TY - JOUR
T1 - Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project
AU - Kan, Mengyuan
AU - Auer, Paul L.
AU - Wang, Gao T.
AU - Bucasas, Kristine L.
AU - Hooker, Stanley
AU - Rodriguez, Alejandra
AU - Li, Biao
AU - Ellis, Jaclyn
AU - Adrienne Cupples, L.
AU - Ida Chen, Yii Der
AU - Dupuis, Josée
AU - Fox, Caroline S.
AU - Gross, Myron D.
AU - Smith, Joshua D.
AU - Heard-Costa, Nancy
AU - Meigs, James B.
AU - Pankow, James S.
AU - Rotter, Jerome I.
AU - Siscovick, David
AU - Wilson, James G.
AU - Shendure, Jay
AU - Jackson, Rebecca
AU - Peters, Ulrike
AU - Zhong, Hua
AU - Lin, Danyu
AU - Hsu, L.
AU - Franceschini, Nora
AU - Carlson, Chris
AU - Abecasis, Goncalo
AU - Gabriel, Stacey
AU - Bamshad, Michael J.
AU - Altshuler, David
AU - Nickerson, Deborah A.
AU - North, Kari E.
AU - Lange, Leslie A.
AU - Reiner, Alexander P.
AU - Leal, Suzanne M.
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
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U2 - 10.1038/ejhg.2015.272
DO - 10.1038/ejhg.2015.272
M3 - Article
C2 - 26757982
AN - SCOPUS:84954348268
SN - 1018-4813
VL - 24
SP - 1181
EP - 1187
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 8
ER -