Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity
(2017) In Scientific Reports 7(1).- 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... (More)
- 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. © 2017 The Author(s). (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/c5657066-b459-4277-b6d3-3097012e0068
- author
- Hendricks, A. E. ; Bochukova, E. G. ; Marenne, Gaëlle ; Keogh, J. M. ; Atanassova, N ; Bounds, R. and Melander, Olle LU
- author collaboration
- organization
- publishing date
- 2017
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 7
- issue
- 1
- article number
- 4394
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85021671193
- pmid:28663568
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-017-03054-8
- language
- English
- LU publication?
- yes
- additional info
- Export Date: 18 July 2017
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- c5657066-b459-4277-b6d3-3097012e0068
- date added to LUP
- 2017-07-18 11:05:35
- date last changed
- 2024-01-14 00:45:21
@article{c5657066-b459-4277-b6d3-3097012e0068, 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. © 2017 The Author(s).}}, author = {{Hendricks, A. E. and Bochukova, E. G. and Marenne, Gaëlle and Keogh, J. M. and Atanassova, N and Bounds, R. and Melander, Olle}}, issn = {{2045-2322}}, language = {{eng}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Scientific Reports}}, title = {{Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity}}, url = {{http://dx.doi.org/10.1038/s41598-017-03054-8}}, doi = {{10.1038/s41598-017-03054-8}}, volume = {{7}}, year = {{2017}}, }