CoChat
Sign Up
Cited by 398Genetic Associations and EpidemiologyMental Health and PsychiatryMental Health Research Topics

Psychiatric genetics and the structure of psychopathology

Open access
Smoller, Jordan W., Andreassen, Ole A., Edenberg, Howard J., Faraone, Stephen V., Glatt, Stephen J., Kendler, Kenneth S.·2019·Molecular Psychiatry
DOI 10.1038/s41380-017-0010-4PMC PMC6684352
Open this paper in CoChat — free account

Abstract

For over a century, psychiatric disorders have been defined by expert opinion and clinical observation. The modern DSM has relied on a consensus of experts to define categorical syndromes based on clusters of symptoms and signs, and, to some extent, external validators, such as longitudinal course and response to treatment. In the absence of an established etiology, psychiatry has struggled to validate these descriptive syndromes, and to define the boundaries between disorders and between normal and pathologic variation. Recent advances in genomic research, coupled with large-scale collaborative efforts like the Psychiatric Genomics Consortium, have identified hundreds of common and rare genetic variations that contribute to a range of neuropsychiatric disorders. At the same time, they have begun to address deeper questions about the structure and classification of mental disorders: To what extent do genetic findings support or challenge our clinical nosology? Are there genetic boundaries between psychiatric and neurologic illness? Do the data support a boundary between disorder and normal variation? Is it possible to envision a nosology based on genetically informed disease mechanisms? This review provides an overview of conceptual issues and genetic findings that bear on the relationships among and boundaries between psychiatric disorders and other conditions. We highlight implications for the evolving classification of psychopathology and the challenges for clinical translation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41380-017-0010-4

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Twin and large-scale genomic studies have established that genetic variation strongly affects risk for many psychiatric disorders.

    “The substantial influence of genetic variation on risk for a broad range of psychiatric disorders has been established by both twin and, more recently, large-scale genomic studies”

    From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Smoller et al., 2019

  • These results augment a substantial body of research demonstrating that genetic influences on psychopathology do not map cleanly onto the clinical nosology instantiated in the DSM or ICD.

    “These results augment a substantial body of research demonstrating that genetic influences on psychopathology do not map cleanly onto the clinical nosology instantiated in the DSM or ICD (Geschwind and Flint, 2015; Smoller et al., 2019)”

    From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Smoller et al., 2019

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 111 · Cited by 398

Research works printed but not linked: 91

  1. [2]Rudin E Studien uber Vererbung und entstehung geistiger Storungen. I. Zur vererbung und neuentstehung der Dementia praecox (Studies on the inheritance and origin of mental illness. I. The problem of the inheritance and primary origin of dementia praecox). Monographien aus dem Gesamtgebiet der Neurologie und Psychiatrie, Number 12 Berlin: Springer; 1916. [Google Scholar]
  2. [3]Luxenburger H Vorlaufiger Bericht uder psychiatrische Serienuntersuchungen und Zwillingen. Z Gesamte Neurol Psychiatr 1928; 116: 297–326. [Google Scholar]
  3. [4]Heston LL. Psychiatric disorder in foster home reared children of schizophrenic mothers. British Journal of Psychiatry 1966; 112: 819–825. [DOI] [PubMed] [Google Scholar]
  4. [5]Kendler KS, Eaves LJ. Psychiatric Genetics, Review of Psychiatry, Vol 24, vol. American Psychiatric Publishing, Inc: Arlington,VA, 2005. [Google Scholar]
  5. [6]Kendler KS. Twin studies of psychiatric illness: an update. Arch Gen Psychiatry 2001; 58(11): 1005–1014. [DOI] [PubMed] [Google Scholar]
  6. [8]Kety SS. The significance of genetic factors in the etiology of schizophrenia: results from the national study of adoptees in Denmark. J Psychiatr Res 1987; 21(4): 423–429. [DOI] [PubMed] [Google Scholar]
  7. [10]Verhulst B, Neale MC, Kendler KS. The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Psychol Med 2015; 45(5): 1061–1072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. [11]Kendler KS, Aggen SH, Knudsen GP, Roysamb E, Neale MC, Reichborn-Kjennerud T. The structure of genetic and environmental risk factors for syndromal and subsyndromal common DSM-IV axis I and all axis II disorders. The American journal of psychiatry 2011; 168(1): 29–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. [14]Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. [15]International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455(7210): 237–241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. [16]Psychiatric GWAS Consortium Coordinating Committee. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 2009; 166(5): 540–556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. [17]Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA et al. 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet 2017; 101(1): 5–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. [19]Wray NR, Lee SH, Mehta D, Vinkhuyzen AA, Dudbridge F, Middeldorp CM. Research review: Polygenic methods and their application to psychiatric traits. J Child Psychol Psychiatry 2014; 55(10): 1068–1087. [DOI] [PubMed] [Google Scholar]
  14. [20]Otowa T, Hek K, Lee M, Byrne EM, Mirza SS, Nivard MG et al. Meta-analysis of genome-wide association studies of anxiety disorders. Mol Psychiatry 2016; 21(10): 1485. [DOI] [PubMed] [Google Scholar]
  15. [21]Duncan LE, Ratanatharathorn A, Aiello AE, Almli LM, Amstadter AB, Ashley-Koch AE et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. [22]Cross-Disorder Group of the Psychiatric Genomics C, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45(9): 984–994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. [23]Charney AW, Ruderfer DM, Stahl EA, Moran JL, Chambert K, Belliveau RA et al. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry 2017; 7(1): e993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. [24]CNV Schizophrenia Working Groups of the Psychiatric Genomics Consortium. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 2017; 49(1): 27–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. [25]Genovese G, Fromer M, Stahl EA, Ruderfer DM, Chambert K, Landen M et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci 2016; 19(11): 1433–1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [26]Deciphering Developmental Disorders S. Prevalence and architecture of de novo mutations in developmental disorders. Nature 2017; 542(7642): 433–438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. [27]Willsey AJ, Fernandez TV, Yu D, King RA, Dietrich A, Xing J et al. De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron 2017; 94(3): 486–499 e489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. [28]Vorstman JA, Parr JR, Moreno-De-Luca D, Anney RJ, Nurnberger JI Jr., ,Hallmayer JF. Autism genetics: opportunities and challenges for clinical translation. Nat Rev Genet 2017. [DOI] [PubMed] [Google Scholar]
  23. [29]de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH. Advancing the understanding of autism disease mechanisms through genetics. Nat Med 2016; 22(4): 345–361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. [30]Singh T, Kurki MI, Curtis D, Purcell SM, Crooks L, McRae J et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci 2016; 19(4): 571–577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [31]Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller JW. Pleiotropy in complex traits: challenges and strategies. Nat Rev Genet 2013; 14(7): 483–495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. [32]Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 2012; 148(6): 1223–1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. [33]Tesli M, Espeseth T, Bettella F, Mattingsdal M, Aas M, Melle I et al. Polygenic risk score and the psychosis continuum model. Acta psychiatrica Scandinavica 2014; 130(4): 311–317. [DOI] [PubMed] [Google Scholar]
  28. [34]Hatzimanolis A, Bhatnagar P, Moes A, Wang R, Roussos P, Bitsios P et al. Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood. Am J Med Genet B Neuropsychiatr Genet 2015; 168(5): 392–401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. [35]McIntosh AM, Gow A, Luciano M, Davies G, Liewald DC, Harris SE et al. Polygenic risk for schizophrenia is associated with cognitive change between childhood and old age. Biol Psychiatry 2013; 73(10): 938–943. [DOI] [PubMed] [Google Scholar]
  30. [36]Roussos P, Giakoumaki SG, Zouraraki C, Fiullard JF, Karagiorga V-E, Tsapakis E-M et al. The relationship of common risk variants and polygenic risk for schizophrenia to sensorimotor gating Biological Psychiatry In Press. [DOI] [PubMed] [Google Scholar]
  31. [37]Kauppi K, Westlye LT, Tesli M, Bettella F, Brandt CL, Mattingsdal M et al. Polygenic risk for schizophrenia associated with working memory-related prefrontal brain activation in patients with schizophrenia and healthy controls. Schizophr Bull 2015; 41(3): 736–743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. [38]Riglin L, Collishaw S, Richards A, Thapar AK, Maughan B, O’Donovan MC et al. Schizophrenia risk alleles and neurodevelopmental outcomes in childhood: a population-based cohort study. Lancet Psychiatry 2017; 4(1): 57–62. [DOI] [PubMed] [Google Scholar]
  33. [40]Nivard MG, Gage SH, Hottenga JJ, van Beijsterveldt CE, Abdellaoui A, Bartels M et al. Genetic Overlap Between Schizophrenia and Developmental Psychopathology: Longitudinal and Multivariate Polygenic Risk Prediction of Common Psychiatric Traits During Development. Schizophr Bull 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. [41]Jones HJ, Stergiakouli E, Tansey KE, Hubbard L, Heron J, Cannon M et al. Phenotypic Manifestation of Genetic Risk for Schizophrenia During Adolescence in the General Population. JAMA Psychiatry 2016; 73(3): 221–228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. [42]Lo MT, Hinds DA, Tung JY, Franz C, Fan CC, Wang Y et al. Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders. Nat Genet 2017; 49(1): 152–156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. [44]Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci 2015; 18(2): 199–209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. [45]Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N et al. Schizophrenia risk from complex variation of complement component 4. Nature 2016; 530(7589): 177–183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. [46]Devor A, Andreassen OA, Wang Y, Maki-Marttunen T, Smeland OB, Fan CC et al. Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia. Mol Psychiatry 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. [47]Gandal MJ, Leppa V, Won H, Parikshak NN, Geschwind DH. The road to precision psychiatry: translating genetics into disease mechanisms. Nat Neurosci 2016; 19(11): 1397–1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. [48]Breen G, Li Q, Roth BL, O’Donnell P, Didriksen M, Dolmetsch R et al. Translating genome-wide association findings into new therapeutics for psychiatry. Nat Neurosci 2016; 19(11): 1392–1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. [49]Kathiresan S Developing Medicines That Mimic the Natural Successes of the Human Genome: Lessons From NPC1L1, HMGCR, PCSK9, APOC3, and CETP. Journal of the American College of Cardiology 2015; 65(15): 1562–1566. [DOI] [PubMed] [Google Scholar]
  42. [50]Lahey BB, Applegate B, Hakes JK, Zald DH, Hariri AR, Rathouz PJ. Is there a general factor of prevalent psychopathology during adulthood? J Abnorm Psychol 2012; 121(4): 971–977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. [51]Kerekes N, Brandstrom S, Lundstrom S, Rastam M, Nilsson T, Anckarsater H. ADHD, autism spectrum disorder, temperament, and character: phenotypical associations and etiology in a Swedish childhood twin study. Compr Psychiatry 2013; 54(8): 1140–1147. [DOI] [PubMed] [Google Scholar]
  44. [53]Larsson H, Anckarsater H, Rastam M, Chang Z, Lichtenstein P. Childhood attention-deficit hyperactivity disorder as an extreme of a continuous trait: a quantitative genetic study of 8,500 twin pairs. J Child Psychol Psychiatry 2012; 53(1): 73–80. [DOI] [PubMed] [Google Scholar]
  45. [55]Groen-Blokhuis MM, Middeldorp CM, Kan KJ, Abdellaoui A, van Beijsterveldt CE, Ehli EA et al. Attention-deficit/hyperactivity disorder polygenic risk scores predict attention problems in a population-based sample of children. J Am Acad Child Adolesc Psychiatry 2014; 53(10): 1123–1129 e1126. [DOI] [PubMed] [Google Scholar]
  46. [56]Robinson EB, St Pourcain B, Anttila V, Kosmicki JA, Bulik-Sullivan B, Grove J et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat Genet 2016; 48(5): 552–555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. [57]Germine L, Robinson EB, Smoller JW, Calkins ME, Moore TM, Hakonarson H et al. Association between polygenic risk for schizophrenia, neurocognition and social cognition across development. Transl Psychiatry 2016; 6(10): e924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. [58]Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 2010; 167(7): 748–751. [DOI] [PubMed] [Google Scholar]
  49. [60]Hyman SE. The diagnosis of mental disorders: the problem of reification. Annu Rev Clin Psychol 2010; 6: 12.11–12.25. [DOI] [PubMed] [Google Scholar]
  50. [61]Kendler KS. Levels of explanation in psychiatric and substance use disorders: implications for the development of an etiologically based nosology. Mol Psychiatry 2012; 17(1): 11–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. [62]Duncan L, Yilmaz Z, Gaspar H, Walters R, Goldstein J, Anttila V et al. Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa. Am J Psychiatry 2017: appiajp201716121402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. [64]Kendler KS. Toward a scientific psychiatric nosology. Strengths and limitations. Archives of general psychiatry 1990; 47(10): 969–973. [DOI] [PubMed] [Google Scholar]
  53. [65]Tsuang M, Faraone S, Lyons M. Identification of the phenotype in psychiatric genetics. European archives of psychiatry and clinical neuroscience 1993; 243: 131–142. [DOI] [PubMed] [Google Scholar]
  54. [66]Kendler KS. Reflections on the relationship between psychiatric genetics and psychiatric nosology. Am J Psychiatry 2006; 163(7): 1138–1146. [DOI] [PubMed] [Google Scholar]
  55. [67]Kendler KS. An historical framework for psychiatric nosology. Psychol Med 2009; 39(12): 1935–1941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. [69]Okser S, Pahikkala T, Airola A, Salakoski T, Ripatti S, Aittokallio T. Regularized machine learning in the genetic prediction of complex traits. PLoS Genet 2014; 10(11): e1004754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. [70]Wray NR, Yang J, Hayes BJ, Price AL, Goddard ME, Visscher PM. Pitfalls of predicting complex traits from SNPs. Nat Rev Genet 2013; 14(7): 507–515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. [71]Levinson DF, Mostafavi S, Milaneschi Y, Rivera M, Ripke S, Wray NR et al. Genetic studies of major depressive disorder: why are there no genome-wide association study findings and what can we do about it? Biol Psychiatry 2014; 76(7): 510–512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. [72]Holland D, Wang Y, Thompson WK, Schork A, Chen CH, Lo MT et al. Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics. Front Genet 2016; 7: 15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. [74]Moutsianas L, Agarwala V, Fuchsberger C, Flannick J, Rivas MA, Gaulton KJ et al. The power of gene-based rare variant methods to detect disease-associated variation and test hypotheses about complex disease. PLoS Genet 2015; 11(4): e1005165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. [75]Sullivan PF, Agrawal A, Bulik CM, Andreassen OA, Borglum A, Breen G et al. Psychiatric genomics: An update and an agenda. BiorXiv 2017; 10.1101/115600. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  62. [76]Boyle EA, Li YI, Pritchard JK. An Expanded View of Complex Traits: From Polygenic to Omnigenic. Cell 2017; 169(7): 1177–1186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. [77]Anttila V, Bulik-Sullivan B, Finucane H, Bras J, Duncan L, Escott-Price V et al. Analysis of shared heritability in common disorders of the brain. BioRXiv 2016; 10.1101/048991. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  64. [78]Smoller JW. The use of electronic health records for psychiatric phenotyping and genomics. Am J Med Genet B Neuropsychiatr Genet 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. [79]Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med 2015; 12(3): e1001779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. [80]Precision Medicine Initiative (PMI) Working Group. The Precision Medicine Initiative Cohort Program – Building a Research Foundation for 21st Century Medicine2015 September 17, 2015. [Google Scholar]
  67. [81]Bush WS, Oetjens MT, Crawford DC. Unravelling the human genome-phenome relationship using phenome-wide association studies. Nat Rev Genet 2016; 17(3): 129–145. [DOI] [PubMed] [Google Scholar]
  68. [82]Riglin L, Collishaw S, Thapar AK, Dalsgaard S, Langley K, Smith GD et al. Association of Genetic Risk Variants With Attention-Deficit/Hyperactivity Disorder Trajectories in the General Population. JAMA Psychiatry 2016; 73(12): 1285–1292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. [83]Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 2013; 154(3): 518–529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. [84]Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 2013; 155(5): 997–1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. [85]Niarchou M, Zammit S, Lewis G. The Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort as a resource for studying psychopathology in childhood and adolescence: a summary of findings for depression and psychosis. Soc Psychiatry Psychiatr Epidemiol 2015; 50(7): 1017–1027. [DOI] [PubMed] [Google Scholar]
  72. [86]Mors O, Perto GP, Mortensen PB. The Danish Psychiatric Central Research Register. Scand J Public Health 2011; 39(7 Suppl): 54–57. [DOI] [PubMed] [Google Scholar]
  73. [87]Lee PH, Baker JT, Holmes AJ, Jahanshad N, Ge T, Jung JY et al. Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia. Mol Psychiatry 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. [88]Bearden CE, Thompson PM. Emerging Global Initiatives in Neurogenetics: The Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) Consortium. Neuron 2017; 94(2): 232–236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. [89]Cuthbert BN. Research Domain Criteria: toward future psychiatric nosologies. Dialogues Clin Neurosci 2015; 17(1): 89–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. [90]Evans DM, Davey Smith G. Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality. Annu Rev Genomics Hum Genet 2015; 16: 327–350. [DOI] [PubMed] [Google Scholar]
  77. [92]Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380(9841): 572–580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. [93]Vaucher J, Keating BJ, Lasserre AM, Gan W, Lyall DM, Ward J et al. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol Psychiatry 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. [94]Pickrell JK, Berisa T, Liu JZ, Segurel L, Tung JY, Hinds DA. Detection and interpretation of shared genetic influences on 42 human traits. Nat Genet 2016; 48(7): 709–717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. [95]Schaefer GB, Mendelsohn NJ, Professional P, Guidelines C. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med 2013; 15(5): 399–407. [DOI] [PubMed] [Google Scholar]
  81. [97]Robinson EB, Samocha KE, Kosmicki JA, McGrath L, Neale BM, Perlis RH et al. Autism spectrum disorder severity reflects the average contribution of de novo and familial influences. Proc Natl Acad Sci U S A 2014; 111(42): 15161–15165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. [98]Zhu X, Need AC, Petrovski S, Goldstein DB. One gene, many neuropsychiatric disorders: lessons from Mendelian diseases. Nat Neurosci 2014; 17(6): 773–781. [DOI] [PubMed] [Google Scholar]
  83. [99]Davis LK, Yu D, Keenan CL, Gamazon ER, Konkashbaev AI, Derks EM et al. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet 2013; 9(10): e1003864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. [102]Song J, Bergen SE, Kuja-Halkola R, Larsson H, Landen M, Lichtenstein P. Bipolar disorder and its relation to major psychiatric disorders: a family-based study in the Swedish population. Bipolar Disord 2015; 17(2): 184–193. [DOI] [PubMed] [Google Scholar]
  85. [103]Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry 2002; 159(4): 539–545. [DOI] [PubMed] [Google Scholar]
  86. [104]McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003; 60(5): 497–502. [DOI] [PubMed] [Google Scholar]
  87. [105]Bulik CM, Thornton LM, Root TL, Pisetsky EM, Lichtenstein P, Pedersen NL. Understanding the relation between anorexia nervosa and bulimia nervosa in a Swedish national twin sample. Biological psychiatry 2010; 67(1): 71–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. [106]Mathews CA, Grados MA. Familiality of Tourette syndrome, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder: heritability analysis in a large sib-pair sample. Journal of the American Academy of Child and Adolescent Psychiatry 2011; 50(1): 46–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. [107]Cederlof M, Thornton LM, Baker J, Lichtenstein P, Larsson H, Ruck C et al. Etiological overlap between obsessive-compulsive disorder and anorexia nervosa: a longitudinal cohort, multigenerational family and twin study. World Psychiatry 2015; 14(3): 333–338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. [108]Tick B, Bolton P, Happe F, Rutter M, Rijsdijk F. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J Child Psychol Psychiatry 2016; 57(5): 585–595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. [109]Stein MB, Jang KL, Taylor S, Vernon PA, Livesley WJ. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry 2002; 159(10): 1675–1681. [DOI] [PubMed] [Google Scholar]

Authors
Smoller, J. W., Andreassen, O. A., Edenberg, H. J., Faraone, S. V., Glatt, S. J., & Kendler, K. S.
Affiliations
  • Broad Institute (US)
  • Oslo University Hospital (NO)
  • Indiana University School of Medicine (US)
  • SUNY Upstate Medical University (US)
  • Virginia Commonwealth University (US)
Corresponding author
Smoller, Jordan W.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-01-09
Volume
24
Issue
3
Pages
409-420
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-017-0010-4
PMC
PMC6684352
OpenAlex
W2782859134
Cited by
398
References
111
Citations by year
2026: 25 · 2025: 35 · 2024: 57 · 2023: 53 · 2022: 62 · 2021: 54 · 2020: 55 · 2019: 44 · 2018: 12
FWCI
5.77
Type
journal article
Language
en
Update notices
correction (2018-03-14)
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Author eBooks
Funders
National Institute of Mental Health (U01MH109536, K24MH094614)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Mental Health Research Topics
Keywords
psychiatric genetics, psychopathology classification, disease classification, Psychiatric Genomics Consortium, genetic risk variants, neuropsychiatric disorders
MeSH terms
Mental Disorders, Humans, Psychiatry, Psychopathology, Genomics, Diagnostic and Statistical Manual of Mental Disorders, History, 19th Century, History, 20th Century, History, 21st Century, Neurodevelopmental Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review