A Common 16p11.2 Inversion Underlies the Joint Susceptibility to Asthma and Obesity
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 inversio...
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| Veröffentlicht in: | American journal of human genetics 2014-03, Vol.94 (3), p.361-372 |
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| creator | 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 Pérez-Jurado, Luis A. |
| description | 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. |
| doi_str_mv | 10.1016/j.ajhg.2014.01.015 |
| format | Article |
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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.</description><identifier>ISSN: 0002-9297</identifier><identifier>ISSN: 1537-6605</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1016/j.ajhg.2014.01.015</identifier><identifier>PMID: 24560518</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Algorithms ; Alleles ; Asthma ; Asthma - genetics ; Chromosome Inversion ; Chromosome Mapping ; Chromosomes, Human, Pair 16 - genetics ; Cohort Studies ; Female ; Gene Expression Regulation ; Gene Frequency ; Genes ; Genetic Predisposition to Disease - genetics ; Genetics ; Genetics, Population ; Genocide ; Genome, Human ; Genotype ; Genotype & phenotype ; Haplotypes ; Human health and pathology ; Humans ; Life Sciences ; Male ; Mitochondria ; Obesity ; Obesity - genetics ; Odds Ratio ; Phenotype ; Polymorphism, Single Nucleotide ; Pulmonology and respiratory tract ; Santé publique et épidémiologie</subject><ispartof>American journal of human genetics, 2014-03, Vol.94 (3), p.361-372</ispartof><rights>2014 The American Society of Human Genetics</rights><rights>Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Cell Press Mar 6, 2014</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2014 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2014 The American Society of Human Genetics</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c550t-d81d46ad10601591930cbbf34b162292e107b8e3590497cd366d52f9056fc3c83</citedby><cites>FETCH-LOGICAL-c550t-d81d46ad10601591930cbbf34b162292e107b8e3590497cd366d52f9056fc3c83</cites><orcidid>0000-0003-4938-9339</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951940/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ajhg.2014.01.015$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,3539,27907,27908,45978,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24560518$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04315107$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>González, Juan R.</creatorcontrib><creatorcontrib>Cáceres, Alejandro</creatorcontrib><creatorcontrib>Esko, Tonu</creatorcontrib><creatorcontrib>Cuscó, Ivon</creatorcontrib><creatorcontrib>Puig, Marta</creatorcontrib><creatorcontrib>Esnaola, Mikel</creatorcontrib><creatorcontrib>Reina, Judith</creatorcontrib><creatorcontrib>Siroux, Valerie</creatorcontrib><creatorcontrib>Bouzigon, Emmanuelle</creatorcontrib><creatorcontrib>Nadif, Rachel</creatorcontrib><creatorcontrib>Reinmaa, Eva</creatorcontrib><creatorcontrib>Milani, Lili</creatorcontrib><creatorcontrib>Bustamante, Mariona</creatorcontrib><creatorcontrib>Jarvis, Deborah</creatorcontrib><creatorcontrib>Antó, Josep M.</creatorcontrib><creatorcontrib>Sunyer, Jordi</creatorcontrib><creatorcontrib>Demenais, Florence</creatorcontrib><creatorcontrib>Kogevinas, Manolis</creatorcontrib><creatorcontrib>Metspalu, Andres</creatorcontrib><creatorcontrib>Cáceres, Mario</creatorcontrib><creatorcontrib>Pérez-Jurado, Luis A.</creatorcontrib><title>A Common 16p11.2 Inversion Underlies the Joint Susceptibility to Asthma and Obesity</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>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.</description><subject>Adult</subject><subject>Algorithms</subject><subject>Alleles</subject><subject>Asthma</subject><subject>Asthma - genetics</subject><subject>Chromosome Inversion</subject><subject>Chromosome Mapping</subject><subject>Chromosomes, Human, Pair 16 - genetics</subject><subject>Cohort Studies</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Gene Frequency</subject><subject>Genes</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Genetics</subject><subject>Genetics, Population</subject><subject>Genocide</subject><subject>Genome, Human</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Haplotypes</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Mitochondria</subject><subject>Obesity</subject><subject>Obesity - 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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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24560518</pmid><doi>10.1016/j.ajhg.2014.01.015</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-4938-9339</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ScienceDirect Journals (5 years ago - present); PubMed Central |
| subjects | Adult Algorithms Alleles Asthma Asthma - genetics Chromosome Inversion Chromosome Mapping Chromosomes, Human, Pair 16 - genetics Cohort Studies Female Gene Expression Regulation Gene Frequency Genes Genetic Predisposition to Disease - genetics Genetics Genetics, Population Genocide Genome, Human Genotype Genotype & phenotype Haplotypes Human health and pathology Humans Life Sciences Male Mitochondria Obesity Obesity - genetics Odds Ratio Phenotype Polymorphism, Single Nucleotide Pulmonology and respiratory tract Santé publique et épidémiologie |
| title | A Common 16p11.2 Inversion Underlies the Joint Susceptibility to Asthma and Obesity |
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