Multi-ethnic fine-mapping of 14 central adiposity loci.
The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ± 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.
Department of Biostatistics, Boston University, Boston, MA, USA ctliu@bu.edu adrienne@bu.edu.
Ching-Ti
CT
Liu
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA.
Martin L
ML
Buchkovich
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
Thomas W
TW
Winkler
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany Institute of Epidemiology, Helmholtz ZentrumMuenchen-German Research Center for Environmental Health, Neuherberg, Germany.
Iris M
IM
Heid
Division of Statistical Genomics, Department of Genetics, Washington University, St Louis, MO, USA.
Ingrid B
IB
Borecki
NHLBI Framingham Heart Study, Framingham, MA, USA.
Caroline S
CS
Fox
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA.
Karen L
KL
Mohlke
Department of Epidemiology and Carolina Population Center, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
Kari E
KE
North
Department of Biostatistics, Boston University, Boston, MA, USA NHLBI Framingham Heart Study, Framingham, MA, USA ctliu@bu.edu adrienne@bu.edu.
L
L
Adrienne Cupples
D050154:Adiposity / Q000235:genetics*; D000886:Anthropometry; D019295:Computational Biology; D005006:Ethnicity / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D058977:Molecular Sequence Annotation; D020161:Physical Chromosome Mapping / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics