Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity

Audrey E. Hendricks; Elena G. Bochukova; Gaëlle Marenne; Julia M Keogh; Neli Atanassova; Rebecca Bounds; Eleanor Wheeler; Vanisha Mistry; Elana Henning; Understanding Society Scientific Group; Antje Körner; Dawn Muddyman; Shane McCarthy; Anke Hinney; Johannes Hebebrand; Robert A Scott; Claudia Langenberg; Nick J Wareham; Praveen Surendran; Joanna Mm Howson; Adam S Butterworth; John Danesh; EPIC-CVD Consortium; Børge Nordestgaard; Sune Fallgaard Nielsen; Shoaib Afzal; Sofia Papadia; Sofie Ashford; Sumedha Garg; Glenn L. Millhauser; Rafael I. Palomino; Alexandra Kwasniewska; Ioanna Tachmazidou; Stephen O'Rahilly; Eleftheria Zeggini; UK10K Consortium; Inês Barroso; I Sadaf Farooqi

doi:10.1038/s41598-017-03054-8

Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity

Audrey E. Hendricks, Elena G. Bochukova, Gaëlle Marenne, Julia M Keogh, Neli Atanassova, Rebecca Bounds, Eleanor Wheeler, Vanisha Mistry, Elana Henning, Understanding Society Scientific Group, Antje Körner, Dawn Muddyman, Shane McCarthy, Anke Hinney, Johannes Hebebrand, Robert A Scott, Claudia Langenberg, Nick J Wareham, Praveen Surendran, Joanna Mm HowsonAdam S Butterworth, John Danesh, EPIC-CVD Consortium, Børge Nordestgaard, Sune Fallgaard Nielsen, Shoaib Afzal, Sofia Papadia, Sofie Ashford, Sumedha Garg, Glenn L. Millhauser, Rafael I. Palomino, Alexandra Kwasniewska, Ioanna Tachmazidou, Stephen O'Rahilly, Eleftheria Zeggini, UK10K Consortium, Inês Barroso^*, I Sadaf Farooqi

^*Corresponding author for this work

Department of Clinical Medicine

25 Citations (Scopus)

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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.

Original language	English
Article number	4394
Journal	Scientific Reports
Volume	7
Number of pages	14
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-017-03054-8
Publication status	Published - 2017

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Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood ObesityFinal published version, 2.15 MBLicence: CC BY

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Hendricks, A. E., Bochukova, E. G., Marenne, G., Keogh, J. M., Atanassova, N., Bounds, R., Wheeler, E., Mistry, V., Henning, E., Understanding Society Scientific Group, Körner, A., Muddyman, D., McCarthy, S., Hinney, A., Hebebrand, J., Scott, R. A., Langenberg, C., Wareham, N. J., Surendran, P., ... Farooqi, I. S. (2017). Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity. Scientific Reports, 7, [4394]. https://doi.org/10.1038/s41598-017-03054-8

Hendricks, AE, Bochukova, EG, Marenne, G, Keogh, JM, Atanassova, N, Bounds, R, Wheeler, E, Mistry, V, Henning, E, Understanding Society Scientific Group, Körner, A, Muddyman, D, McCarthy, S, Hinney, A, Hebebrand, J, Scott, RA, Langenberg, C, Wareham, NJ, Surendran, P, Howson, JM, Butterworth, AS, Danesh, J, EPIC-CVD Consortium, Nordestgaard, B, Nielsen, SF, Afzal, S, Papadia, S, Ashford, S, Garg, S, Millhauser, GL, Palomino, RI, Kwasniewska, A, Tachmazidou, I, O'Rahilly, S, Zeggini, E, UK10K Consortium, Barroso, I & Farooqi, IS 2017, 'Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity', Scientific Reports, vol. 7, 4394. https://doi.org/10.1038/s41598-017-03054-8

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title = "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 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.",

author = "Hendricks, {Audrey E.} and Bochukova, {Elena G.} and Ga{\"e}lle Marenne and Keogh, {Julia M} and Neli Atanassova and Rebecca Bounds and Eleanor Wheeler and Vanisha Mistry and Elana Henning and {Understanding Society Scientific Group} and Antje K{\"o}rner and Dawn Muddyman and Shane McCarthy and Anke Hinney and Johannes Hebebrand and Scott, {Robert A} and Claudia Langenberg and Wareham, {Nick J} and Praveen Surendran and Howson, {Joanna Mm} and Butterworth, {Adam S} and John Danesh and {EPIC-CVD Consortium} and B{\o}rge Nordestgaard and Nielsen, {Sune Fallgaard} and Shoaib Afzal and Sofia Papadia and Sofie Ashford and Sumedha Garg and Millhauser, {Glenn L.} and Palomino, {Rafael I.} and Alexandra Kwasniewska and Ioanna Tachmazidou and Stephen O'Rahilly and Eleftheria Zeggini and {UK10K Consortium} and In{\^e}s Barroso and Farooqi, {I Sadaf}",

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T1 - Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity

AU - Hendricks, Audrey E.

AU - Bochukova, Elena G.

AU - Marenne, Gaëlle

AU - Keogh, Julia M

AU - Atanassova, Neli

AU - Bounds, Rebecca

AU - Wheeler, Eleanor

AU - Mistry, Vanisha

AU - Henning, Elana

AU - Understanding Society Scientific Group

AU - Körner, Antje

AU - Muddyman, Dawn

AU - McCarthy, Shane

AU - Hinney, Anke

AU - Hebebrand, Johannes

AU - Scott, Robert A

AU - Langenberg, Claudia

AU - Wareham, Nick J

AU - Surendran, Praveen

AU - Howson, Joanna Mm

AU - Butterworth, Adam S

AU - Danesh, John

AU - EPIC-CVD Consortium

AU - Nordestgaard, Børge

AU - Nielsen, Sune Fallgaard

AU - Afzal, Shoaib

AU - Papadia, Sofia

AU - Ashford, Sofie

AU - Garg, Sumedha

AU - Millhauser, Glenn L.

AU - Palomino, Rafael I.

AU - Kwasniewska, Alexandra

AU - Tachmazidou, Ioanna

AU - O'Rahilly, Stephen

AU - Zeggini, Eleftheria

AU - UK10K Consortium

AU - Barroso, Inês

AU - Farooqi, I Sadaf

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-017-03054-8

DO - 10.1038/s41598-017-03054-8

M3 - Journal article

C2 - 28663568

AN - SCOPUS:85021671193

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

M1 - 4394

ER -

Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity

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