A Common 16p11.2 Inversion Underlies the Joint Susceptibility to Asthma and Obesity

作者：Gonzalez Juan R^*; Caceres Alejandro; Esko Tonu; Cusco Ivon; Puig Marta; Esnaola Mikel; Reina Judith; Siroux Valerie; Bouzigon Emmanuelle; Nadif Rachel; Reinmaa Eva; Milani Lili; Bustamante Mariona; Jarvis Deborah; Anto Josep M; Sunyer Jordi; Demenais Florence; Kogevinas Manolis; Metspalu Andres; Caceres Mario; Perez Jurado Luis A

来源：American Journal of Human Genetics, 2014, 94(3): 361-372.

DOI：10.1016/j.ajhg.2014.01.015

The prevalence of asthma and obesity is increasing worldwide, and obesity is a well-documented risk factor for asthma. The mechanisms underlying this association and parallel time trends remain largely unknown but genetic factors may be involved. Here, we report on a common similar to 0.45 Mb genomic inversion at 16p11.2 that can be accurately genotyped via SNP array data. We show that the inversion allele protects against the joint occurrence of asthma and obesity in five large independent studies (combined sample size of 317 cases and 543 controls drawn from a total of 5,809 samples; combined OR = 0.48, p = 5.5 3 x 10(-6)). Allele frequencies show remarkable worldwide population stratification, ranging from 10% in East Africa to 49% in Northern Europe, consistent with discordant and extreme genetic drifts or adaptive selections after human migration out of Africa. Inversion alleles strongly correlate with expression levels of neighboring genes, especially TUFM (p = 3.0 x 10(-40)) that encodes a mitochondrial protein regulator of energy balance and inhibitor of type 1 interferon, and other candidates for asthma (IL27) and obesity (APOB48R and SH2B1). Therefore, by affecting gene expression, the similar to 0.45 Mb 16p11.2 inversion provides a genetic basis for the joint susceptibility to asthma and obesity, with a population attributable risk of 39.7%. Differential mitochondrial function and basal energy balance of inversion alleles might also underlie the potential selection signature that led to their uneven distribution in world populations.

• 出版日期2014-3-6