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 an inversion association analysis 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 for 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.

在大多数世界人口中，包括肥胖，糖尿病，高血压，哮喘和抑郁症在内的几种常见疾病的负担正在增加。然而，这些疾病之间众多流行病学和遗传相关性的潜在机制仍然未知。我们调查了常见的多态性倒置是否是这些疾病的共同遗传影响的基础。我们对总共408,898个欧洲人进行了包括21个倒立和25个与肥胖相关的性状的倒立关联分析，并在67,299个独立个体中验证了结果。七个倒置与多种疾病相关，而在8p23.1、16p11.2和11q13.2的倒置与肥胖与其他常见疾病的同时发生密切相关。跨许多组织的转录组分析揭示了肥胖相关性状的强大候选基因。对人体胰岛的分析表明，通过破坏糖尿病的易感性，可以逆转糖尿病易感性的潜在机制。SNPs从其靶基因的顺式调节作用。我们的数据强调了反演作为常见复杂疾病联合易感性的主要遗传因素的作用。