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

TitleGeneralization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.
Publication TypeJournal Article
Year of Publication2017
AuthorsYoneyama S, Yao J, Guo X, Fernández-Rhodes L, Lim U, Boston J, Buzková P, Carlson CS, Cheng I, Cochran B, Cooper R, Ehret G, Fornage M, Gong J, Gross M, Gu CC, Haessler J, Haiman CA, Henderson B, Hindorff LA, Houston D, Irvin MR, Jackson R, Kuller L, Leppert M, Lewis CE, Li R, Le Marchand L, Matise TC, Nguyen K-D, Chakravarti A, Pankow JS, Pankratz N, Pooler L, Ritchie MD, Bien SA, Wassel CL, Chen Y-DI, Taylor KD, Allison M, Rotter JI, Schreiner PJ, Schumacher F, Wilkens L, Boerwinkle E, Kooperberg C, Peters U, Buyske S, Graff M
Secondary AuthorsNorth KE
JournalInt J Obes (Lond)
Volume41
Issue2
Pagination324-331
Date Published2017 02
ISSN1476-5497
KeywordsAdiposity, Adult, African Continental Ancestry Group, Body Fat Distribution, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Obesity, Abdominal, Polymorphism, Single Nucleotide, Waist-Hip Ratio
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.

DOI10.1038/ijo.2016.207
Alternate JournalInt J Obes (Lond)
PubMed ID27867202
PubMed Central IDPMC5296276
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
N01WH32111 / WH / WHI NIH HHS / United States
N01WH32100 / WH / WHI NIH HHS / United States
N01 WH044221 / WH / WHI NIH HHS / United States
HHSN268201300026C / HL / NHLBI NIH HHS / United States
N01 WH32115 / WH / WHI NIH HHS / United States
U01 HG007419 / HG / NHGRI NIH HHS / United States
R01 HL071251 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01WH24152 / WH / WHI NIH HHS / United States
R01 HL071259 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
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