TY - JOUR T1 - 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. JF - PLoS Genet Y1 - 2013 A1 - Peters, Ulrike A1 - North, Kari E A1 - Sethupathy, Praveen A1 - Buyske, Steve A1 - Haessler, Jeff A1 - Jiao, Shuo A1 - Fesinmeyer, Megan D A1 - Jackson, Rebecca D A1 - Kuller, Lew H A1 - Rajkovic, Aleksandar A1 - Lim, Unhee A1 - Cheng, Iona A1 - Schumacher, Fred A1 - Wilkens, Lynne A1 - Li, Rongling A1 - Monda, Keri A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Cooper, Richard A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Gu, C Charles A1 - Houston, Denise A1 - Bůzková, Petra A1 - Ritchie, Marylyn A1 - Matise, Tara C A1 - Le Marchand, Loïc A1 - Hindorff, Lucia A A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Kooperberg, Charles KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alleles KW - Body Mass Index KW - Chromosome Mapping KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Obesity KW - Proteins AB -

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 r(2)>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.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract ER - TY - JOUR T1 - Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study. JF - Am J Hematol Y1 - 2018 A1 - Jo Hodonsky, Chani A1 - Schurmann, Claudia A1 - Schick, Ursula M A1 - Kocarnik, Jonathan A1 - Tao, Ran A1 - van Rooij, Frank Ja A1 - Wassel, Christina A1 - Buyske, Steve A1 - Fornage, Myriam A1 - Hindorff, Lucia A A1 - Floyd, James S A1 - Ganesh, Santhi K A1 - Lin, Dan-Yu A1 - North, Kari E A1 - Reiner, Alex P A1 - Loos, Ruth Jf A1 - Kooperberg, Charles A1 - Avery, Christy L AB -

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

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