Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans.

Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE

Original Publication: Washington, DC : National Academy of Sciences

Gene Dosage* ; Genetic Linkage* ; Genetic Variation*; Schizophrenia/*genetics; Cohort Studies ; Genome, Human ; Humans ; South Africa

To elucidate the genetic architecture of familial schizophrenia we combine linkage analysis with studies of fine-level chromosomal variation in families recruited from the Afrikaner population in South Africa. We demonstrate that individually rare inherited copy number variants (CNVs) are more frequent in cases with familial schizophrenia as compared to unaffected controls and affect almost exclusively genic regions. Interestingly, we find that while the prevalence of rare structural variants is similar in familial and sporadic cases, the type of variants is markedly different. In addition, using a high-density linkage scan with a panel of nearly 2,000 markers, we identify a region on chromosome 13q34 that shows genome-wide significant linkage to schizophrenia and show that in the families not linked to this locus, there is evidence for linkage to chromosome 1p36. No causative CNVs were identified in either locus. Overall, our results from approaches designed to detect risk variants with relatively low frequency and high penetrance in a well-defined and relatively homogeneous population, provide strong empirical evidence supporting the notion that multiple genetic variants, including individually rare ones, that affect many different genes contribute to the genetic risk of familial schizophrenia. They also highlight differences in the genetic architecture of the familial and sporadic forms of the disease.

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R01 MH061399 United States MH NIMH NIH HHS; R01 MH077235 United States MH NIMH NIH HHS; MH061399 United States MH NIMH NIH HHS; MH077235 United States MH NIMH NIH HHS

Date Created: 20091007 Date Completed: 20091228 Latest Revision: 20211020

20240829

PMC2757863

10.1073/pnas.0908584106

19805367