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

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• 作者：Juan R. Gonzá ; lez¹ ; ² ; ³ ; ⁴ ; ²⁰ ; ^{jrgonzalez@creal.cat" class="auth_mail} ; Alejandro Cá ; ceres¹ ; ² ; ²⁰ ; Tonu Esko⁵ ; ⁶ ; Ivon Cuscó ; ² ; ⁷ ; ⁸ ; Marta Puig⁹ ; Mikel Esnaola¹ ; ² ; ³ ; Judith Reina² ; ⁷ ; ⁸ ; Valerie Siroux¹⁰ ; ¹¹ ; Emmanuelle Bouzigon¹² ; ¹³ ; Rachel Nadif¹⁴ ; ¹⁵ ; Eva Reinmaa⁵ ; Lili Milani⁵ ; Mariona Bustamante¹ ; ² ; ³ ; ¹⁶ ; Deborah Jarvis¹⁷ ; Josep M. Antó ; ¹ ; ² ; ⁴ ; ⁷ ; Jordi Sunyer¹ ; ² ; ⁴ ; ⁷ ; Florence Demenais¹² ; ¹³ ; Manolis Kogevinas¹ ; ² ; ³ ; ¹⁸ ; Andres Metspalu⁵ ; ⁶ ; Mario Cá ; ceres⁹ ; ¹⁹ ; Luis A. Pé ; rez-Jurado² ; ⁷ ; ⁸ ; ^{luis.perez@upf.edu" class="auth_mail}
• 刊名：The American Journal of Human Genetics
• 出版年：6 March, 2014
• 年：2014
• 卷：94
• 期：3
• 页码：361-372
• 全文大小：1821 K

文摘

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 鈭?.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聽脳 10^鈭?). 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聽脳 10^鈭?0) 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 鈭?.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.