Gender differences in CNV burden do not confound schizophrenia CNV associations

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Rare copy number variants (CNVs) are linked to schizophrenia.
• Females may carry more large, rare CNVs than males, potentially affecting schizophrenia studies.
• Schizophrenia datasets often lack balanced gender representation, necessitating investigation into sex differences in CNV burden.

Purpose of the Study:

• To investigate sex differences in the burden of large, rare CNVs in schizophrenia cases and controls.
• To determine if gender affects the association between specific CNVs and schizophrenia risk.
• To explore potential female protective mechanisms against deleterious CNVs.

Main Methods:

• Analysis of a large dataset comprising 13,276 schizophrenia cases and 17,863 controls.
• Comparison of the prevalence of large (≥500 Kb), rare (<1%) CNVs between females and males.
• Statistical analysis to assess the burden of 11 known schizophrenia-associated CNVs and their risk in relation to gender.

Main Results:

• A significant excess of large, rare CNVs was observed in females compared to males in both cases (OR=1.11, P=0.045) and controls (OR=1.17, P=0.0012).
• The burden of 11 schizophrenia-associated CNVs was higher in female cases than male cases (OR=1.38, P=0.0055).
• After adjusting for control CNV rates, no significant gender difference in the risk conferred by these loci was found, and controlling for gender minimally impacted association significance.

Conclusions:

• Females exhibit a higher burden of large, rare CNVs, suggesting a potential female protective mechanism against deleterious CNVs.
• This protective mechanism may extend beyond neurodevelopmental disorders.
• Gender-adjusted analyses confirm that CNV burden differences do not significantly alter schizophrenia risk associations at specific loci.