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.

Fig. 1.

Inherited CNVs in families with SCZ. (A) Frequency distribution of rare CNVs identified in familial and sporadic cases of SCZ at the resolution afforded by the Affymetrix Genome-Wide Human SNP 5.0 arrays. There is a ≈20% basal rate of inherited CNVs in unaffected controls, while the overall frequency of carriers of all rare CNVs is the same between familial and sporadic cases (≈40%). (B) Rare inherited CNVs showing co-segregation with the clinical diagnosis in the respective affected families. For each CNV, the structure of the affected family, as well as the genomic position of the CNV, are indicated. Affected individuals are marked in black. Probands are indicated by red arrows. Individuals who carry rare CNVs are indicated by an asterisk. Individuals where no genotype information is available are indicated by question marks.

Fig. 2.

MOD score analysis. Green line shows MOD scores for the narrow classification. Blue line shows MOD scores for the broad classification.