Genetic Overlap Between Schizophrenia and Volumes of Hippocampus, Putamen, and Intracranial Volume Indicates Shared Molecular Genetic Mechanisms

Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICY). However, little is known about the underlying etiology of these brain alterations. Here, we explored whether brain structure volumes and SCZ share genetic risk factors. Using conditional false discovery rate (FDR) analysis, we integrated genome-wide association study (GWAS) data on SCZ (n = 82 315) and GWAS data on 7 subcortical brain volumes and ICY = 11840). By conditioning the FDR on overlapping associations, this statistical approach increases power to discover genetic loci. To assess the credibility of our approach, we studied the identified loci in larger GWAS samples on ICY (n = 26577) and hippocampal volume (n = 26814). We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional FDR < 0.05, we identified 2 loci shared between SCZ and ICY implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), 2 loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and 2 loci shared between SCZ and volume of putamen implicating DCC(rs4632195) and DLG2 (rs11233632). The loci shared between SCZ and hippocampal volume or ICY had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, 2 loci did reach genome-wide significance with ICY (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. Three of the 6 identified loci are novel for SCZ. Altogether, the findings provide new insights into the relationship between SCZ and brain structure volumes, suggesting that their genetic architectures are not independent.