Polymorphic inversions underlie the shared genetic susceptibility to prevalent common diseases

Abstract

The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed the largest inversion association analysis to date, including 21 inversions and 25 obesity-related traits, on a total of 408,898 Europeans, and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2 and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes of obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.