Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Abstract

BACKGROUND: Sex differences in the incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across these disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (GxS) interaction analysis of risk for these disorders, using data from 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTS: Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 gene (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes important for neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) with various potential functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a locus in the MOCOS gene (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the SCZ PGC dataset detected a noteworthy interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with an immunoregulatory function previously implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05). CONCLUSIONS: In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

“…The phenotypes that showed sex differences were among those with the largest available sample sizes, indicating that sample size impacts power to detect sex differences, and consequently, the lack of significant differences for a given phenotype may be due to limited power resulting from small sample sizes ( Table S12 in Supplement 2 ). For example, a recent larger analysis of gene-by-sex interaction in schizophrenia, BD, and MDD revealed significant associations for schizophrenia and MDD ( 20 ). We found that some pairs of genetically correlated traits also share sex-differentiated associations (e.g., ASD and ADHD; BD and schizophrenia).…”

“…We used the Functional Mapping and Annotation of GWAS (FUMA) SNP2GENE web tool ( 37 ) to perform gene-based analysis using MAGMA v1.08 ( 38 , 39 ). We examined whether the genes exhibiting a genome-wide significant sex difference (from MAGMA) demonstrate sex-differentiated gene expression in brain tissues from the Genotype-Tissue Expression project v8 ( https://www.gtexportal.org/home/datasets ) ( 20 ). After mapping SNPs to genes (using a default window size of 0), we performed gene set enrichment analysis on the union (across phenotypes) of genes with sex-differentiated effects using GSEA ( https://software.broadinstitute.org/gsea/index.jsp ).…”

“…Traits with significant gene associations include number of children born ( GLB1L2 ), risk-taking behavior ( HFE2 and AGO2 ), and schizophrenia ( SLTM ). SLTM , which is highly expressed in cerebellum (Genotype-Tissue Expression Portal, www.gtexportal.org ), was also identified in a larger (and therefore better-powered) gene-based gene-by-sex interaction for schizophrenia and across schizophrenia, bipolar disorder (BD), and MDD ( 20 ). The full set of gene-based MAGMA association statistics is provided in Table S7 in Supplement 3 .…”

“…Several recent studies have investigated sex-differentiated genetic effects for a number of neuropsychiatric traits ( 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ). Given evidence of phenotypic sex differences in prevalence and presentation as well as genetic correlations between these traits ( 13 ), we aimed to systematically test the hypothesis that neuropsychiatric and behavioral phenotypes have a partially sex-differentiated autosomal genetic architecture that may be shared across traits.…”

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

“…Genome-wide association studies (GWAS) have identified robustly associated risk alleles for both disorders, accounting for 26% of variance in anxiety and 8.7% of variance in major depressive disorder (MDD) [ 10 , 11 ]. The genetic correlation between males and females is very high for each of these disorders and larger samples are needed to identify SNPs showing a genome-wide significant sex difference in allele frequency [ 12 , 13 ]. GWAS have also demonstrated that a significant proportion of the genetic liabilities of anxiety and MDD are shared with other psychiatric disorders in males and females [ 10 – 12 , 14 ].…”