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A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study
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نویسنده
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peters u. ,north k.e. ,sethupathy p. ,buyske s. ,haessler j. ,jiao s. ,fesinmeyer m.d. ,jackson r.d. ,kuller l.h. ,rajkovic a. ,lim u. ,cheng i. ,schumacher f. ,wilkens l. ,li r. ,monda k. ,ehret g. ,nguyen k.-d.h. ,cooper r. ,lewis c.e. ,leppert m. ,irvin m.r. ,gu c.c. ,houston d. ,buzkova p. ,ritchie m. ,matise t.c. ,le marchand l. ,hindorff l.a. ,crawford d.c. ,haiman c.a. ,kooperberg c.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 1
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چکیده
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Genetic variants in intron 1 of the fat mass- and obesity-associated (fto) gene have been consistently associated with body mass index (bmi) in europeans. however,follow-up studies in african americans (aa) have shown no support for some of the most consistently bmi-associated fto index single nucleotide polymorphisms (snps). this is most likely explained by different race-specific linkage disequilibrium (ld) patterns and lower correlation overall in aa,which provides the opportunity to fine-map this region and narrow in on the functional variant. to comprehensively explore the 16q12.2/fto locus and to search for second independent signals in the broader region,we fine-mapped a 646-kb region,encompassing the large fto gene and the flanking gene rpgrip1l by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 aas across five studies. we observed associations between bmi and variants in the known fto intron 1 locus: the snp with the most significant p-value,rs56137030 (8.3×10-6) had not been highlighted in previous studies. while rs56137030was correlated at r2>0.5 with 103 snps in europeans (including the gwas index snps),this number was reduced to 28 snps in aa. among rs56137030 and the 28 correlated snps,six were located within candidate intronic regulatory elements,including rs1421085,for which we predicted allele-specific binding affinity for the transcription factor cux1,which has recently been implicated in the regulation of fto. we did not find strong evidence for a second independent signal in the broader region. in summary,this large fine-mapping study in aa has substantially reduced the number of common alleles that are likely to be functional candidates of the known fto locus. importantly our study demonstrated that comprehensive fine-mapping in aa provides a powerful approach to narrow in on the functional candidate(s) underlying the initial gwas findings in european populations.
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آدرس
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division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States, carolina center for genome sciences,university of north carolina at chapel hill,chapel hill,nc,united states,department of epidemiology,school of public health,university of north carolina at chapel hill,chapel hill,nc, United States, carolina center for genome sciences,university of north carolina at chapel hill,chapel hill,nc,united states,department of genetics,school of medicine,university of north carolina at chapel hill,chapel hill,nc, United States, department of genetics,rutgers university,piscataway,nj,united states,department of statistics and biostatistics,rutgers university,piscataway,nj, United States, division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States, division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States, division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States, department of internal medicine,ohio state medical center,columbus,oh, United States, department of epidemiology,graduate school of public health,university of pittsburgh,pittsburgh,pa, United States, department of obstetrics and gynecology,university of pittsburgh,pittsburgh,pa, United States, epidemiology program,university of hawaii cancer center,honolulu,hi, United States, department of obstetrics and gynecology,university of pittsburgh,pittsburgh,pa, United States, department of preventive medicine,keck school of medicine and norris comprehensive cancer center,university of southern california,los angeles,ca, United States, epidemiology program,university of hawaii cancer center,honolulu,hi, United States, office of population genomics,national human genome research institute,national institutes of health,bethesda,md, United States, carolina center for genome sciences,university of north carolina at chapel hill,chapel hill,nc,united states,department of epidemiology,school of public health,university of north carolina at chapel hill,chapel hill,nc, United States, center for complex disease genomics,mckusick-nathans institute of genetic medicine,johns hopkins university school of medicine,baltimore,md,united states,division of cardiology,geneva university hospital,geneva, Switzerland, center for complex disease genomics,mckusick-nathans institute of genetic medicine,johns hopkins university school of medicine,baltimore,md, United States, preventive medicine and epidemiology,loyola university,chicago,il, United States, department of medicine,university of alabama,birmingham,al, United States, department of human genetics,university of utah,salt lake city,ut, United States, department of biostatistics,university of alabama,birmingham,al, United States, department of biostatistics,washington university,st. louis,mo, United States, wake forest university school of medicine,winston-salem,nc, United States, department of biostatistics,university of washington,seattle,wa, United States, pennsylvania state university,state college,pa, United States, department of genetics,rutgers university,piscataway,nj, United States, epidemiology program,university of hawaii cancer center,honolulu,hi, United States, office of population genomics,national human genome research institute,national institutes of health,bethesda,md, United States, vanderbilt epidemiology center,vanderbilt university medical center,nashville,tn,united states,center for human genetics research,vanderbilt university medical center,nashville,tn, United States, department of preventive medicine,keck school of medicine and norris comprehensive cancer center,university of southern california,los angeles,ca, United States, division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States
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Authors
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