism. Although GWAS effects are indeed small individually, their cumulative impact may be more salient. Taking aggregate genetic profile scores derived from large discovery samples has already proved informative in exploring developmentally-oriented issues in smaller samples (see e.g. Belsky et al., 2012), and we can soon expect many more findings of this kind. In addition, evidence from genome-wide studies in other diseases has identified relevant biological features, including known drug targets, suggesting that in the future they may also help identify novel targets for therapeutics in the psychiatric field. A second major puzzle raised by genome-wide findings is what has come to be known as ‘missing heritability’. At least in the samples studied so far, polygenic methods typically only identify a small proportion of the genetic variance estimated in twin
© 2014 Association for Child and Adolescent Mental Health. Published by John Wiley & Sons Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA
1066
Editorial
studies of the same disorders. What might this mean? Wray et al., Thapar and Harold (Editorial Commentary) and Munaf o, Zammit and Flint (Practitioner Review) all discuss this thorny issue. Like other commentators, they remind us that the ‘heritability’ estimates derived from these two types of studies are different. The h2 from twin studies includes all types of genetic variation, including gene–gene and gene–environment interactions. Studies using polygenic methods, by contrast, are limited to estimating additive effects of common single nucleotide polymorphisms (SNPs) that can be detected in currently available DNA microarrays. With sufficiently large samples, it seems likely that these will eventually account for perhaps 50% of the heritability estimated in twin studies. The rest will need to be sought via studies of rare variants, other types of DNA variants, and non-additive (gene–gene, or gene–environment) interactions. Munaf o et al. focus on gene–environment interactions (G 9 E) and the part they might play in accounting for the ‘missing heritability’. The notion that genetic risks are moderated by environmental exposures is intuitively appealing; studies have consistently found marked individual differences in children’s responses to adversity, and genetically-based factors are very likely to contribute to such effects. Despite this, empirical research on locus-specific G 9 E has been highly controversial (see, e.g. Manuck & McCaffery, 2014), with proponents of G 9 E models and findings on one side of the argument matched by equally determined objectors on the other. The 2013 Special Issue of JCPP (on gene–environment interplay more generally; see Petrill, Bartlett, & Blair, 2013) highlighted a number of the issues involved, as well as the many challenges that still remain. Munaf o et al. take an avowedly critical perspective on locus-specific G 9 E for psychiatric phenotypes, while the accompanying commentary by Rutter offers an alternative view. Munaf o et al. set out the difficulties they see in research in this area: the statistical complexities of testing for interaction effects; the problems of low statistical power in some of the locus-specific G 9 E studies reported to date; the lack of replication of some early findings; and the fact that potentially supportive evidence from animal or experimental studies is not always itself consistent. More generally, they see adequately-powered GWAS studies as more likely to help account for the missing heritability, and suggest that we await robustly associated loci identified in this way if we wish to test for environmental effect modifiers. Rutter takes issue with their stance – and their interpretations of the evidence – on many of these points. He notes that replicated effects have been achieved in some important areas; that less than ‘exact’ replication can still be informative, provided conceptually similar associations are investigated; and that interpretation of
the animal evidence is less problematic than implied. More generally, he is less sanguine about the potential of GWAS in helping us find the way forward, and at a conceptual level points to the need for a broader perspective that takes account of other aspects of gene–environment interplay, including both gene–environment correlation and the mechanisms whereby environmental exposures influence gene expression. The arguments on both sides of these debates are important, and warrant attention. Where the contributors agree is that at this stage, the main messages for practitioners can still only be framed in quite general terms: that while genes are influential, they function in dynamic rather than determinative ways; that individual differences occur in response to all experiences; and that all substantial experiences have biological effects. What all of these articles underscore is that we are now embarked on a new phase of genetic research in psychiatry. This clearly holds out the promise of new discoveries – but it also presents equally important new challenges. Some of these are methodological: how, for example, can investigators ensure that the quality of their phenotyping is maintained in the face of calls for ever larger samples? Some are conceptual, centring on issues such as genetic heterogeneity, and the very real likelihood of genetic sub-types in many of the disorders that we study and treat. And some touch on links between research and clinical practice and how we can ensure an ongoing dialogue between these worlds as new findings and their implications continue to emerge. From a scientific point of view, these debates, discussions and disagreements are evidence of a wonderfully vibrant field, full of great minds and fascinating studies. But what should the clinician make of all of this? While a translational science of child psychiatric genetics may be currently no more than a distant dream, it is essential that practitioners remain informed about progress in this vital field. It is especially important that they are made aware of the uncertainties that continue to exist and the fact that, given the current state of knowledge, leading scientists can hold very different views about these vital questions. Indeed, it is our view that journals such as the JCPP have an important role to play in making progress in psychiatric genetics, with its methods and concepts that are intrinsically highly technical and complex, understandable to the non-specialist. We hope the invited reviews and accompanying commentaries brought together in this issue go some way in achieving this.
Barbara Maughan Joint Editor Edmund J.S. Sonuga-Barke Editor-in-Chief © 2014 Association for Child and Adolescent Mental Health.
doi:10.1111/jcpp.12323
Acknowledgement B.M. has disclosed interests in relation to her role as Joint Editor of JCPP as below, but has also declared that she has no specific competing or potential conflicts of interest in relation to this Editorial. E.J.S.S.-B. has disclosed interests in relation to his role as Editor-in-Chief as below, but has no specific competing or potential conflicts of interest in relation to this Editorial. B.M.: Grants awarded from MRC and ESRC. Publication royalties: Cambridge University Press, Oxford University Press, Wiley. Formerly Section Editor for Longitudinal and Life Course Studies. E.J.S.S.-B.:Professor in Psychology, Developmental Psychopathology, School of Psychology and Director, Developmental Brain-Behaviour Laboratory, University of Southampton, UK. Visiting chairs at Ghent University and Aarhus University. Grants awarded from MRC, ESRC, Wellcome Trust, Solent NHS Trust, European Union, Child Health Research Foundation New Zealand, NIHR, Nuffield Foundation, Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO). Pharma industry speaker fees and consultancy: Shire Pharmaceuticals: speaker fees, consultancy, advisory board membership, research support and conference attendance funds; Janssen-Cilag: speaker fees.
© 2014 Association for Child and Adolescent Mental Health.
Editorial
1067
Note 1. Articles that are in this issue (with italicized names on first mention) can be found at: http:// onlinelibrary.wiley.com/doi/10.1111/jcpp.2014. 55.issue-10/issuetoc.
References Belsky, D.W., Moffitt, T.E., Houts, R., Bennett, G.G., Biddle, A.K., Blumenthal, J.A., . . . & Caspi, A. (2012). Polygenic risk, rapid childhood growth, and the development of obesity: Evidence from a 4-decade longitudinal study. Archives of Pediatrics and Adolescent Medicine, 166, 515–521. Gaugler, T., Klei, L., Sanders, S.J., Bodea, C.A., Goldberg, A.P., Lee, A.B., . . . & Buxbaum, J.D. (2014). Most genetic risk for autism resides with common variation. Nature Genetics, 46, 881–885. Manuck, S.B., & McCaffery, J.M. (2014). Gene-environment interaction. Annual Review of Psychology, 65, 41–70. Petrill, S.A., Bartlett, C.W., & Blair, C. (2013). Editorial: Gene– environment interplay in child psychology and psychiatry – Challenges and ways forward. Journal of Child Psychology and Psychiatry, 54, 1029; Special Issue available at: http:// onlinelibrary.wiley.com/doi/10.1111/jcpp.2013.54.issue10/issuetoc. Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511, 421–427.
doi:10.1111/jcpp.12323
Editorial: Translational genetics of child psychopathology: a distant dream? For decades now twin, family and adoption studies have pointed to a substantial role for genetic factors in risk for psychiatric disorder. Behaviour genetic studies are not, of course, designed to tell us about the ‘genetic architecture’ of disorders – the number of risk variants involved, their frequency, or their effects sizes – but their findings clearly suggest that given the high levels of heritability detected, identifying the gene variants involved could provide important pointers to aetiology, and might well have implications for treatment. In and of themselves, heritability findings have little practical value as a basis for a translational genetics of psychiatric disorders. They cannot help us identify pathophysiological pathways that need to be targeted through therapeutic innovation or inform the sort of tailoring of treatments to individual biological ‘types’ to promote personalized medicine. To do these things we need to move from estimating heritability to identifying specific genetic markers implicating specific neuro-biological systems. The initial pioneering work in the mid-to-late 1990s using candidate gene approaches produced a great sense of optimism that practical benefits of genetic science would follow relatively quickly. The reality, however, has been that the more we have discovered about the complexity and heterogeneity of the genetic underpinnings of psychiatric disorders, the less sanguine we have become and the further away into the future any possible practical benefits of genetic enquiry appear to move. Progress in identifying the relevant DNA variants has been slow, and much more challenging than expected. Candidate gene studies came up with few replicated findings, and the move to genome-wide association studies (GWAS), designed to identify key variants in a hypothesis-free way, also initially produced few significant hits in the psychiatric domain. What they did tell us, however (as Wray and colleagues1 put it in this issue’s Research Review), is that ‘. . .common variants of large effect are not part of nature’s repertoire’. Instead, it seems that psychiatric disorders and related traits are truly polygenic, and associated with many gene variants of extremely small effect. As a result, extremely large studies (often only achievable via international collaborations) will be needed to detect them. The Wray et al. review provides overview of the polygenic methods now being used in the new generation of studies of this kind, and summarizes progress to date. Their review is timely: this summer has seen the publication of two widely-publicized reports of this
kind, one identifying over 100 common loci where variation is associated with schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014), the second suggesting that common variation, as well as rare variants, is likely to While a translational be important in risk for science of child autism (Gaugler et al., psychiatric genetics may be currently no 2014). From the perspective more than a distant of our understanding of dream, it is essential the ‘genetic architecture’ that practitioners of these disorders, such remain informed about findings are clearly of progress in this vital major importance. But field. what do they mean for clinicians, and for developmental and other researchers keen to include markers of genetic variants in their studies? What is likely to be the value of identifying genome-wide effects of individual genes, if their effects are so very tiny? Can current approaches really help us in the search for the biological mechanisms that underlie disorder; or in identifying new targets for treatments; or in the quest for personalized medicine? In the short term, the answer is probably that we shouldn’t hold our breath. In the schizophrenia study, for example, the associations identified were enriched in genes involved in glutamatergic neurotransmission, and also those expressed in tissues with roles in immunity. Investigating the biological basis of such associations will undoubtedly be complex, and far more difficult than in the case of rare variants with larger effects. In the longer term, however, Wray et al. argue that there should be grounds for optimism. Although GWAS effects are indeed small individually, their cumulative impact may be more salient. Taking aggregate genetic profile scores derived from large discovery samples has already proved informative in exploring developmentally-oriented issues in smaller samples (see e.g. Belsky et al., 2012), and we can soon expect many more findings of this kind. In addition, evidence from genome-wide studies in other diseases has identified relevant biological features, including known drug targets, suggesting that in the future they may also help identify novel targets for therapeutics in the psychiatric field. A second major puzzle raised by genome-wide findings is what has come to be known as ‘missing heritability’. At least in the samples studied so far, polygenic methods typically only identify a small proportion of the genetic variance estimated in twin
© 2014 Association for Child and Adolescent Mental Health. Published by John Wiley & Sons Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA
1066
Editorial
studies of the same disorders. What might this mean? Wray et al., Thapar and Harold (Editorial Commentary) and Munaf o, Zammit and Flint (Practitioner Review) all discuss this thorny issue. Like other commentators, they remind us that the ‘heritability’ estimates derived from these two types of studies are different. The h2 from twin studies includes all types of genetic variation, including gene–gene and gene–environment interactions. Studies using polygenic methods, by contrast, are limited to estimating additive effects of common single nucleotide polymorphisms (SNPs) that can be detected in currently available DNA microarrays. With sufficiently large samples, it seems likely that these will eventually account for perhaps 50% of the heritability estimated in twin studies. The rest will need to be sought via studies of rare variants, other types of DNA variants, and non-additive (gene–gene, or gene–environment) interactions. Munaf o et al. focus on gene–environment interactions (G 9 E) and the part they might play in accounting for the ‘missing heritability’. The notion that genetic risks are moderated by environmental exposures is intuitively appealing; studies have consistently found marked individual differences in children’s responses to adversity, and genetically-based factors are very likely to contribute to such effects. Despite this, empirical research on locus-specific G 9 E has been highly controversial (see, e.g. Manuck & McCaffery, 2014), with proponents of G 9 E models and findings on one side of the argument matched by equally determined objectors on the other. The 2013 Special Issue of JCPP (on gene–environment interplay more generally; see Petrill, Bartlett, & Blair, 2013) highlighted a number of the issues involved, as well as the many challenges that still remain. Munaf o et al. take an avowedly critical perspective on locus-specific G 9 E for psychiatric phenotypes, while the accompanying commentary by Rutter offers an alternative view. Munaf o et al. set out the difficulties they see in research in this area: the statistical complexities of testing for interaction effects; the problems of low statistical power in some of the locus-specific G 9 E studies reported to date; the lack of replication of some early findings; and the fact that potentially supportive evidence from animal or experimental studies is not always itself consistent. More generally, they see adequately-powered GWAS studies as more likely to help account for the missing heritability, and suggest that we await robustly associated loci identified in this way if we wish to test for environmental effect modifiers. Rutter takes issue with their stance – and their interpretations of the evidence – on many of these points. He notes that replicated effects have been achieved in some important areas; that less than ‘exact’ replication can still be informative, provided conceptually similar associations are investigated; and that interpretation of
the animal evidence is less problematic than implied. More generally, he is less sanguine about the potential of GWAS in helping us find the way forward, and at a conceptual level points to the need for a broader perspective that takes account of other aspects of gene–environment interplay, including both gene–environment correlation and the mechanisms whereby environmental exposures influence gene expression. The arguments on both sides of these debates are important, and warrant attention. Where the contributors agree is that at this stage, the main messages for practitioners can still only be framed in quite general terms: that while genes are influential, they function in dynamic rather than determinative ways; that individual differences occur in response to all experiences; and that all substantial experiences have biological effects. What all of these articles underscore is that we are now embarked on a new phase of genetic research in psychiatry. This clearly holds out the promise of new discoveries – but it also presents equally important new challenges. Some of these are methodological: how, for example, can investigators ensure that the quality of their phenotyping is maintained in the face of calls for ever larger samples? Some are conceptual, centring on issues such as genetic heterogeneity, and the very real likelihood of genetic sub-types in many of the disorders that we study and treat. And some touch on links between research and clinical practice and how we can ensure an ongoing dialogue between these worlds as new findings and their implications continue to emerge. From a scientific point of view, these debates, discussions and disagreements are evidence of a wonderfully vibrant field, full of great minds and fascinating studies. But what should the clinician make of all of this? While a translational science of child psychiatric genetics may be currently no more than a distant dream, it is essential that practitioners remain informed about progress in this vital field. It is especially important that they are made aware of the uncertainties that continue to exist and the fact that, given the current state of knowledge, leading scientists can hold very different views about these vital questions. Indeed, it is our view that journals such as the JCPP have an important role to play in making progress in psychiatric genetics, with its methods and concepts that are intrinsically highly technical and complex, understandable to the non-specialist. We hope the invited reviews and accompanying commentaries brought together in this issue go some way in achieving this.
Barbara Maughan Joint Editor Edmund J.S. Sonuga-Barke Editor-in-Chief © 2014 Association for Child and Adolescent Mental Health.
doi:10.1111/jcpp.12323
Acknowledgement B.M. has disclosed interests in relation to her role as Joint Editor of JCPP as below, but has also declared that she has no specific competing or potential conflicts of interest in relation to this Editorial. E.J.S.S.-B. has disclosed interests in relation to his role as Editor-in-Chief as below, but has no specific competing or potential conflicts of interest in relation to this Editorial. B.M.: Grants awarded from MRC and ESRC. Publication royalties: Cambridge University Press, Oxford University Press, Wiley. Formerly Section Editor for Longitudinal and Life Course Studies. E.J.S.S.-B.:Professor in Psychology, Developmental Psychopathology, School of Psychology and Director, Developmental Brain-Behaviour Laboratory, University of Southampton, UK. Visiting chairs at Ghent University and Aarhus University. Grants awarded from MRC, ESRC, Wellcome Trust, Solent NHS Trust, European Union, Child Health Research Foundation New Zealand, NIHR, Nuffield Foundation, Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO). Pharma industry speaker fees and consultancy: Shire Pharmaceuticals: speaker fees, consultancy, advisory board membership, research support and conference attendance funds; Janssen-Cilag: speaker fees.
© 2014 Association for Child and Adolescent Mental Health.
Editorial
1067
Note 1. Articles that are in this issue (with italicized names on first mention) can be found at: http:// onlinelibrary.wiley.com/doi/10.1111/jcpp.2014. 55.issue-10/issuetoc.
References Belsky, D.W., Moffitt, T.E., Houts, R., Bennett, G.G., Biddle, A.K., Blumenthal, J.A., . . . & Caspi, A. (2012). Polygenic risk, rapid childhood growth, and the development of obesity: Evidence from a 4-decade longitudinal study. Archives of Pediatrics and Adolescent Medicine, 166, 515–521. Gaugler, T., Klei, L., Sanders, S.J., Bodea, C.A., Goldberg, A.P., Lee, A.B., . . . & Buxbaum, J.D. (2014). Most genetic risk for autism resides with common variation. Nature Genetics, 46, 881–885. Manuck, S.B., & McCaffery, J.M. (2014). Gene-environment interaction. Annual Review of Psychology, 65, 41–70. Petrill, S.A., Bartlett, C.W., & Blair, C. (2013). Editorial: Gene– environment interplay in child psychology and psychiatry – Challenges and ways forward. Journal of Child Psychology and Psychiatry, 54, 1029; Special Issue available at: http:// onlinelibrary.wiley.com/doi/10.1111/jcpp.2013.54.issue10/issuetoc. Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511, 421–427.
