title: A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS).
abstract: Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (nmax = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, PDOM = 1.62x10-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, PDOM = 1.00x10-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (nmax = 4156) and the strongest signal was rs1471880 (PDOM = 8.38x10-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation.
authors.affiliation: Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Chuan
authors.initials: C
authors.lastname: Gao
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America.|Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Julie T
authors.initials: JT
authors.lastname: Ziegler
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, United States of America.
authors.forename: Anny H
authors.initials: AH
authors.lastname: Xiang
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hai
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kridel
authors.affiliation: Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.affiliation: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Raffel
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.affiliation: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America.|Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Speliotes
authors.affiliation: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
mesh_terms: D050154:Adiposity / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D008565:Membrane Proteins; C000608448:ZGRF1 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human