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

Mengyuan Kan, Paul L. Auer, Gao T. Wang, Kristine L. Bucasas, Stanley Hooker, Alejandra Rodriguez, Biao Li, Jaclyn Ellis, L. Adrienne Cupples, Yii Der Ida Chen, Josée Dupuis, Caroline S. Fox, Myron D. Gross, Joshua D. Smith, Nancy Heard-Costa, James B. Meigs, James S. Pankow, Jerome I. Rotter, David Siscovick, James G. WilsonJay Shendure, Rebecca Jackson, Ulrike Peters, Hua Zhong, Danyu Lin, L. Hsu, Nora Franceschini, Chris Carlson, Goncalo Abecasis, Stacey Gabriel, Michael J. Bamshad, David Altshuler, Deborah A. Nickerson, Kari E. North, Leslie A. Lange, Alexander P. Reiner, Suzanne M. Leal

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1181-1187
Number of pages7
JournalEuropean Journal of Human Genetics
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2016

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    Kan, M., Auer, P. L., Wang, G. T., Bucasas, K. L., Hooker, S., Rodriguez, A., Li, B., Ellis, J., Adrienne Cupples, L., Ida Chen, Y. D., Dupuis, J., Fox, C. S., Gross, M. D., Smith, J. D., Heard-Costa, N., Meigs, J. B., Pankow, J. S., Rotter, J. I., Siscovick, D., ... Leal, S. M. (2016). Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project. European Journal of Human Genetics, 24(8), 1181-1187. https://doi.org/10.1038/ejhg.2015.272