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

Juan R. González, Alejandro Cáceres, Tonu Esko, Ivon Cuscó, Marta Puig, Mikel Esnaola, Judith Reina, Valerie Siroux, Emmanuelle Bouzigon, Rachel Nadif, Eva Reinmaa, Lili Milani, Mariona Bustamante, Deborah Jarvis, Josep M. Antó, Jordi Sunyer, Florence Demenais, Manolis Kogevinas, Andres Metspalu, Mario Cáceres & 1 others Luis Perez-Jurado

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

LanguageEnglish
Pages361-372
Number of pages12
JournalAmerican Journal of Human Genetics
Volume94
Issue number3
DOIs
Publication statusPublished - 6 Mar 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

González, Juan R. ; Cáceres, Alejandro ; Esko, Tonu ; Cuscó, Ivon ; Puig, Marta ; Esnaola, Mikel ; Reina, Judith ; Siroux, Valerie ; Bouzigon, Emmanuelle ; Nadif, Rachel ; Reinmaa, Eva ; Milani, Lili ; Bustamante, Mariona ; Jarvis, Deborah ; Antó, Josep M. ; Sunyer, Jordi ; Demenais, Florence ; Kogevinas, Manolis ; Metspalu, Andres ; Cáceres, Mario ; Perez-Jurado, Luis. / A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 3. pp. 361-372.
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González, JR, Cáceres, A, Esko, T, Cuscó, I, Puig, M, Esnaola, M, Reina, J, Siroux, V, Bouzigon, E, Nadif, R, Reinmaa, E, Milani, L, Bustamante, M, Jarvis, D, Antó, JM, Sunyer, J, Demenais, F, Kogevinas, M, Metspalu, A, Cáceres, M & Perez-Jurado, L 2014, 'A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity', American Journal of Human Genetics, vol. 94, no. 3, pp. 361-372. https://doi.org/10.1016/j.ajhg.2014.01.015

A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity. / González, Juan R.; Cáceres, Alejandro; Esko, Tonu; Cuscó, Ivon; Puig, Marta; Esnaola, Mikel; Reina, Judith; Siroux, Valerie; Bouzigon, Emmanuelle; Nadif, Rachel; Reinmaa, Eva; Milani, Lili; Bustamante, Mariona; Jarvis, Deborah; Antó, Josep M.; Sunyer, Jordi; Demenais, Florence; Kogevinas, Manolis; Metspalu, Andres; Cáceres, Mario; Perez-Jurado, Luis.

In: American Journal of Human Genetics, Vol. 94, No. 3, 06.03.2014, p. 361-372.

Research output: Contribution to journalArticle

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AU - Cáceres, Alejandro

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AU - Cuscó, Ivon

AU - Puig, Marta

AU - Esnaola, Mikel

AU - Reina, Judith

AU - Siroux, Valerie

AU - Bouzigon, Emmanuelle

AU - Nadif, Rachel

AU - Reinmaa, Eva

AU - Milani, Lili

AU - Bustamante, Mariona

AU - Jarvis, Deborah

AU - Antó, Josep M.

AU - Sunyer, Jordi

AU - Demenais, Florence

AU - Kogevinas, Manolis

AU - Metspalu, Andres

AU - Cáceres, Mario

AU - Perez-Jurado, Luis

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N2 - 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.

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