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The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma.

ABSTRACT: In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10(-8), per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17-1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10(-14)) and rs12617313 (P = 7.48 × 10(-12)), both highly correlated with rs9679290 (r(2) > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r(2) < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10(-9), per-allele OR = 1.28, 95% CI: 1.18-1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.

SUBMITTER: Han SS

PROVIDER: S-EPMC3277315 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma.

Han Summer S SS Yeager Meredith M Moore Lee E LE Wei Ming-Hui MH Pfeiffer Ruth R Toure Ousmane O Purdue Mark P MP Johansson Mattias M Scelo Ghislaine G Chung Charles C CC Gaborieau Valerie V Zaridze David D Schwartz Kendra K Szeszenia-Dabrowska Neonilia N Davis Faith F Bencko Vladimir V Colt Joanne S JS Janout Vladimir V Matveev Vsevolod V Foretova Lenka L Mates Dana D Navratilova M M Boffetta Paolo P Berg Christine D CD Grubb Robert L RL Stevens Victoria L VL Thun Michael J MJ Diver W Ryan WR Gapstur Susan M SM Albanes Demetrius D Weinstein Stephanie J SJ Virtamo Jarmo J Burdett Laurie L Brisuda Antonin A McKay James D JD Fraumeni Joseph F JF Chatterjee Nilanjan N Rosenberg Philip S PS Rothman Nathaniel N Brennan Paul P Chow Wong-Ho WH Tucker Margaret A MA Chanock Stephen J SJ Toro Jorge R JR

Human molecular genetics 20111123 5

In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10(-8), per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17-1.39]. Impu ...[more]

PMID: 22113997

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Project description:A goal of modern biology is to develop the genotype-phenotype (G→P) map, a predictive understanding of how genomic information generates trait variation that forms the basis of both natural and managed communities. As microbiome research advances, however, it has become clear that many of these traits are symbiotic extended phenotypes, being governed by genetic variation encoded not only by the host's own genome, but also by the genomes of myriad cryptic symbionts. Building a reliable G→P map therefore requires accounting for the multitude of interacting genes and even genomes involved in symbiosis. Here, we use naturally occurring genetic variation in 191 strains of the model microbial symbiont Sinorhizobium meliloti paired with two genotypes of the host Medicago truncatula in four genome-wide association studies (GWAS) to determine the genomic architecture of a key symbiotic extended phenotype-partner quality, or the fitness benefit conferred to a host by a particular symbiont genotype, within and across environmental contexts and host genotypes. We define three novel categories of loci in rhizobium genomes that must be accounted for if we want to build a reliable G→P map of partner quality; namely, (i) loci whose identities depend on the environment, (ii) those that depend on the host genotype with which rhizobia interact, and (iii) universal loci that are likely important in all or most environments. IMPORTANCE Given the rapid rise of research on how microbiomes can be harnessed to improve host health, understanding the contribution of microbial genetic variation to host phenotypic variation is pressing, and will better enable us to predict the evolution of (and select more precisely for) symbiotic extended phenotypes that impact host health. We uncover extensive context-dependency in both the identity and functions of symbiont loci that control host growth, which makes predicting the genes and pathways important for determining symbiotic outcomes under different conditions more challenging. Despite this context-dependency, we also resolve a core set of universal loci that are likely important in all or most environments, and thus, serve as excellent targets both for genetic engineering and future coevolutionary studies of symbiosis.

Dataset Information

The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma.

Publications

The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma.

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