Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations Journal Article


Authors: Yoneyama, S.; Yao, J; Guo, X; Fernandez-Rhodes, L.; Lim, U; Boston, J.; Buzkova, P.; Carlson, C. S.; Cheng, I.; Cochran, B.; Cooper, R; Ehret, G; Fornage, M; Gong, J; Gross, M.; Gu, C. C.; Haessler, J.; Haiman, C. A.; Henderson, B.; Hindorff, L. A.; Houston, D.; Irvin, M. R.; Jackson, R.; Kuller, L.; Leppert, M.; Lewis, C. E.; Li, R; Le Marchand, L.; Matise, T. C.; Nguyen, K. D.; Chakravarti, A; Pankow, J. S.; Pankratz, N.; Pooler, L.; Ritchie, M. D.; Bien, S. A.; Wassel, C. L.; Chen, Y. D.; Taylor, K. D.; Allison, M.; Rotter, J. I.; Schreiner, P. J.; Schumacher, F.; Wilkens, L.; Boerwinkle, E; Kooperberg, C; Peters, U; Buyske, S; Graff, M; North, K. E.
Article Title: Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations
Abstract: BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.
Keywords: Public Health Services
Journal Title: International journal of obesity (2005)
Volume: 41
Issue: 2
ISSN: 1476-5497; 0307-0565
Publisher: Unknown  
Journal Place: England
Date Published: 2017
Start Page: 324
End Page: 331
Language: eng
DOI/URL:
Notes: LR: 20170408; GR: HHSN268201100012C/HL/NHLBI NIH HHS/United States; GR: UL1 RR033176/RR/NCRR NIH HHS/United States; GR: N01WH32111/WH/WHI NIH HHS/United States; GR: N01WH32100/WH/WHI NIH HHS/United States; GR: N01 WH044221/WH/WHI NIH HHS/United States; GR: HHSN268201300026C/HL/NHLBI NIH HHS/United States; GR: N01 WH32115/WH/WHI NIH HHS/United States; GR: R01 HL071251/HL/NHLBI NIH HHS/United States; GR: HHSN268201100010C/HL/NHLBI NIH HHS/United States; GR: N01WH24152/WH/WHI NIH HHS/United States; GR: R01 HL071259/HL/NHLBI NIH HHS/United States; GR: UL1 RR025005/RR/NCRR NIH HHS/United States; GR: R01 AG015928/AG/NIA NIH HHS/United States; GR: N01HC95163/HL/NHLBI NIH HHS/United States; GR: HHSN268201100008C/HL/NHLBI NIH HHS/United States; GR: U01 HG004790/HG/NHGRI NIH HHS/United States; GR: UL1 TR001079/TR/NCATS NIH HHS/United States; GR: N01 HC075150/HC/NHLBI NIH HHS/United States; GR: U01 HG004802/HG/NHGRI NIH HHS/United States; GR: R01 HL059367/HL/NHLBI NIH HHS/United States; GR: HHSN268201100007C/HL/NHLBI NIH HHS/United States; GR: N01 HC015103/HC/NHLBI NIH HHS/United States; GR: N01HC95169/HL/NHLBI NIH HHS/United States; GR: R01 HL071250/HL/NHLBI NIH HHS/United States; GR: HHSN268201100011C/HL/NHLBI NIH HHS/United States; GR: R01 HL086694/HL/NHLBI NIH HHS/United States; GR: N01 WH032122/WH/WHI NIH HHS/United States; GR: N01WH32118/WH/WHI NIH HHS/United States; GR: U01 HG004402/HG/NHGRI NIH HHS/United States; GR: R01 HL098077/HL/NHLBI NIH HHS/United States; GR: N01HC95164/HL/NHLBI NIH HHS/United States; GR: UL1 TR000124/TR/NCATS NIH HHS/United States; GR: HHSN268201300025C/HL/NHLBI NIH HHS/United States; GR: N01 HC095160/HC/NHLBI NIH HHS/United States; GR: N01HC55222/HL/NHLBI NIH HHS/United States; GR: N02HL64278/HL/NHLBI NIH HHS/United States; GR: N01HC95162/HL/NHLBI NIH HHS/United States; GR: N01HC85086/HL/NHLBI NIH HHS/United States; GR: N01HC95168/HL/NHLBI NIH HHS/United States; GR: P50 ES015915/ES/NIEHS NIH HHS/United States; GR: P30 DK063491/DK/NIDDK NIH HHS/United States; GR: R01 HL071051/HL/NHLBI NIH HHS/United States; GR: HHSN268201300027C/HL/NHLBI NIH HHS/United States; GR: HHSN268201100006C/HL/NHLBI NIH HHS/United States; GR: HHSN268201200036C/HL/NHLBI NIH HHS/United States; GR: HHSN268200900041C/HL/NHLBI NIH HHS/United States; GR: HHSN268201300028C/HL/NHLBI NIH HHS/United States; GR: U01 HG004803/HG/NHGRI NIH HHS/United States; GR: N01HC95165/HL/NHLBI NIH HHS/United States; GR: P01 CA033619/CA/NCI NIH HHS/United States; GR: N01HC95161/HL/NHLBI NIH HHS/United States; GR: U01 DK048443/DK/NIDDK NIH HHS/United States; GR: N01WH42107/WH/WHI NIH HHS/United States; GR: N01WH32105/WH/WHI NIH HHS/United States; GR: R01 CA129063/CA/NCI NIH HHS/United States; GR: R01 AG020098/AG/NIA NIH HHS/United States; GR: N01HC95167/HL/NHLBI NIH HHS/United States; GR: HHSN268201100009C/HL/NHLBI NIH HHS/United States; GR: T32 HD007168/HD/NICHD NIH HHS/United States; GR: U01 CA098758/CA/NCI NIH HHS/United States; GR: HHSN268201100005C/HL/NHLBI NIH HHS/United States; GR: R01 HL071205/HL/NHLBI NIH HHS/United States; GR: UL1 TR000040/TR/NCATS NIH HHS/United States; GR: N01 HC085079/HC/NHLBI NIH HHS/United States; GR: N01HC95166/HL/NHLBI NIH HHS/United States; GR: HHSN268201300029C/HL/NHLBI NIH HHS/United States; GR: R01 AG023629/AG/NIA NIH HHS/United States; GR: R01 HL087641/HL/NHLBI NIH HHS/United States; GR: P2C HD050924/HD/NICHD NIH HHS/United States; GR: R01 AG027058/AG/NIA NIH HHS/United States; GR: N01 HC045133/HC/NHLBI NIH HHS/United States; GR: N01WH32119/WH/WHI NIH HHS/United States; GR: U01 CA136792/CA/NCI NIH HHS/United States; GR: R01 HL071258/HL/NHLBI NIH HHS/United States; GR: N01WH32108/WH/WHI NIH HHS/United States; GR: R37 CA054281/CA/NCI NIH HHS/United States; GR: N01 HC035129/HC/NHLBI NIH HHS/United States; GR: N01WH22110/WH/WHI NIH HHS/United States; GR: N01 WH042129/WH/WHI NIH HHS/United States; GR: N01 HC095159/HC/NHLBI NIH HHS/United States; GR: U01 HG004801/HG/NHGRI NIH HHS/United States; JID: 101256108; NIHMS825343; PMCR: 2017/05/21; 2016/01/19 [received]; 2016/10/12 [revised]; 2016/10/23 [accepted]; ppublish