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.
| Language | English |
|---|---|
| Pages | 361-372 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 94 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 6 Mar 2014 |
| Externally published | Yes |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
}
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 journal › Article
TY - JOUR
T1 - A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity
AU - González, Juan R.
AU - Cáceres, Alejandro
AU - Esko, Tonu
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
PY - 2014/3/6
Y1 - 2014/3/6
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84895917957&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2014.01.015
DO - 10.1016/j.ajhg.2014.01.015
M3 - Article
VL - 94
SP - 361
EP - 372
JO - American Journal of Human Genetics
T2 - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -