CIENCIASMEDICASNEWS: AJHG - A Common 16p11.2 Inversion Underlies the Joint Susceptibility to Asthma and Obesity

domingo, 23 de febrero de 2014

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

Copyright © 2014 The American Society of Human Genetics All rights reserved.
The American Journal of Human Genetics, 20 February 2014

doi:10.1016/j.ajhg.2014.01.015

ARTICLE

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

Juan R. González¹^,²^,³^,⁴^,²⁰^,^, , Alejandro Cáceres¹^,²^,²⁰, Tonu Esko⁵^,⁶, Ivon Cuscó²^,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. Antó¹^,²^,⁴^,⁷, Jordi Sunyer¹^,²^,⁴^,⁷, Florence Demenais¹²^,¹³, Manolis Kogevinas¹^,²^,³^,¹⁸, Andres Metspalu⁵^,⁶, Mario Cáceres⁹^,¹⁹ and Luis A. Pérez-Jurado²^,⁷^,⁸^,^,

¹ Center for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain
² Hospital del Mar Research Institute (IMIM), Barcelona 08003, Spain
³ Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona 08003, Spain
⁴ Department of Mathematics, Universitat Autònoma de Barcelona, Bellaterra (Barcelona) 08193, Spain
⁵ Estonian Genome Center, University of Tartu, Tartu 50090, Estonia
⁶ Institute of Molecular and Cell Biology, University of Tartu, Tartu 50090, Estonia
⁷ Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain
⁸ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona 08003, Spain
⁹ Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona) 08193, Spain
¹⁰ INSERM-UJF, U823, Institut Albert Bonniot, 38042 Grenoble, France
¹¹ Université Joseph Fourier - BP 53, 38041 Grenoble, France
¹² INSERM, UMRS-946, Genetic Variation of Human Diseases Unit, 75010 Paris, France
¹³ Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, 75010 Paris, France
¹⁴ INSERM, U1018, CESP Centre for Research in Epidemiology and Population Health, Respiratory and Environmental Epidemiology Team, 94807 Villejuif, France
¹⁵ Université Paris-Sud 11, UMRS 1018, 94807 Villejuif, France
¹⁶ Genes and Disease Group, Centre for Genomic Regulation (CRG), Barcelona 08003, Spain
¹⁷ National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK
¹⁸ National School of Public Health, Athens 115 21, Greece
¹⁹ Institució Catalana de Recerca i Estudis Avancats (ICREA), Barcelona 08010, Spain

Corresponding author

Corresponding author

²⁰ These authors contributed equally to this work

Abstract

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 ∼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 × 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 × 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 ∼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.