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Eur J Hum Genet. 2016 Aug;24(8):1181-7. doi: 10.1038/ejhg.2015.272. Epub 2016 Jan 13.

Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project.

Author information

1
Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
2
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
3
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
5
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
6
National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
7
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, at Harbor-UCLA Medical Center, Torrance, CA, USA.
8
Department of Pediatrics, at Harbor-UCLA Medical Center, Torrance, CA, USA.
9
Department of Medicine, at Harbor-UCLA Medical Center, Torrance, CA, USA.
10
Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
11
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
12
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
13
General Medicine Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
14
Department of Medicine, University of Washington, Seattle, WA, USA.
15
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
16
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
17
Center for Clinical and Translational Science, Ohio State University, Columbus, OH, USA.
18
Division of Biostatistics, Departments of Environmental Medicine and Population Health, NYU Langone Medical Center, New York, NY, USA.
19
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
20
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
21
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
22
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Abstract

Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P=4.0 × 10(-8)) in European-Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P=2.23 × 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response.

PMID:
26757982
PMCID:
PMC4970686
DOI:
10.1038/ejhg.2015.272
[Indexed for MEDLINE]
Free PMC Article

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