title: Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans.
abstract: 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.
authors.affiliation: Departments of Psychiatry, Physiology and Cellular Biophysics, and Neuroscience, Columbia University Medical Center, New York, NY 10032.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Abigail
authors.initials: A
authors.lastname: Woodroffe
authors.forename: Laura
authors.initials: L
authors.lastname: Rodriguez-Murillo
authors.forename: J Louw
authors.initials: JL
authors.lastname: Roos
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: van Rensburg
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
mesh_terms: D015331:Cohort Studies; D018628:Gene Dosage; D008040:Genetic Linkage; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D012559:Schizophrenia / Q000235:genetics*; D013019:South Africa