59 - GENOME-WIDE ANALYSIS OF SNP-BY-SEX INTERACTION EFFECTS ON RISK FOR SCHIZOPHRENIA, MAJOR DEPRESSIVE DISORDER, AND BIPOLAR DISORDER

Abstract

Background Sex differences are pervasive in psychiatric disorders, including Major Depressive Disorder (MDD), Schizophrenia (SZ), and Bipolar Disorder (BD). MDD is more prevalent in females; SZ more prevalent in males. BD prevalence is similar by sex, but age at onset, illness course, and prognosis vary considerably by sex, for all three disorders. Although the direction of sex effects in prevalence differ, there may be shared sex effects in genetic risk, given shared sex differences in brain abnormalities across these disorders. This is not surprising given previous findings on cross-disorder genetic risk in the Psychiatric Genomics Consortium (PGC) of SZ, BD, and MDD cohorts. Thus using the PGC data we performed a genome-wide analysis of SNP-by-sex interactions. Methods 30,608 SZ patients (65% male) and 38,441 controls (50% male), 18,958 BD patients (65% male) and 29,996 controls (65% male), and 15,961 MDD patients (33% male) and 24,923 controls (49% male) were included. SZ data include 7.6% East Asian (EAS) subjects; all others are of European (EUR) ancestry. Analyses included and excluded EAS subjects. The PGC already described sample acquisition, genotyping, quality control, and 1000 Genomes imputation. Cohort-specific genome-wide association analyses were performed using linear regression in PLINK with a main effect for each SNP, SNP-by-sex interaction terms, and using an additive model. Ancestry principal components were included to control for population stratification. SNPs with poor imputation quality (IMPUTE2 INFO score Results One locus on Chromosome 8 showed genome-wide significant evidence for SNP-by-sex interaction across disorders (EUR: p=3.7×10^−8) with the most significant marker being rs80198067, intronic to the ANKRD46 gene. The association was driven by SZ (p=1.6×10^−4) and MDD (p=8.7×10^−4), not BD (p=1.5×10^−2). ANKRD46 encodes a protein containing multiple ankyrin repeat domains that function in protein-protein interactions in a variety of cellular processes. ANKRD46 is highly expressed in the brain (GTEx; www.gtexportal.org), particularly in frontal cortex. Additionally, several loci showed suggestive (p Discussion Phenotypic sex differences in brain function and structure are commonly observed in SZ, MDD, and BD. We identified one locus with genome-significant evidence for SNP-by-sex interaction across SZ, BD, and MDD. The locus contains the ANKRD46 gene, which is most strongly expressed in the frontal cortex, similar areas of which are abnormal structurally and functionally in SZ and MDD. Further, the shared sex-by-genotype interaction effect on risk of SZ and MDD, but not BD, is consistent with stronger sex differences in prevalence for these disorders than for BD. Future investigation of this locus will be important for understanding the interactions between sex, genes, and brain pathophysiology that cross psychiatric disorders.