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What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn

Molecular Psychiatry volume 18, pages 1058–1066 (2013)Cite this article

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Abstract

Psychiatric genetics has taught us a great deal about the nature of psychiatric disorders. Traditional family, twin and adoption studies have demonstrated the substantial role of genetic factors in their etiology, clarified the role of genetic factors in comorbidity, elucidated development pathways, and documented the importance of gene–environment correlation and interaction. We have also received some hard lessons when we were unable to detect replicable genes of large effect size and found that our much-valued candidate genes did not live up to their expected promise. With more mature molecular and statistical methods, we are entering now a different era. Statistical analyses of aggregate molecular signals are validating earlier heritability estimates. Replicated findings from genome-wide association studies are beginning to emerge, as are discoveries of large-effect size rare genomic variants. The number of such findings is likely to soon grow dramatically. The most pressing question facing the field is what biological picture these results will reveal. I articulate four possible scenarios that reflect (i) no, (ii) minimal, (iii) moderate and (iv) high biological coherence in the replicated molecular variant findings, which are soon likely to emerge. I discuss the factors that will likely influence these patterns, including the problems of etiological heterogeneity and multiple realizability. These findings could provide critical insights into the underlying biology of our psychiatric syndromes and potentially permit us to perceive, ‘through a glass darkly,’ the levels of the mind–brain system that are disordered.

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References

  1. Turkheimer E . Three Laws of Behavior Genetics and what they mean. Curr Dir Psychol Sci 2001; 9: 160–164.

    Article  Google Scholar 

  2. Sullivan PF, Neale MC, Kendler KS . Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.

    Article  CAS  PubMed  Google Scholar 

  3. Sullivan PF, Kendler KS, Neale MC . Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192.

    Article  PubMed  Google Scholar 

  4. Verweij KJ, Zietsch BP, Lynskey MT, Medland SE, Neale MC, Martin NG et al. Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction 2010; 105: 417–430.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Prescott CA . The genetic epidemiology of alcoholism: sex differences and future directions. In: Agarwal DP, Seitz HK, (eds) Alcohol in Health and Disease. Marcel Dekker, Inc: New York pp 125–149 2001.

    Chapter  Google Scholar 

  6. Sullivan PF, Daly MJ, O'Donovan M . Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jenner E . An Inquiry into the Causes and Effects of the Variolae Vaccinae, a Disease Discovered in Some of the Western Counties of England Particularly Gloucestershire, and Known by the Name of the Cow Pox. S. Low: London, UK, 1798.

    Google Scholar 

  8. Snow J . On The Mode of Communication of Cholera. John Churchill, New Burlington Street, England: London, UK, 1855.

    Google Scholar 

  9. Doll R, HILL AB . Smoking and carcinoma of the lung; preliminary report. Br Med J 1950; 2: 739–748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Plomin R, Corley R, DeFries JC, Fulker DW . Individual differences in television viewing in early childhood: nature as well as nurture. Psychol Sci 1990; 1: 371–377.

    Article  Google Scholar 

  11. Maia JA, Thomis M, Beunen G . Genetic factors in physical activity levels: a twin study. Am J Prev Med 2002; 23 (2 Suppl): 87–91.

    Article  PubMed  Google Scholar 

  12. Kendler KS, Myers JA . Developmental twin study of church attendance and alcohol and nicotine consumption: a model for analyzing the changing impact of genes and environment. Am J Psychiatry 2009; 166: 1150–1155.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Olson JM, Vernon PA, Harris JA, Jang KL . The heritability of attitudes: a study of twins. J Person Soc Psychol 2001; 80: 845–860.

    Article  CAS  Google Scholar 

  14. Waldron M, Heath AC, Turkheimer E, Emery R, Bucholz KK, Madden PAF et al. Age at first sexual intercourse and teenage pregnancy in Australian female twins. Twin Res Hum Genet 2007; 10: 440–449.

    Article  PubMed  Google Scholar 

  15. Kendler KS . Twin studies of psychiatric illness. Current status and future directions. Arch Gen Psychiatry 1993; 50: 905–915.

    Article  CAS  PubMed  Google Scholar 

  16. Kendler KS . Twin studies of psychiatric illness: an update. Arch Gen Psychiatry 2001; 58: 1005–1014.

    Article  CAS  PubMed  Google Scholar 

  17. Kendler KS, Prescott CA . Genes, Environment, and Psychopathology: Understanding the Causes of Psychiatric and Substance Use Disorders 1st edn Guilford Press: New York, 2006).

    Google Scholar 

  18. Kendler KS, Gatz M, Gardner C, Pedersen NL . Personality and major depression: a Swedish longitudinal, population-based twin study. Arch Gen Psychiatry 2006; 63: 1113–1120.

    Article  PubMed  Google Scholar 

  19. Kendler KS, Gardner CO, Prescott CA . Toward a comprehensive developmental model for alcohol use disorders in men. Twin Res Hum Genet 2011; 14: 1–15.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Prescott CA, Sullivan PF, Kuo PH, Webb BT, Vittum J, Patterson DG et al. Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4. Mol Psychiatry 2006; 11: 603–611.

    Article  CAS  PubMed  Google Scholar 

  21. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990; 336: 13–16.

    Article  CAS  PubMed  Google Scholar 

  23. Kendler KS, Schaffner KF . The Dopamine hypothesis of Schizophrenia: an historical and philosophical analysis. Philos Psychiatry Psychol 2011; 18: 41–63.

    Article  Google Scholar 

  24. Hirschfeld RMA . History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 2000; 61 (suppl 6): 4–6.

    CAS  PubMed  Google Scholar 

  25. Walsh T, Mcclellan JM, Mccarthy SE, Addington AM, Pierce SB, Cooper GM et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008; 320: 539–543.

    Article  CAS  PubMed  Google Scholar 

  26. Stone JL, O'Donovan MC, Gurling H, Kirov GK, Blackwood DHR, Corvin A et al. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241.

    Article  CAS  Google Scholar 

  27. Marshall CR, Scherer SW . Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol Biol 2012; 838: 115–135.

    Article  CAS  PubMed  Google Scholar 

  28. Lencz T, Morgan TV, Athanasiou M, Dain B, Reed CR, Kane JM et al. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry 2007; 12: 572–580.

    Article  CAS  PubMed  Google Scholar 

  29. Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ et al. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet 2008; 4: e28.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kirov G, Zaharieva I, Georgieva L, Moskvina V, Nikolov I, Cichon S et al. A genome-wide association study in 574 schizophrenia trios using DNA pooling. Mol Psychiatry 2009; 14: 796–803.

    Article  CAS  PubMed  Google Scholar 

  31. Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 2010; 42: 441–447.

    Article  Google Scholar 

  32. Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969–976.

    Article  CAS  Google Scholar 

  33. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43: 977–983.

    Article  Google Scholar 

  34. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.

    CAS  PubMed  Google Scholar 

  35. Whalley HC, Papmeyer M, Sprooten E, Romaniuk L, Blackwood DH, Glahn DC et al. The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI. Transl Psychiatry 2012; 2: e130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hamshere ML, O'Donovan MC, Jones IR, Jones L, Kirov G, Green EK et al. Polygenic dissection of the bipolar phenotype. Br J Psychiatry 2011; 198: 284–288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang J, Lee SH, Goddard ME, Visscher PM . GCTA: a tool for genome-wide complex trait analysis. Am J Human Genet 2011; 88: 76–82.

    Article  CAS  Google Scholar 

  38. Lee SH, DeCandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 2012; 44: 247–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM et al. Cross-Disorder Group of the Psychiatric Genomics Consortium(PGC-CDG). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 2013 (under review).

  40. Lee SH, Wray NR, Goddard ME, Visscher PM . Estimating missing heritability for disease from genome-wide association studies. Am J Human Genet 2011; 88: 294–305.

    Article  Google Scholar 

  41. Lubke GH, Hottenga JJ, Walters R, Laurin C, de Geus EJ, Willemsen G et al. Estimating the genetic variance of major depressive disorder due to all single nucleotide polymorphisms. Biol Psychiatry 2012; 72: 707–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 2012; 3: 9.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Turkheimer E . Genome wide association studies of behavior are social science. In: Plaisance KS, Reydon TAC, (eds). Philosophy of Behavioral Biology: Boston Studies in the Philosophy of Science. Springer Science & Busines Media B.V, 2012 pp 43–64.

    Chapter  Google Scholar 

  44. Lewontin RC, Rose S, Kamin LJ . Not in Our Genes: Biology, Ideology, and Human Nature. Pantheon, 1985.

    Google Scholar 

  45. Joseph J . The Missing Gene: Psychiatry, Heredity, And the Fruitless Search for Genes. Algora Publishing, 2006.

    Google Scholar 

  46. Kendler KS, Sundquist K, Ohlsson H, Palmer K, Maes H, Winkleby MA et al. Genetic and familial-environmental influences on risk for drug abuse: A National Swedish Adoption Study. Arch Gen Psychiatry 2012; 69: 690–697.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Cichon S, Craddock N, Daly M, Faraone SV, Gejman PV, Kelsoe J et al. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 2009; 166: 540–556.

    Article  PubMed  Google Scholar 

  48. Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 2011; 168: 302–316.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Xu B, Roos JL, Dexheimer P, Boone B, Plummer B, Levy S et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet 2011; 43: 864–868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Need AC, McEvoy JP, Gennarelli M, Heinzen EL, Ge D, Maia JM et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Human Genet 2012; 91: 303–312.

    Article  CAS  Google Scholar 

  51. Johansen CT, Wang J, Lanktree MB, Cao H, McIntyre AD, Ban MR et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet 2010; 42: 684–687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 2011; 43: 1066–1073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Engstrom EJ . Clinical Psychiatry in Imperial Germany: A History of Psychiatric Practice. Cornell University Press: Ithaca, NY, 2003.

    Google Scholar 

  54. Carandini M . From circuits to behavior: a bridge too far? Nat Neurosci 2012; 15: 507–509.

    Article  CAS  PubMed  Google Scholar 

  55. Anderson PW . More is different. Science 1972; 177: 393–396.

    Article  CAS  PubMed  Google Scholar 

  56. Kendler KS . Levels of explanation in psychiatric and substance use disorders: implications for the development of an etiologically based nosology. Mol Psychiatry 2012; 17: 11–21.

    Article  CAS  PubMed  Google Scholar 

  57. Kendler KS . The dappled nature of causes of psychiatric illness: replacing the organic-functional/hardware-software dichotomy with empirically based pluralism. Mol Psychiatry 2012; 17: 377–388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Panksepp J, Biven L . The Archaeology of Mind: Neuroevolutionary Origins of Human Emotions First ed. W.W. Norton & Company, Inc: New York, NY, 2012.

    Google Scholar 

  59. Fodor JA . Special sciences (OR: The disunity of science as a working hypothesis). Synthese 1974; 28: 97–115.

    Article  Google Scholar 

  60. Mackie JL . I. Causes and Conditions. Am Phil Q 1965; 2: 245–264.

    Google Scholar 

  61. Flint J, Mott R . Applying mouse complex-trait resources to behavioural genetics. Nature 2008; 456: 724–727.

    Article  CAS  PubMed  Google Scholar 

  62. Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF . Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 2006; 11: 195–269.

    Article  CAS  PubMed  Google Scholar 

  63. Kendler KS, Aggen SH, Patrick CJ . A multivariate twin study of the DSM-IV criteria for antisocial personality disorder. Biol Psychiatry 2012; 71: 247–253.

    Article  PubMed  Google Scholar 

  64. Kendler KS, Aggen SH, Prescott CA, Crabbe J, Neale MC . Evidence for multiple genetic factors underlying the DSM-IV criteria for alcohol dependence. Mol Psychiatry 2011; 17: 1306–1315.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Kendler KS, Aggen SH, Patrick CJ . Familial influences on conduct disorder reflect two genetic and one shared environmental factor. Arch Gen Psychiatry 2012; 70: 78–86.

    Google Scholar 

  66. Kendler KS, Aggen SH, Neale MC . Evidence for multiple genetic factors underlying DSM-IV criteria for major depression. Arch Gen Psychiatry 2012; 17: 1306–1315.

    CAS  Google Scholar 

  67. Wang K, Li M, Hakonarson H . Analysing biological pathways in genome-wide association studies. Nat Rev Genet 2010; 11: 843–854.

    Article  CAS  PubMed  Google Scholar 

  68. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, Steinthorsdottir V et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012; 44: 981–990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Holmans P, Green EK, Pahwa JS, Ferreira MA, Purcell SM, Sklar P et al. Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. Am J Human Genet 2009; 85: 13–24.

    Article  CAS  Google Scholar 

  70. Parkes M . Evidence from genetics for a role of autophagy and innate immunity in IBD pathogenesis. Digest Dis 2012; 30: 330–333.

    Article  Google Scholar 

  71. Wang K, Zhang H, Kugathasan S, Annese V, Bradfield JP, Russell RK et al. Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease. Am J Human Genet 2009; 84: 399–405.

    Article  CAS  Google Scholar 

  72. Martin I, Dawson VL, Dawson TM . Recent advances in the genetics of Parkinson’s disease. Ann Rev Genom Human Genet 2011; 12: 301–325.

    Article  CAS  Google Scholar 

  73. Baranzini SE, Nickles D . Genetics of multiple sclerosis: swimming in an ocean of data. Curr Opin Neurol 2012; 25: 239–245.

    Article  PubMed  Google Scholar 

  74. Bertram L, Tanzi RE . The genetics of Alzheimer's disease. Progr Mol Biol Transl Sci 2012; 107: 79–100.

    Article  CAS  Google Scholar 

  75. Lango AH, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 2010; 467: 832–838.

    Article  Google Scholar 

  76. Lui JC, Nilsson O, Chan Y, Palmer CD, Andrade AC, Hirschhorn JN et al. Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height. Hum Mol Genet 2012; 21: 5193–5201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu XM, Li MF et al. Spatio-temporal transcriptome of the human brain. Nature 2011; 478: 483–489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jia P, Wang L, Fanous AH, Pato CN, Edwards TL, Zhao Z . Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia. PLoS Comput Biol 2012; 8: e1002587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD et al. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry 2012; 17: 887–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. O'Dushlaine C, Kenny E, Heron E, Donohoe G, Gill M, Morris D et al. Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Mol Psychiatry 2011; 16: 286–292.

    Article  CAS  PubMed  Google Scholar 

  81. Ben-David E, Shifman S . Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol Psychiatry, advance online publication, 13 November 2012.

  82. Lee PH, Perlis RH, Jung JY, Byrne EM, Rueckert E, Siburian R et al. Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder. Transl Psychiatry 2012; 2: e184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cross-Disorder Group of the Psychiatric GWAS Consortium. Genome-wide analysis identifies loci with shared effects on five major psychiatric disorders. Lancet, advance online publication, 28 February 2013 (in press).

  84. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 2012; 337: 1190–1195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. State MW, Sestan N . The emerging biology of autism spectrum disorders. Science 2012; 337: 1301–1303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Meehl PE . Specific etiology and other forms of strong influence: some quantitative meanings. J Med Philos 1977; 2: 33–55.

    Article  Google Scholar 

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Acknowledgements

This paper benefited greatly from discussions of this material with and/or comments on early drafts from Eric Turkheimer, Mark Reimers, John Campbell, Naomi Wray, Jordan Smoller and Jonathan Flint.

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Kendler, K. What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn. Mol Psychiatry 18, 1058–1066 (2013). https://doi.org/10.1038/mp.2013.50

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