Abstract
Compared with the general population, an excess of rare copy number variants (CNVs) has been identified in people with schizophrenia. Females with neurodevelopmental disorders and in the general population have been reported to carry more large, rare CNVs than males. Given that many schizophrenia datasets do not have equal gender ratios in cases and controls, sex differences in CNV burden might have impacted on estimates of case-related CNV burden and also on associations to individual loci. In a sample of 13,276 cases and 17,863 controls, we observed a small but significant excess of large (≥500 Kb), rare (<1%) CNVs in females compared with males in both cases and controls (OR = 1.17, P = 0.0012 for controls; OR = 1.11, P = 0.045 for cases). The burden of 11 schizophrenia-associated CNVs was significantly higher in female cases compared with male cases (OR = 1.38, P = 0.0055), but after accounting for the rates of CNVs in controls, we found no significant gender difference in the risk conferred by these loci. Controlling for gender had a negligible effect on the significance of association between specific CNVs and schizophrenia. The female excess of large CNVs in both cases and controls suggests a female protective mechanism exists for deleterious CNVs that may extend beyond neurodevelopmental phenotypes.
Highlights
Schizophrenia has a strong genetic component involving rare and common alleles distributed across many genes[1,2]
The effect size for schizophrenia conferred by all large, rare copy number variants (CNVs) in females (OR = 1.24, 95% CI = 1.12–1.38, P = 8.22 × 10−5) and in males (OR = 1.32, 95% CI = 1.20–1.45, P = 4.13 × 10−9) did not statistically differ (Z-test P = 0.19)
Despite the excess burden of large deletions in female controls, we found no significant difference between males and females for the number of genes overlapping CNVs for any class of CNV tested (Supplementary Table S3)
Summary
Schizophrenia has a strong genetic component involving rare and common alleles distributed across many genes[1,2]. The lower prevalence of ASD and higher mutational burden in females with the disorder is consistent with a different liability threshold for females compared to males whereby females require a greater risk factor load to manifest neurodevelopmental disorders[15,19,20]. Given the excess burdens of CNVs in females in both neurodevelopmental and control samples, we tested whether similar differences in burden exist in schizophrenia using a large case control dataset (N = 31,139 individuals). Consistent with earlier findings, we found an increased CNV burden for large (≥500 Kb), rare (
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