title: Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project.
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.
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Kan
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Auer
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Gao T
authors.initials: GT
authors.lastname: Wang
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Bucasas
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Hooker
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Ellis
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Adrienne Cupples
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, at Harbor-UCLA Medical Center, Torrance, CA, USA.|Department of Pediatrics, at Harbor-UCLA Medical Center, Torrance, CA, USA.|Department of Medicine, at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Yii-Der
authors.initials: YD
authors.lastname: Ida Chen
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
authors.forename: Myron D
authors.initials: MD
authors.lastname: Gross
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.|Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Heard-Costa
authors.affiliation: General Medicine Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, at Harbor-UCLA Medical Center, Torrance, CA, USA.|Department of Pediatrics, at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.|Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Siscovick
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Center for Clinical and Translational Science, Ohio State University, Columbus, OH, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Division of Biostatistics, Departments of Environmental Medicine and Population Health, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Danyu
authors.initials: D
authors.lastname: Lin
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Carlson
authors.affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Goncalo
authors.initials: G
authors.lastname: Abecasis
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Reiner
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D059472:Exome; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*; D049629:Waist-Hip Ratio; D044465:White People / Q000235:genetics*
chemical_list: C584084:COBLL1 protein, human; D014157:Transcription Factors; D051550:I-kappa B Kinase; C496560:IKBKB protein, human