Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity
Abstract Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants...
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2017
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oai:doaj.org-article:54a92d82de8240b1979f1209871a88992021-12-02T15:06:12ZRare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity10.1038/s41598-017-03054-82045-2322https://doaj.org/article/54a92d82de8240b1979f1209871a88992017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03054-8https://doaj.org/toc/2045-2322Abstract Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.Audrey E. HendricksElena G. BochukovaGaëlle MarenneJulia M. KeoghNeli AtanassovaRebecca BoundsEleanor WheelerVanisha MistryElana HenningAntje KörnerDawn MuddymanShane McCarthyAnke HinneyJohannes HebebrandRobert A. ScottClaudia LangenbergNick J. WarehamPraveen SurendranJoanna M. HowsonAdam S. ButterworthJohn DaneshBørge G NordestgaardSune F NielsenShoaib AfzalSofia PapadiaSofie AshfordSumedha GargGlenn L. MillhauserRafael I. PalominoAlexandra KwasniewskaIoanna TachmazidouStephen O’RahillyEleftheria ZegginiInês BarrosoI. Sadaf FarooqiUnderstanding Society Scientific GroupEPIC-CVD ConsortiumUK10K ConsortiumNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017) |
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DOAJ |
| collection |
DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Audrey E. Hendricks Elena G. Bochukova Gaëlle Marenne Julia M. Keogh Neli Atanassova Rebecca Bounds Eleanor Wheeler Vanisha Mistry Elana Henning Antje Körner Dawn Muddyman Shane McCarthy Anke Hinney Johannes Hebebrand Robert A. Scott Claudia Langenberg Nick J. Wareham Praveen Surendran Joanna M. Howson Adam S. Butterworth John Danesh Børge G Nordestgaard Sune F Nielsen Shoaib Afzal Sofia Papadia Sofie Ashford Sumedha Garg Glenn L. Millhauser Rafael I. Palomino Alexandra Kwasniewska Ioanna Tachmazidou Stephen O’Rahilly Eleftheria Zeggini Inês Barroso I. Sadaf Farooqi Understanding Society Scientific Group EPIC-CVD Consortium UK10K Consortium Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity |
| description |
Abstract Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies. |
| format |
article |
| author |
Audrey E. Hendricks Elena G. Bochukova Gaëlle Marenne Julia M. Keogh Neli Atanassova Rebecca Bounds Eleanor Wheeler Vanisha Mistry Elana Henning Antje Körner Dawn Muddyman Shane McCarthy Anke Hinney Johannes Hebebrand Robert A. Scott Claudia Langenberg Nick J. Wareham Praveen Surendran Joanna M. Howson Adam S. Butterworth John Danesh Børge G Nordestgaard Sune F Nielsen Shoaib Afzal Sofia Papadia Sofie Ashford Sumedha Garg Glenn L. Millhauser Rafael I. Palomino Alexandra Kwasniewska Ioanna Tachmazidou Stephen O’Rahilly Eleftheria Zeggini Inês Barroso I. Sadaf Farooqi Understanding Society Scientific Group EPIC-CVD Consortium UK10K Consortium |
| author_facet |
Audrey E. Hendricks Elena G. Bochukova Gaëlle Marenne Julia M. Keogh Neli Atanassova Rebecca Bounds Eleanor Wheeler Vanisha Mistry Elana Henning Antje Körner Dawn Muddyman Shane McCarthy Anke Hinney Johannes Hebebrand Robert A. Scott Claudia Langenberg Nick J. Wareham Praveen Surendran Joanna M. Howson Adam S. Butterworth John Danesh Børge G Nordestgaard Sune F Nielsen Shoaib Afzal Sofia Papadia Sofie Ashford Sumedha Garg Glenn L. Millhauser Rafael I. Palomino Alexandra Kwasniewska Ioanna Tachmazidou Stephen O’Rahilly Eleftheria Zeggini Inês Barroso I. Sadaf Farooqi Understanding Society Scientific Group EPIC-CVD Consortium UK10K Consortium |
| author_sort |
Audrey E. Hendricks |
| title |
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity |
| title_short |
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity |
| title_full |
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity |
| title_fullStr |
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity |
| title_full_unstemmed |
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity |
| title_sort |
rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/54a92d82de8240b1979f1209871a8899 |
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