Sex differences in disease risk from reported genome-wide association study findings

Abstract

Men and women differ in susceptibility to many diseases and in responses to treatment. Recent advances in genome-wide association studies (GWAS) provide a wealth of data for associating genetic profiles with disease risk; however, in general, these data have not been systematically probed for sex differences in gene-disease associations. Incorporating sex into the analysis of GWAS results can elucidate new relationships between single nucleotide polymorphisms (SNPs) and human disease. In this study, we performed a sex-differentiated analysis on significant SNPs from GWAS data of the seven common diseases studied by the Wellcome Trust Case Control Consortium. We employed and compared three methods: logistic regression, Woolf’s test of heterogeneity, and a novel statistical metric that we developed called permutation method to assess sex effects (PMASE). After correction for false discovery, PMASE finds SNPs that are significantly associated with disease in only one sex. These sexually dimorphic SNP-disease associations occur in Coronary Artery Disease and Crohn’s Disease. GWAS analyses that fail to consider sex-specific effects may miss discovering sexual dimorphism in SNP-disease associations that give new insights into differences in disease mechanism between men and women.

A childhood acute lymphoblastic leukemia genome-wide association study identifies novel sex-specific risk variants

“…Likewise, reanalysis of GWAS datasets revealed that coronary artery diseases, Crohn disease, rheumatoid arthritis, and type1 diabetes show sex-specific associations with increased risk in only 1 gender. [22,23] In the present GWAS, we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases with childhood ALL using a case-only study design.…”

Assessment of gene-by-sex interaction effect on bone mineral density

“…However, direct comprehensive assessment of SNP-by-sex interactions for BMD has not been previously reported. The availability of large-scale GWAS collaborations allows for massive testing of SNP-by-sex interaction effects (20) and for rigorous replication of proposed discovered interactions that would allay the risk of false positives (21). To study potential genetic contributions to the sexual dimorphism in BMD, we first performed a comprehensive study of genome-wide gene-by-sex interactions in cohorts with both men and women who are part of the Genetic Factors for Osteoporosis (“GEFOS”) consortium.…”

Sex Dependency of Human Metabolic Profiles Revisited

“…Correspondingly, either sex stratification or sex adjustment is commonly advised in the epidemiological and molecular analysis of such traits [4][5][6]. For example, sex differences have been reported recently to characterize even well-established disease associations between single nucleotide polymorphisms and both Coronary Artery Disease and Crohn Disease [7]. Many metabolites are known to play an intermediate, gene-and environment-dependent role in the etiology of complex traits.…”