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The contribution of copy number variants to psychiatric symptoms and cognitive ability

Molecular Psychiatry volume 28, pages 1480–1493 (2023)Cite this article

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Abstract

Copy number variants (CNVs) are deletions and duplications of DNA sequence. The most frequently studied CNVs, which are described in this review, are recurrent CNVs that occur in the same locations on the genome. These CNVs have been strongly implicated in neurodevelopmental disorders, namely autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay (DD), but also in schizophrenia. More recent work has also shown that CNVs increase risk for other psychiatric disorders, namely, depression, bipolar disorder, and post-traumatic stress disorder. Many of the same CNVs are implicated across all of these disorders, and these neuropsychiatric CNVs are also associated with cognitive ability in the general population, as well as with structural and functional brain alterations. Neuropsychiatric CNVs also show incomplete penetrance, such that carriers do not always develop any psychiatric disorder, and may show only mild symptoms, if any. Variable expressivity, whereby the same CNVs are associated with many different phenotypes of varied severity, also points to highly complex mechanisms underlying disease risk in CNV carriers. Comprehensive and longitudinal phenotyping studies of individual CNVs have provided initial insights into these mechanisms. However, more work is needed to estimate and predict the effect of non-recurrent, ultra-rare CNVs, which also contribute to psychiatric and cognitive outcomes. Moreover, delineating the broader phenotypic landscape of neuropsychiatric CNVs in both clinical and general population cohorts may also offer important mechanistic insights.

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Fig. 1: Types of copy number variants (CNVs).
Fig. 2: Summary of known associations between CNVs and psychiatric phenotypes.
Fig. 3: Prevalence and effect size estimates for select CNVs.
Fig. 4: Detectable mean trait difference by number of CNV carriers.

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References

  1. Kirov G. CNVs in neuropsychiatric disorders. Hum Mol Genet. 2015;24:R45–49.

    Article  CAS  PubMed  Google Scholar 

  2. Kirov G, Rees E, Walters J. What a psychiatrist needs to know about copy number variants. BJPsych Adv. 2018;21:157–63.

    Article  Google Scholar 

  3. Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148:1223–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sonderby IE, Ching CRK, Thomopoulos SI, van der Meer D, Sun D, Villalon-Reina JE, et al. Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs. Hum Brain Mapp. 2022;43:300–28.

    Article  PubMed  Google Scholar 

  5. Zhang F, Gu W, Hurles ME, Lupski JR. Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009;10:451–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Alkan C, Coe BP, Eichler EE. Genome structural variation discovery and genotyping. Nat Rev Genet. 2011;12:363–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009;10:551–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wilfert AB, Sulovari A, Turner TN, Coe BP, Eichler EE. Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Med. 2017;9:1–16.

    Article  Google Scholar 

  9. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55.

    Article  CAS  PubMed  Google Scholar 

  10. Smajlagic D, Lavrichenko K, Berland S, Helgeland O, Knudsen GP, Vaudel M, et al. Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents. Eur J Hum Genet. 2021;29:205–15.

    Article  CAS  PubMed  Google Scholar 

  11. Gillentine MA, Lupo PJ, Stankiewicz P, Schaaf CP. An estimation of the prevalence of genomic disorders using chromosomal microarray data. J Hum Genet. 2018;63:795–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease–common variant… or not? Hum Mol Genet. 2002;11:2417–23.

    Article  CAS  PubMed  Google Scholar 

  13. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003;33:177–82.

    Article  CAS  PubMed  Google Scholar 

  14. Graham DSC, Vyse TJ. The common disease common variant concept. Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics. John Wiley & Sons, Ltd.; 2004.

  15. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11:415–25.

    Article  CAS  PubMed  Google Scholar 

  16. Schork NJ, Murray SS, Frazer KA, Topol EJ. Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev. 2009;19:212–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bomba L, Walter K, Soranzo N. The impact of rare and low-frequency genetic variants in common disease. Genome Biol. 2017;18:1–17.

    Article  Google Scholar 

  18. Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008;40:695–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang Q, Dhindsa RS, Carss K, Harper AR, Nag A, Tachmazidou I, et al. Rare variant contribution to human disease in 281,104 UK Biobank exomes. Nature. 2021;597:527–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Association AP. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub, 2013.

  21. Hollocks MJ, Lerh JW, Magiati I, Meiser-Stedman R, Brugha TS. Anxiety and depression in adults with autism spectrum disorder: a systematic review and meta-analysis. Psychol Med. 2019;49:559–72.

    Article  PubMed  Google Scholar 

  22. Stahlberg O, Soderstrom H, Rastam M, Gillberg C. Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders. J Neural Transm. 2004;111:891–902.

    Article  CAS  PubMed  Google Scholar 

  23. Kincaid DL, Doris M, Shannon C, Mulholland C. What is the prevalence of autism spectrum disorder and ASD traits in psychosis? A systematic review. Psychiatry Res. 2017;250:99–105.

    Article  PubMed  Google Scholar 

  24. Jensen CM, Steinhausen H-C. Comorbid mental disorders in children and adolescents with attention-deficit/hyperactivity disorder in a large nationwide study. ADHD Atten Deficit Hyperactivity Disord. 2015;7:27–38.

    Article  Google Scholar 

  25. Reale L, Bartoli B, Cartabia M, Zanetti M, Costantino MA, Canevini MP, et al. Comorbidity prevalence and treatment outcome in children and adolescents with ADHD. Eur child Adolesc psychiatry. 2017;26:1443–57.

    Article  PubMed  Google Scholar 

  26. Antshel KM, Russo N. Autism spectrum disorders and ADHD: overlapping phenomenology, diagnostic issues, and treatment considerations. Curr Psychiatry Rep. 2019;21:34.

    Article  PubMed  Google Scholar 

  27. Antshel KM, Zhang-James Y, Wagner KE, Ledesma A, Faraone SV. An update on the comorbidity of ADHD and ASD: a focus on clinical management. Expert Rev Neurother. 2016;16:279–93.

    Article  CAS  PubMed  Google Scholar 

  28. Stevens T, Peng L, Barnard-Brak L. The comorbidity of ADHD in children diagnosed with autism spectrum disorder. Res Autism Spectr Disord. 2016;31:11–8.

    Article  Google Scholar 

  29. Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P. et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014;46:1063–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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;57:585–95.

    Article  PubMed  Google Scholar 

  31. Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A. The heritability of autism spectrum disorder. Jama. 2017;318:1182–4.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Reichenberg A, Cederlöf M, McMillan A, Trzaskowski M, Kapra O, Fruchter E, et al. Discontinuity in the genetic and environmental causes of the intellectual disability spectrum. Proc Natl Acad Sci. 2016;113:1098–103.

    Article  CAS  PubMed  Google Scholar 

  33. Lichtenstein P, Tideman M, Sullivan PF, Serlachius E, Larsson H, Kuja‐Halkola R, et al. Familial risk and heritability of intellectual disability: a population‐based cohort study in Sweden. J Child Psychol Psychiatry. 2022;63:1092–102.

  34. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24:562–75.

    Article  CAS  PubMed  Google Scholar 

  35. Grimm O, Kranz TM, Reif A. Genetics of ADHD: what should the clinician know? Curr Psychiatry Rep. 2020;22:1–8.

    Article  Google Scholar 

  36. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51:431–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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;48:552–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019;51:63–75.

    Article  CAS  PubMed  Google Scholar 

  39. Rees E, Kirov G. Copy number variation and neuropsychiatric illness. Curr Opin Genet Dev. 2021;68:57–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Iakoucheva LM, Muotri AR, Sebat J. Getting to the cores of Autism. Cell. 2019;178:1287–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dinneen TJ, Ghralaigh FN, Walsh R, Lopez LM, Gallagher L. How does genetic variation modify ND-CNV phenotypes? Trends Genet. 2022;38:140–51.

    Article  CAS  PubMed  Google Scholar 

  42. Alinejad-Rokny H, Heng JIT, Forrest ARR. Brain-enriched coding and long non-coding RNA genes are overrepresented in recurrent neurodevelopmental disorder CNVs. Cell Rep. 2020;33:108307.

    Article  CAS  PubMed  Google Scholar 

  43. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43:838–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22:245–57.

    Article  PubMed  Google Scholar 

  46. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13:680–5.

    Article  PubMed  Google Scholar 

  47. Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, et al. Insights into Autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015;87:1215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gudmundsson OO, Walters GB, Ingason A, Johansson S, Zayats T, Athanasiu L, et al. Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder. Transl Psychiatry. 2019;9:258.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Myers SM, Challman TD, Bernier R, Bourgeron T, Chung WK, Constantino JN, et al. Insufficient Evidence for “Autism-Specific” Genes. Am J Hum Genet. 2020;106:587–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wu Y, Cao H, Baranova A, Huang H, Li S, Cai L, et al. Multi-trait analysis for genome-wide association study of five psychiatric disorders. Transl Psychiatry. 2020;10:209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ghirardi L, Pettersson E, Taylor MJ, Freitag CM, Franke B, Asherson P, et al. Genetic and environmental contribution to the overlap between ADHD and ASD trait dimensions in young adults: a twin study. Psychol Med. 2019;49:1713–21.

    Article  PubMed  Google Scholar 

  52. Verhoef E, Grove J, Shapland CY, Demontis D, Burgess S, Rai D, et al. Shared polygenetic variation between ASD and ADHD exerts opposite association patterns with educational attainment. bioRxiv. 2019:580365.

  53. Yoon J, Mao Y. Dissecting molecular genetic mechanisms of 1q21.1 CNV in neuropsychiatric disorders. Int J Mol Sci. 2021;22:5811.

  54. Osborne LR, Mervis CB. 7q11.23 deletion and duplication. Curr Opin Genet Dev. 2021;68:41–8.

    Article  CAS  PubMed  Google Scholar 

  55. Rein B, Yan Z. 16p11.2 copy number variations and neurodevelopmental disorders. Trends Neurosci. 2020;43:886–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, et al. Recurrent reciprocal 1q21. 1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008;40:1466–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Morris CA, Mervis CB, Paciorkowski AP, Abdul-Rahman O, Dugan SL, Rope AF, et al. 7q11.23 Duplication syndrome: Physical characteristics and natural history. Am J Med Genet A. 2015;167A:2916–35.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Shinawi M, Liu P, Kang S-HL, Shen J, Belmont JW, Scott DA, et al. Recurrent reciprocal 16p11. 2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet. 2010;47:332–41.

    Article  CAS  PubMed  Google Scholar 

  59. Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, et al. A recurrent 16p12. 1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet. 2010;42:203–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pizzo L, Jensen M, Polyak A, Rosenfeld JA, Mannik K, Krishnan A, et al. Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants. Genet Med. 2019;21:816–25.

    Article  CAS  PubMed  Google Scholar 

  61. He X, Sanders SJ, Liu L, De Rubeis S, Lim ET, Sutcliffe JS, et al. Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Genet. 2013;9:e1003671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, Rubeis SD, An JY, et al. Novel genes for autism implicate both excitatory and inhibitory cell lineages in risk. BioRxiv 2018:484113.

  63. Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Br Med J (Clin Res ed). 1987;295:681.

    Article  CAS  PubMed  Google Scholar 

  64. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–9.

    Article  CAS  PubMed  Google Scholar 

  65. Rapoport J, Giedd J, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry. 2012;17:1228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rapoport JL, Addington AM, Frangou S, Psych M. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 2005;10:434–49.

    Article  CAS  PubMed  Google Scholar 

  67. Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, et al. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish twin register. Biol Psychiatry. 2018;83:492–8.

    Article  PubMed  Google Scholar 

  68. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:1187–92.

    Article  PubMed  Google Scholar 

  69. Cannon TD, Kaprio J, Lönnqvist J, Huttunen M, Koskenvuo M. The genetic epidemiology of schizophrenia in a Finnish twin cohort: a population-based modeling study. Arch Gen Psychiatry. 1998;55:67–74.

    Article  CAS  PubMed  Google Scholar 

  70. Ripke S, Neale BM, Corvin A, Walters JT, Farh K-H, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421.

    Article  CAS  PubMed Central  Google Scholar 

  71. Ripke S, O’dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Glahn DC, Almasy L, Blangero J, Burk GM, Estrada J, Peralta JM, et al. Adjudicating neurocognitive endophenotypes for schizophrenia. Am J Med Genet Part B: Neuropsychiatr Genet. 2007;144:242–9.

    Article  Google Scholar 

  73. Reichenberg A, Harvey PD. Neuropsychological impairments in schizophrenia: Integration of performance-based and brain imaging findings. Psychol Bull. 2007;133:833–58.

    Article  PubMed  Google Scholar 

  74. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12:426.

    Article  CAS  PubMed  Google Scholar 

  75. WHO J. International classification of diseases, 11th revision (ICD-11). Who Geneva, 2018.

  76. International Schizophrenia C. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455:237–41.

    Article  Google Scholar 

  77. McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67–76.

    Article  PubMed  Google Scholar 

  78. Strålin P, Hetta J. First episode psychosis and comorbid ADHD, autism and intellectual disability. Eur Psychiatry. 2019;55:18–22.

    Article  PubMed  Google Scholar 

  79. De Giorgi R, De Crescenzo F, D’Alò GL, Rizzo Pesci N, Di Franco V, Sandini C, et al. Prevalence of non-affective psychoses in individuals with autism spectrum disorders: a systematic review. J Clin Med. 2019;8:1304.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Byrne EM, Zhu Z, Qi T, Skene NG, Bryois J, Pardinas AF, et al. Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders. Mol Psychiatry. 2021;26:2070–81.

    Article  CAS  PubMed  Google Scholar 

  81. Solberg BS, Zayats T, Posserud MB, Halmoy A, Engeland A, Haavik J, et al. Patterns of psychiatric comorbidity and genetic correlations provide new insights into differences between attention-deficit/hyperactivity disorder and Autism spectrum disorder. Biol Psychiatry. 2019;86:587–98.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Cross-Disorder Group of the Psychiatric Genomics Consortium. Electronic address pmhe, cross-disorder group of the psychiatric genomics C. genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell. 2019;179:1469–82.e1411.

    Article  PubMed Central  Google Scholar 

  83. Reay WR, Cairns MJ. Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations. Transl Psychiatry. 2020;10:134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, et al. A population-based study of the 22q11. 2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 2003;112:101–7.

    Article  PubMed  Google Scholar 

  85. Wapner RJ, Babiarz JE, Levy B, Stosic M, Zimmermann B, Sigurjonsson S, et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol. 2015;212:332–e1.

  86. Grati FR, Molina Gomes D, Ferreira JCPB, Dupont C, Alesi V, Gouas L, et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn. 2015;35:801–9.

    Article  PubMed  Google Scholar 

  87. Schneider M, Debbané M, Bassett AS, Chow EW, Fung WLA, Van Den Bree MB, et al. Psychiatric disorders from childhood to adulthood in 22q11. 2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11. 2 Deletion Syndrome. Am J Psychiatry. 2014;171:627–39.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Zinkstok JR, Boot E, Bassett AS, Hiroi N, Butcher NJ, Vingerhoets C, et al. Neurobiological perspective of 22q11.2 deletion syndrome. Lancet Psychiatry. 2019;6:951–60.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Fiksinski AM, Schneider M, Murphy CM, Armando M, Vicari S, Canyelles JM, et al. Understanding the pediatric psychiatric phenotype of 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176:2182–91.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Morrow BE, McDonald-McGinn DM, Emanuel BS, Vermeesch JR, Scambler PJ. Molecular genetics of 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176:2070–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gonzalez-Castro TB, Hernandez-Diaz Y, Juarez-Rojop IE, Lopez-Narvaez ML, Tovilla-Zarate CA, Fresan A. The Role of a Catechol-O-Methyltransferase (COMT) Val158Met genetic polymorphism in schizophrenia: a systematic review and updated meta-analysis on 32,816 Subjects. Neuromol Med. 2016;18:216–31.

    Article  CAS  Google Scholar 

  92. Guo X, Tang P, Yang C, Li R. Proline dehydrogenase gene (PRODH) polymorphisms and schizophrenia susceptibility: a meta-analysis. Metab Brain Dis. 2018;33:89–97.

    Article  CAS  PubMed  Google Scholar 

  93. Bassett AS, Lowther C, Merico D, Costain G, Chow EWC, van Amelsvoort T, et al. Rare genome-wide copy number variation and expression of Schizophrenia in 22q11.2 deletion syndrome. Am J Psychiatry. 2017;174:1054–63.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Cleynen I, Engchuan W, Hestand MS, Heung T, Holleman AM, Johnston HR, et al. Genetic contributors to risk of schizophrenia in the presence of a 22q11. 2 deletion. Mol Psychiatry. 2021;26:4496–510.

    Article  CAS  PubMed  Google Scholar 

  95. Davies RW, Fiksinski AM, Breetvelt EJ, Williams NM, Hooper SR, Monfeuga T, et al. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11. 2 deletion syndrome. Nat Med. 2020;26:1912–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vorstman JA, Breetvelt EJ, Duijff SN, Eliez S, Schneider M, Jalbrzikowski M, et al. Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. JAMA Psychiatry. 2015;72:377–85.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ramanathan S, Mattiaccio LM, Coman IL, Botti J-AC, Fremont W, Faraone SV, et al. Longitudinal trajectories of cortical thickness as a biomarker for psychosis in individuals with 22q11. 2 deletion syndrome. Schizophrenia Res. 2017;188:35–41.

    Article  Google Scholar 

  98. Rees E, Walters JT, Georgieva L, Isles AR, Chambert KD, Richards AL, et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry. 2014;204:108–14.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Rees E, Walters JT, Chambert KD, O’Dushlaine C, Szatkiewicz J, Richards AL, et al. CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1. Hum Mol Genet. 2014;23:1669–76.

    Article  CAS  PubMed  Google Scholar 

  100. Szatkiewicz JP, O’Dushlaine C, Chen G, Chambert K, Moran JL, Neale BM, et al. Copy number variation in schizophrenia in Sweden. Mol Psychiatry. 2014;19:762–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wu X, Huai C, Shen L, Li M, Yang C, Zhang J, et al. Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios. iScience. 2021;24:102894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kendall KM, Rees E, Bracher-Smith M, Legge S, Riglin L, Zammit S, et al. Association of rare copy number variants with risk of depression. JAMA Psychiatry. 2019;76:818–25.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Green EK, Rees E, Walters JT, Smith KG, Forty L, Grozeva D, et al. Copy number variation in bipolar disorder. Mol Psychiatry. 2016;21:89–93.

    Article  CAS  PubMed  Google Scholar 

  104. McGrath LM, Yu D, Marshall C, Davis LK, Thiruvahindrapuram B, Li B, et al. Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study. J Am Acad Child Adolesc Psychiatry. 2014;53:910–9.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Cuccaro D, De Marco EV, Cittadella R, Cavallaro S. Copy number variants in Alzheimer’s disease. J Alzheimers Dis. 2017;55:37–52.

    Article  CAS  PubMed  Google Scholar 

  106. Maihofer AX, Engchuan W, Huguet G, Klein M, MacDonald JR, Shanta O, et al. Rare copy number variation in posttraumatic stress disorder. Mol Psychiatry. 2022;27:5062–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chapman J, Rees E, Harold D, Ivanov D, Gerrish A, Sims R, et al. A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer’s disease risk. Hum Mol Genet. 2013;22:816–24.

    Article  CAS  PubMed  Google Scholar 

  108. Nievergelt CM, Maihofer AX, Mustapic M, Yurgil KA, Schork NJ, Miller MW, et al. Genomic predictors of combat stress vulnerability and resilience in US Marines: a genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene. Psychoneuroendocrinology. 2015;51:459–71.

    Article  CAS  PubMed  Google Scholar 

  109. Charney AW, Stahl EA, Green EK, Chen CY, Moran JL, Chambert K, et al. Contribution of rare copy number variants to bipolar disorder risk is limited to Schizoaffective Cases. Biol Psychiatry. 2019;86:110–9.

    Article  CAS  PubMed  Google Scholar 

  110. Priebe L, Degenhardt FA, Herms S, Haenisch B, Mattheisen M, Nieratschker V, et al. Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Mol Psychiatry. 2012;17:421–32.

    Article  CAS  PubMed  Google Scholar 

  111. O’Dushlaine C, Ripke S, Ruderfer DM, Hamilton SP, Fava M, Iosifescu DV, et al. Rare copy number variation in treatment-resistant major depressive disorder. Biol psychiatry. 2014;76:536–41.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Auwerx C, Lepamets M, Sadler MC, Patxot M, Stojanov M, Baud D, et al. The individual and global impact of copy-number variants on complex human traits. Am J Hum Genet. 2022;109:647–68.

  113. Eysenck H. Dimensions of personality. Routledge 2018.

  114. Spitzer R, Sheehy M.DSM III: A classification Syst Dev. 1976;6:102–9.SLACK Incorporated Thorofare, NJ..

  115. Bayer R, Spitzer RLNeurosis. psychodynamics, and DSM-III: A history of the controversy. Arch Gen Psychiatry. 1985;42:187–96.

    Article  CAS  PubMed  Google Scholar 

  116. Goldstein WN, Anthony RN. The diagnosis of depression and the DSM s. Am J Psychother. 1988;42:180–96.

    Article  CAS  PubMed  Google Scholar 

  117. Barlow DH, Sauer-Zavala S, Carl JR, Bullis JR, Ellard KK. The nature, diagnosis, and treatment of neuroticism. Clin Psychol Sci. 2013;2:344–65.

    Article  Google Scholar 

  118. Griffith JW, Zinbarg RE, Craske MG, Mineka S, Rose RD, Waters AM, et al. Neuroticism as a common dimension in the internalizing disorders. Psychol Med. 2010;40:1125–36.

    Article  CAS  PubMed  Google Scholar 

  119. Van OsJ, Jones PB. Neuroticism as a risk factor for schizophrenia. Psychol Med. 2001;31:1129–34.

    Article  Google Scholar 

  120. Brandes CM, Herzhoff K, Smack AJ, Tackett JL. The p factor and the n factor: Associations between the general factors of psychopathology and neuroticism in children. Clin Psychol Sci. 2019;7:1266–84.

    Article  Google Scholar 

  121. Ormel J, Rosmalen J, Farmer A. Neuroticism: a non-informative marker of vulnerability to psychopathology. Soc Psychiatry Psychiatr Epidemiol. 2004;39:906–12.

    Article  PubMed  Google Scholar 

  122. Lee PH, Feng YA, Smoller JW. Pleiotropy and cross-disorder genetics among psychiatric disorders. Biol Psychiatry. 2021;89:20–31.

    Article  CAS  PubMed  Google Scholar 

  123. Roelfs D, Alnaes D, Frei O, van der Meer D, Smeland OB, Andreassen OA, et al. Phenotypically independent profiles relevant to mental health are genetically correlated. Transl Psychiatry. 2021;11:202.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Taylor MJ, Martin J, Lu Y, Brikell I, Lundstrom S, Larsson H, et al. Association of genetic risk factors for psychiatric disorders and traits of these disorders in a Swedish Population Twin Sample. JAMA Psychiatry. 2019;76:280–9.

    Article  PubMed  Google Scholar 

  125. Caspi A, Houts RM, Belsky DW, Goldman-Mellor SJ, Harrington H, Israel S, et al. The p factor: one general psychopathology factor in the structure of psychiatric disorders? Clin Psychol Sci. 2014;2:119–37.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Castellanos-Ryan N, Brière FN, O’Leary-Barrett M, Banaschewski T, Bokde A, Bromberg U, et al. The structure of psychopathology in adolescence and its common personality and cognitive correlates. J Abnorm Psychol. 2016;125:1039.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Laceulle OM, Vollebergh WA, Ormel J. The structure of psychopathology in adolescence: Replication of a general psychopathology factor in the TRAILS study. Clin Psychol Sci. 2015;3:850–60.

    Article  Google Scholar 

  128. Selzam S, Coleman JRI, Caspi A, Moffitt TE, Plomin R. A polygenic p factor for major psychiatric disorders. Transl Psychiatry. 2018;8:205.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Conway CC, Forbes MK, Forbush KT, Fried EI, Hallquist MN, Kotov R, et al. A hierarchical taxonomy of psychopathology can transform mental health research. Perspect Psychol Sci. 2019;14:419–36.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Allegrini AG, Cheesman R, Rimfeld K, Selzam S, Pingault JB, Eley TC, et al. The p factor: genetic analyses support a general dimension of psychopathology in childhood and adolescence. J Child Psychol Psychiatry. 2020;61:30–9.

    Article  PubMed  Google Scholar 

  131. Douard E, Zeribi A, Schramm C, Tamer P, Loum MA, Nowak S, et al. Effect sizes of deletions and duplications on Autism risk across the genome. Am J Psychiatry. 2021;178:87–98.

    Article  PubMed  Google Scholar 

  132. Bishop SL, Farmer C, Bal V, Robinson EB, Willsey AJ, Werling DM, et al. Identification of developmental and behavioral markers associated with genetic abnormalities in autism spectrum disorder. Am J psychiatry. 2017;174:576–85.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Chawner S, Owen MJ, Holmans P, Raymond FL, Skuse D, Hall J, et al. Genotype-phenotype associations in children with copy number variants associated with high neuropsychiatric risk in the UK (IMAGINE-ID): a case-control cohort study. Lancet Psychiatry. 2019;6:493–505.

    Article  PubMed  Google Scholar 

  134. Cunningham AC, Hall J, Einfeld S, Owen MJ, consortium I-I, van den Bree MBM. Assessment of emotions and behaviour by the Developmental Behaviour Checklist in young people with neurodevelopmental CNVs. Psychol Med. 2022;52:574–86.

    Article  PubMed  Google Scholar 

  135. Cunningham AC, Hall J, Owen MJ, van den Bree MBM. Coordination difficulties, IQ and psychopathology in children with high-risk copy number variants. Psychol Med. 2021;51:290–9.

    Article  PubMed  Google Scholar 

  136. Moberg PJ, Richman MJ, Roalf DR, Morse CL, Graefe AC, Brennan L, et al. Neurocognitive functioning in patients with 22q11.2 deletion syndrome: a meta-analytic review. Behav Genet. 2018;48:259–70.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Lin A, Vajdi A, Kushan-Wells L, Helleman G, Hansen LP, Jonas RK, et al. Reciprocal copy number variations at 22q11.2 produce distinct and convergent neurobehavioral impairments relevant for Schizophrenia and Autism Spectrum Disorder. Biol Psychiatry. 2020;88:260–72.

    Article  PubMed  PubMed Central  Google Scholar 

  138. D’Angelo D, Lebon S, Chen Q, Martin-Brevet S, Snyder LG, Hippolyte L, et al. Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMAPsychiatry. 2016;73:20–30.

    Google Scholar 

  139. Jutla A, Turner JB, Green Snyder L, Chung WK, Veenstra-VanderWeele J. Psychotic symptoms in 16p11.2 copy-number variant carriers. Autism Res. 2020;13:187–98.

    Article  PubMed  Google Scholar 

  140. Chawner S, Doherty JL, Anney RJL, Antshel KM, Bearden CE, Bernier R, et al. A genetics-first approach to dissecting the heterogeneity of autism: phenotypic comparison of autism risk copy number variants. Am J psychiatry. 2021;178:77–86.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Jacquemont S, Huguet G, Klein M, Chawner S, Donald KA, van den Bree MBM, et al. Genes to mental health (G2MH): a framework to map the combined effects of rare and common variants on dimensions of cognition and psychopathology. Am J psychiatry. 2022;179:189–203.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Maenner MJ, Shaw KA, Bakian AV, Bilder DA, Durkin MS, Esler A, et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2018. MMWR Surveill Summaries. 2021;70:1.

    Article  Google Scholar 

  143. Kahn RS, Keefe RS. Schizophrenia is a cognitive illness: time for a change in focus. JAMA Psychiatry. 2013;70:1107–12.

    Article  PubMed  Google Scholar 

  144. Green MF, Harvey PD. Cognition in schizophrenia: Past, present, and future. Schizophrenia Res: Cognition. 2014;1:e1–e9.

    Google Scholar 

  145. Frangou S. Cognitive function in early onset schizophrenia: a selective review. Front Hum Neurosci. 2010;3:79.

    PubMed  PubMed Central  Google Scholar 

  146. Kravariti E, Morris RG, Rabe-Hesketh S, Murray RM, Frangou S. The Maudsley early onset schizophrenia study: cognitive function in adolescents with recent onset schizophrenia. Schizophrenia Res. 2003;61:137–48.

    Article  Google Scholar 

  147. Kumra S, Wiggs E, Bedwell J, Smith AK, Arling E, Albus K, et al. Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified. Schizophrenia Res. 2000;42:135–44.

    Article  CAS  Google Scholar 

  148. Mesholam-Gately RI, Giuliano AJ, Goff KP, Faraone SV, Seidman LJ. Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology. 2009;23:315.

    Article  PubMed  Google Scholar 

  149. Mollon J, David AS, Zammit S, Lewis G, Reichenberg A. Course of cognitive development from infancy to early adulthood in the psychosis spectrum. JAMA psychiatry. 2018;75:270–9.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Mollon J, Reichenberg A. Cognitive development prior to onset of psychosis. Psychol Med. 2018;48:392–403.

    Article  CAS  PubMed  Google Scholar 

  151. Zanelli J, Mollon J, Sandin S, Morgan C, Dazzan P, Pilecka I, et al. Cognitive change in Schizophrenia and other psychoses in the decade following the first episode. Am J Psychiatry. 2019;176:811–9.

    Article  PubMed  Google Scholar 

  152. Zanelli J, Reichenberg A, Sandin S, Morgan C, Dazzan P, Pilecka I, et al. Dynamic and Static Cognitive Deficits in Schizophrenia and Bipolar Disorder After the First Episode. Schizophr Bull. 2022;48:590–8.

  153. Van Rheenen TE, Lewandowski KE, Bauer IE, Kapczinski F, Miskowiak K, Burdick KE, et al. Current understandings of the trajectory and emerging correlates of cognitive impairment in bipolar disorder: An overview of evidence. Bipolar Disord. 2020;22:13–27.

    Article  PubMed  Google Scholar 

  154. Perini G, Cotta Ramusino M, Sinforiani E, Bernini S, Petrachi R, Costa A. Cognitive impairment in depression: recent advances and novel treatments. Neuropsychiatr Dis Treat. 2019;15:1249–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kendall KM, Bracher-Smith M, Fitzpatrick H, Lynham A, Rees E, Escott-Price V, et al. Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank. Br J Psychiatry. 2019;214:297–304.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Kendall KM, Rees E, Escott-Price V, Einon M, Thomas R, Hewitt J, et al. Cognitive performance among carriers of pathogenic copy number variants: analysis of 152,000 UK biobank subjects. Biol Psychiatry. 2017;82:103–10.

    Article  PubMed  Google Scholar 

  157. Mannik K, Magi R, Mace A, Cole B, Guyatt AL, Shihab HA, et al. Copy number variations and cognitive phenotypes in unselected populations. JAMA. 2015;313:2044–54.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014;505:361–6.

    Article  CAS  PubMed  Google Scholar 

  159. Yeo RA, Gangestad SW, Liu J, Ehrlich S, Thoma RJ, Pommy J, et al. The impact of copy number deletions on general cognitive ability and ventricle size in patients with schizophrenia and healthy control subjects. Biol psychiatry. 2013;73:540–5.

    Article  CAS  PubMed  Google Scholar 

  160. Martin AK, Robinson G, Reutens D, Mowry B. Copy number deletion burden is associated with cognitive, structural, and resting-state network differences in patients with schizophrenia. Behav Brain Res. 2014;272:324–34.

    Article  CAS  PubMed  Google Scholar 

  161. Huguet G, Schramm C, Douard E, Jiang L, Labbe A, Tihy F, et al. Measuring and estimating the effect sizes of copy number variants on general intelligence in community-based samples. JAMA Psychiatry. 2018;75:447–57.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Guyatt AL, Stergiakouli E, Martin J, Walters J, O’Donovan M, Owen M, et al. Association of copy number variation across the genome with neuropsychiatric traits in the general population. Am J Med Genet Part B: Neuropsychiatr Genet. 2018;177:489–502.

    Article  Google Scholar 

  163. Yeo RA, Gangestad SW, Gasparovic C, Liu J, Calhoun VD, Thoma RJ, et al. Rare copy number deletions predict individual variation in human brain metabolite concentrations in individuals with alcohol use disorders. Biol Psychiatry. 2011;70:537–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kirkpatrick RM, McGue M, Iacono WG, Miller MB, Basu S, Pankratz N. Low-frequency copy-number variants and general cognitive ability: No evidence of association. Intelligence. 2014;42:98–106.

    Article  PubMed  Google Scholar 

  165. McRae AF, Wright MJ, Hansell NK, Montgomery GW, Martin NG. No association between general cognitive ability and rare copy number variation. Behav Genet. 2013;43:202–7.

    Article  PubMed  Google Scholar 

  166. Van Scheltinga AT, Bakker S, Van Haren N, Derks E, Buizer-Voskamp J, Cahn W, et al. Schizophrenia genetic variants are not associated with intelligence. Psychol Med. 2013;43:2563–70.

    Article  PubMed  Google Scholar 

  167. Thygesen JH, Presman A, Harju-Seppanen J, Irizar H, Jones R, Kuchenbaecker K, et al. Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study. Mol Psychiatry. 2021;26:5307–19.

    Article  PubMed  Google Scholar 

  168. Huguet G, Schramm C, Douard E, Petra T, Main A, Monin P et al. 2020.

  169. Bearden CE, Glahn DC. Cognitive genomics: Searching for the genetic roots of neuropsychological functioning. Neuropsychology. 2017;31:1003–19.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Van Der Sluis S, Verhage M, Posthuma D, Dolan CV. Phenotypic complexity, measurement bias, and poor phenotypic resolution contribute to the missing heritability problem in genetic association studies. PloS one. 2010;5:e13929.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Knowles EE, Carless MA, de Almeida MA, Curran JE, McKay DR, Sprooten E, et al. Genome-wide significant localization for working and spatial memory: Identifying genes for psychosis using models of cognition. Am J Med Genet B Neuropsychiatr Genet. 2014;165B:84–95.

    Article  PubMed  Google Scholar 

  172. Modenato C, Martin-Brevet S, Moreau CA, Rodriguez-Herreros B, Kumar K, Draganski B, et al. Lessons learned from neuroimaging studies of copy number variants: a systematic review. Biol Psychiatry. 2021;90:596–610.

    Article  PubMed  Google Scholar 

  173. Moreau CA, Ching CR, Kumar K, Jacquemont S, Bearden CE. Structural and functional brain alterations revealed by neuroimaging in CNV carriers. Curr Opin Genet Dev. 2021;68:88–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Van Rooij D, Anagnostou E, Arango C, Auzias G, Behrmann M, Busatto GF, et al. Cortical and subcortical brain morphometry differences between patients with autism spectrum disorder and healthy individuals across the lifespan: results from the ENIGMA ASD Working Group. Am J Psychiatry. 2018;175:359–69.

    Article  PubMed  Google Scholar 

  175. Van Erp TG, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, et al. Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium. Biol psychiatry. 2018;84:644–54.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Coe BP, Girirajan S, Eichler EE. The genetic variability and commonality of neurodevelopmental disease. Am J Med Genet C Semin Med Genet. 2012;160C:118–29.

    Article  PubMed  Google Scholar 

  177. Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med. 2012;367:1321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Tansey KE, Rees E, Linden DE, Ripke S, Chambert KD, Moran JL, et al. Common alleles contribute to schizophrenia in CNV carriers. Mol Psychiatry. 2016;21:1085–9.

    Article  CAS  PubMed  Google Scholar 

  179. Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA, Grove J, et al. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat Genet. 2017;49:978–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Martin J, O’Donovan MC, Thapar A, Langley K, Williams N. The relative contribution of common and rare genetic variants to ADHD. Transl Psychiatry. 2015;5:e506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Niemi ME, Martin HC, Rice DL, Gallone G, Gordon S, Kelemen M, et al. Common genetic variants contribute to risk of rare severe neurodevelopmental disorders. Nature. 2018;562:268–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Jensen M, Girirajan S. An interaction-based model for neuropsychiatric features of copy-number variants. PLoS Genet. 2019;15:e1007879.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Veltman JA, Brunner HG. Understanding variable expressivity in microdeletion syndromes. Nat Genet. 2010;42:192–3.

    Article  CAS  PubMed  Google Scholar 

  184. Webber C. Epistasis in neuropsychiatric disorders. Trends Genet. 2017;33:256–65.

    Article  CAS  PubMed  Google Scholar 

  185. Bergen SE, Ploner A, Howrigan D. Joint contributions of rare copy number variants and common SNPs to Risk for Schizophrenia. Am J Psychiatry. 2019;176:29–35. Group CNVA, the Schizophrenia Working Group of the Psychiatric Genomics C, O’Donovan MC et al.

    Article  PubMed  Google Scholar 

  186. Iyer J, Singh MD, Jensen M, Patel P, Pizzo L, Huber E, et al. Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11. 2 deletion in Drosophila melanogaster. Nat Commun. 2018;9:1–19.

    Article  CAS  Google Scholar 

  187. Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49:27–35.

    Article  CAS  PubMed  Google Scholar 

  188. Nielsen J, Fejgin K, Sotty F, Nielsen V, Mørk A, Christoffersen CT, et al. A mouse model of the schizophrenia-associated 1q21. 1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission. Transl Psychiatry. 2017;7:1–12.

    Article  Google Scholar 

  189. Forsingdal A, Jørgensen TN, Olsen L, Werge T, Didriksen M, Nielsen J. Can animal models of copy number variants that predispose to schizophrenia elucidate underlying biology? Biol psychiatry. 2019;85:13–24.

    Article  CAS  PubMed  Google Scholar 

  190. Zinkstok JR, Boot E, Bassett AS, Hiroi N, Butcher NJ, Vingerhoets C, et al. Neurobiological perspective of 22q11. 2 deletion syndrome. Lancet Psychiatry. 2019;6:951–60.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Collins RL, Brand H, Karczewski KJ, Zhao X, Alföldi J, Francioli LC, et al. A structural variation reference for medical and population genetics. Nature. 2020;581:444–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Crespi BJ, Crofts HJ. Association testing of copy number variants in schizophrenia and autism spectrum disorders. J Neurodev Disord. 2012;4:1–9.

    Article  Google Scholar 

  193. Kushima I, Aleksic B, Nakatochi M, Shimamura T, Okada T, Uno Y, et al. Comparative analyses of copy-number variation in autism spectrum disorder and schizophrenia reveal etiological overlap and biological insights. Cell Rep. 2018;24:2838–56.

    Article  CAS  PubMed  Google Scholar 

  194. Gudmundsson OO, Walters GB, Ingason A, Johansson S, Zayats T, Athanasiu L, et al. Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder. Transl Psychiatry. 2019;9:1–9.

    Article  Google Scholar 

  195. Brownstein CA, Douard E, Mollon J, Smith R, Hojlo MA, Das A, et al. Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder. Am J Psychiatry. 2022;179:853–61.

    Article  PubMed  Google Scholar 

  196. Huguet G, Schramm C, Douard E, Tamer P, Main A, Monin P et al. Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability. Mol Psychiatry. 2021.

  197. Moreno FA, Chhatwal J. Diversity and inclusion in psychiatry: the pursuit of health equity. Focus. 2020;18:2–7.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Lázaro‐Muñoz G, Sabatello M, Huckins L, Peay H, Degenhardt F, Meiser B, et al. International society of psychiatric genetics ethics committee: issues facing us. Am J Med Genet Part B: Neuropsychiatr Genet. 2019;180:543–54.

    Article  Google Scholar 

  199. Fatumo S, Chikowore T, Choudhury A, Ayub M, Martin AR, Kuchenbaecker K. A roadmap to increase diversity in genomic studies. Nat Med. 2022: 1-8.

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Acknowledgements

This work was supported by the National Institute of Mental Health (NIMH, U01 MH119690).

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Authors and Affiliations

  1. Department of Psychiatry, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Josephine Mollon & David C. Glahn

  2. Department of Genetics, Perelman School of Medicine, Penn-CHOP Lifespan Brain Institute, University of Pennsylvania, Philadelphia, PA, USA

    Laura Almasy

  3. Department of Pediatrics, Université de Montréal, Montreal, QC, Canada

    Sebastien Jacquemont

  4. Center Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada

    Sebastien Jacquemont

  5. Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA

    David C. Glahn

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Conceptualization: JM, SJ, LA, DG. Manuscript text: JM, SJ, LA, DG. Figures: JM.

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Mollon, J., Almasy, L., Jacquemont, S. et al. The contribution of copy number variants to psychiatric symptoms and cognitive ability. Mol Psychiatry 28, 1480–1493 (2023). https://doi.org/10.1038/s41380-023-01978-4

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