title: Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity.
abstract: Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes, were evaluated by mining GWAS datasets. eQTL analysis identified 1971 and 2078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2 were identified in both tissues. 62.1 % of top cis-eSNPs were within ±50 kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu ) and identified genetically regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes.
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Satria P
authors.initials: SP
authors.lastname: Sajuthi
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Sharma
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Chou
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Diabetes Research and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: McWilliams
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: John
authors.initials: J
authors.lastname: Beal
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Comeau
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.|Division of Endocrinology, Metro Health System, and School of Medicine, Case Western Reserve University, Cleveland, OH, 44105, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Calles-Escandon
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Jamehl
authors.initials: J
authors.lastname: Demons
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Rogers
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Cherry
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Lata
authors.initials: L
authors.lastname: Menon
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Ethel
authors.initials: E
authors.lastname: Kouba
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Davis
authors.affiliation: Clinical Research Unit, Biomedical Research Services and Administration, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Marcie
authors.initials: M
authors.lastname: Burris
authors.affiliation: Clinical Research Unit, Biomedical Research Services and Administration, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Byerly
authors.affiliation: Center for Diabetes Research and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
authors.forename: Nisa M
authors.initials: NM
authors.lastname: Maruthur
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Patel
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Bielak
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Public Health Sciences and Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Michèle M
authors.initials: MM
authors.lastname: Sale
authors.affiliation: Laboratory of Molecular Epidemiology and Nutrition, Department of Epidemiology, Brown University, Providence, RI, 02912, USA.
authors.forename: Kei Hang K
authors.initials: KH
authors.lastname: Chan
authors.affiliation: Center for Observational Research, Amgen, Inc, Thousand Oaks, CA, 91320, USA.
authors.forename: Keri L
authors.initials: KL
authors.lastname: Monda
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Chen
authors.affiliation: Department of Epidemiology and Population Health, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Kira
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Palmer
authors.affiliation: Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27514, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Diabetes Research and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.|Center for Diabetes Research and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. sdas@wakehealth.edu.|Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA. sdas@wakehealth.edu.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Das
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics*