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Am J Hum Genet. 2014 Mar 6;94(3):361-72. doi: 10.1016/j.ajhg.2014.01.015. Epub 2014 Feb 20.

A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity.

Author information

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

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.

PMID:
24560518
PMCID:
PMC3951940
DOI:
10.1016/j.ajhg.2014.01.015
[Indexed for MEDLINE]
Free PMC Article

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