title: A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity.
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.
authors.affiliation: 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.
authors.forename: Juan R
authors.initials: JR
authors.lastname: González
authors.affiliation: Center for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain; Hospital del Mar Research Institute (IMIM), Barcelona 08003, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Cáceres
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 50090, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 50090, Estonia.
authors.forename: Tonu
authors.initials: T
authors.lastname: Esko
authors.affiliation: 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.
authors.forename: Ivon
authors.initials: I
authors.lastname: Cuscó
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona) 08193, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Puig
authors.affiliation: 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.
authors.forename: Mikel
authors.initials: M
authors.lastname: Esnaola
authors.affiliation: 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.
authors.forename: Judith
authors.initials: J
authors.lastname: Reina
authors.affiliation: INSERM-UJF, U823, Institut Albert Bonniot, 38042 Grenoble, France; Université Joseph Fourier - BP 53, 38041 Grenoble, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Siroux
authors.affiliation: 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.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bouzigon
authors.affiliation: 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.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nadif
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 50090, Estonia.
authors.forename: Eva
authors.initials: E
authors.lastname: Reinmaa
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 50090, Estonia.
authors.forename: Lili
authors.initials: L
authors.lastname: Milani
authors.affiliation: 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.
authors.forename: Mariona
authors.initials: M
authors.lastname: Bustamante
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Jarvis
authors.affiliation: 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.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Antó
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Sunyer
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.affiliation: 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.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 50090, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 50090, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Cáceres
authors.affiliation: 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.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
mesh_terms: D000328:Adult; D000465:Algorithms; D000483:Alleles; D001249:Asthma / Q000235:genetics*; D007446:Chromosome Inversion; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005828:Genetics, Population; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D009765:Obesity / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide