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Linking variants from genome-wide association analysis to function via transcriptional network analysis.

ABSTRACT: A current challenge in interpretation of genome-wide association studies is to establish the mechanistic links between the measured genotype and observed phenotype. The integration of gene expression with disease genome-wide association studies is emerging as an important strategy for deciphering these regulatory mechanisms. For renal disease, the availability of both tissue- and disease-specific expression data makes the strategy a compelling option. In this review, three approaches of integrating single nucleotide polymorphism (SNP) genotypes with transcriptional regulation are discussed as follows: (1) interpreting the functional role of transcripts affected by a SNP, (2) identifying the mechanistic role of noncoding SNPs in regulation, and (3) identifying regulatory candidate SNPs with expression associations. Combining these strategies in an integrative manner should allow the discovery of more extensive regulatory information. Linking genetics to systems biology more directly promises the opportunity to explain how genetic variants contribute to disease in a truly holistic manner.

SUBMITTER: Keller B

PROVIDER: S-EPMC2847590 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Linking variants from genome-wide association analysis to function via transcriptional network analysis.

Keller Benjamin B Martini Sebastian S Sedor John J Kretzler Matthias M

Seminars in nephrology 20100301 2

A current challenge in interpretation of genome-wide association studies is to establish the mechanistic links between the measured genotype and observed phenotype. The integration of gene expression with disease genome-wide association studies is emerging as an important strategy for deciphering these regulatory mechanisms. For renal disease, the availability of both tissue- and disease-specific expression data makes the strategy a compelling option. In this review, three approaches of integrat ...[more]

PMID: 20347646

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Project description:CONTEXT:Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE:To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS:Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES:Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS:In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS:We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

Dataset Information

Linking variants from genome-wide association analysis to function via transcriptional network analysis.

Publications

Linking variants from genome-wide association analysis to function via transcriptional network analysis.

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