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 

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

Article  PubMed Central  Google Scholar 

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 

Howrigan DP, Rose SA, Samocha KE, Fromer M, Cerrato F, Chen WJ, et al. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nat Neurosci. 2020;23:185–93.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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;530:177–83.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jablensky A. Subtyping schizophrenia: implications for genetic research. Mol Psychiatry. 2006;11:815–36.

Article  CAS  PubMed  Google Scholar 

Carpenter WT Jr, Kirkpatrick B. The heterogeneity of the long-term course of schizophrenia. Schizophr Bull. 1988;14:645–52.

Article  PubMed  Google Scholar 

Peterson RE, Cai N, Dahl AW, Bigdeli TB, Edwards AC, Webb BT, et al. Molecular genetic analysis subdivided by adversity exposure suggests etiologic heterogeneity in major depression. Am J Psychiatry. 2018;175:545–54.

Article  PubMed  PubMed Central  Google Scholar 

Fanous AH, Kendler KS. Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry. 2005;10:6–13.

Article  CAS  PubMed  Google Scholar 

Smoller JW, Andreassen OA, Edenberg HJ, Faraone SV, Glatt SJ, Kendler KS. Psychiatric genetics and the structure of psychopathology. Mol Psychiatry. 2019;24:409–20.

Article  PubMed  Google Scholar 

Duncan LE, Ostacher M, Ballon J. How genome-wide association studies (GWAS) made traditional candidate gene studies obsolete. Neuropsychopharmacology. 2019;44:1518–23.

Article  PubMed  PubMed Central  Google Scholar 

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–45.

Article  PubMed  Google Scholar 

Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address: douglas.ruderfer@vanderbilt.edu, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell. 2018;173:1705–1715.e16.

Article  PubMed Central  Google Scholar 

Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–90.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Singh T, Walters JTR, Johnstone M, Curtis D, Suvisaari J, Torniainen M, et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat Genet. 2017;49:1167–73.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Escott-Price V, Consortium IPDG, Nalls MA, Morris HR, Lubbe S, Brice A, et al. Polygenic risk of P arkinson disease is correlated with disease age at onset. Ann Neurol. 2015;77:582–91.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Baldessarini RJ, Tondo L, Vazquez GH, Undurraga J, Bolzani L, Yildiz A, et al. Age at onset versus family history and clinical outcomes in 1,665 international bipolar-I disorder patients. World Psychiatry. 2012;11:40–46.

Article  PubMed  PubMed Central  Google Scholar 

Klein DN, Schatzberg AF, McCullough JP, Dowling F, Goodman D, Howland RH, et al. Age of onset in chronic major depression: relation to demographic and clinical variables, family history, and treatment response. J Affect Disord. 1999;55:149–57.

Article  CAS  PubMed  Google Scholar 

Grant BF. The impact of a family history of alcoholism on the relationship between age at onset of alcohol use and DSM-IV alcohol dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. Alcohol Health Res World. 1998;22:144–7.

CAS  PubMed  PubMed Central  Google Scholar 

Monsén U, Broström O, Nordenvall B, Sörstad J, Hellers G. Prevalence of inflammatory bowel disease among relatives of patients with ulcerative colitis. Scand J Gastroenterol. 1987;22:214–8.

Article  PubMed  Google Scholar 

Scheuner MT, Whitworth WC, McGruder H, Yoon PW, Khoury MJ. Expanding the definition of a positive family history for early-onset coronary heart disease. Genet Med. 2006;8:491–501.

Article  PubMed  Google Scholar 

Immonen J, Jääskeläinen E, Korpela H, Miettunen J. Age at onset and the outcomes of schizophrenia: a systematic review and meta-analysis. Early Inter Psychiatry. 2017;11:453–60.

Article  Google Scholar 

Kendler KS. The development of Kraepelin’s mature diagnostic concept of hebephrenia: a close reading of relevant texts of Hecker, Daraszkiewicz, and Kraepelin. Mol Psychiatry. 2020;25:180–93.

Article  PubMed  Google Scholar 

Robinson EB, Lichtenstein P, Anckarsäter H, Happé F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proc Natl Acad Sci USA. 2013;110:5258–62.

Article  CAS  PubMed  PubMed Central  Google Scholar 

McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med. 2004;2:13.

Article  PubMed  PubMed Central  Google Scholar 

Leung MD DA, Chue MRC Psych DP. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand. 2000;101:3–38.

Article  Google Scholar 

Salvatore JE, Cho SB, Dick DM. Genes, environments, and sex differences in alcohol research. J Stud Alcohol Drugs. 2017;78:494–501.

Article  PubMed  PubMed Central  Google Scholar 

Merikangas AK, Almasy L. Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders. Genes Brain Behav. 2020;19:e12660.

Article  PubMed  PubMed Central  Google Scholar 

Peralta V, Cuesta MJ. Familial liability and schizophrenia phenotypes: a polydiagnostic approach. Schizophr Res. 2007;96:125–34.

Article  PubMed  Google Scholar 

Bergen SE, Ploner A, Howrigan D, CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium, O’Donovan MC, Smoller JW, et al. Joint contributions of rare copy number variants and common SNPs to risk for schizophrenia. Am J Psychiatry. 2019;176:29–35.

Article  PubMed  Google Scholar 

Genovese G, Fromer M, Stahl EA, Ruderfer DM, Chambert K, Landén M, et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci. 2016;19:1433–41.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Halvorsen M, Huh R, Oskolkov N, Wen J, Netotea S, Giusti-Rodriguez P, et al. Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia. Nat Commun. 2020;11:1842.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry. 1970;126:983–7.

Article  CAS  PubMed  Google Scholar