Dataset Information

Effect of population stratification on the identification of significant single-nucleotide polymorphisms in genome-wide association studies.

ABSTRACT: The North American Rheumatoid Arthritis Consortium case-control study collected case participants across the United States and control participants from New York. More than 500,000 single-nucleotide polymorphisms (SNPs) were genotyped in the sample of 2000 cases and controls. Careful adjustment for the confounding effect of population stratification must be conducted when analyzing these data; the variance inflation factor (VIF) without adjustment is 1.44. In the primary analyses of these data, a clustering algorithm in the program PLINK was used to reduce the VIF to 1.14, after which genomic control was used to control residual confounding. Here we use stratification scores to achieve a unified and coherent control for confounding. We used the first 10 principal components, calculated genome-wide using a set of 81,500 loci that had been selected to have low pair-wise linkage disequilibrium, as risk factors in a logistic model to calculate the stratification score. We then divided the data into five strata based on quantiles of the stratification score. The VIF of these stratified data is 1.04, indicating substantial control of stratification. However, after control for stratification, we find that there are no significant loci associated with rheumatoid arthritis outside of the HLA region. In particular, we find no evidence for association of TRAF1-C5 with rheumatoid arthritis.

SUBMITTER: Sarasua SM

PROVIDER: S-EPMC2795903 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Effect of population stratification on the identification of significant single-nucleotide polymorphisms in genome-wide association studies.

Sarasua Sara M SM Collins Julianne S JS Williamson Dhelia M DM Satten Glen A GA Allen Andrew S AS

BMC proceedings 20091215

The North American Rheumatoid Arthritis Consortium case-control study collected case participants across the United States and control participants from New York. More than 500,000 single-nucleotide polymorphisms (SNPs) were genotyped in the sample of 2000 cases and controls. Careful adjustment for the confounding effect of population stratification must be conducted when analyzing these data; the variance inflation factor (VIF) without adjustment is 1.44. In the primary analyses of these data, ...[more]

PMID: 20017996

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Project description:Background Genome wide association studies (GWAS) have successfully revealed >40 genetic risk loci associated with coronary artery disease (CAD) in Europeans. Only five loci have been replicated in South Asians. Methods We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) with CAD in a Pakistani sample comprising of 663 clinically ascertained and angiographically confirmed cases and controls. Genotypes were performed using Sequenom’s iPLEX assay. The association of selected SNPs with coronary stenosis was initially determined by chi-square and additive genetic model. We selected 12 SNPs based on additive model and their association was also analyzed by using dominant model. All statistical analyses were performed by R software. Linkage disequilibrium (LD) of significant SNPs was determined by SNAP web portal and functional annotation of SNPs was determined by RegulomeDB. Results We had five significant SNPs out of 47 variants (rs4252120; P=0.003, rs2505083; P=0.006, rs2048327; P=0.04, rs602633; P=0.02 & rs46522; P=0.02) under dominant model and two, PLG/rs4252120 (P=0.003) and KIAA1462/rs2505083 (P=0.006), showed significant association with CAD in our sample after correcting for multiple testing (q<0.05). The odds ratio (OR) in cases vs. controls for two significant SNPs were; [PLG/rs4252120 (OR =1.83; P=0.003, FDR =0.02)] and [KIAA1462/rs2505083 (OR =1.65, P=0.006, FDR =0.03)]. PLG/rs4252120 was in LD with two other functional PLG variants (rs4252126 and rs4252135) having RegulomeDB score of 1f. Likewise, KIAA1462/rs2505083 was in LD with a functional SNP KIAA1462/rs3739998 having RegulomeDB score of 2b (likely affects TF binding). Conclusions We have successfully replicated two previously reported genome-wide significant SNPs in our Pakistani sample. KIAA1462/rs2505083 appears to be functional by itself as well as proxy of a functional SNP (KIAA1462/rs3739998). PLG/rs4252120 is proxy of two functional SNPs. Further association studies in other non-European populations and future functional studies are warranted to assess the impact of these two variants on risk of CAD.

Project description:BACKGROUND: Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation. Identification of large numbers of SNPs is helpful for genetic diversity analysis, map-based cloning, genome-wide association analyses and marker-assisted breeding. Recently, identifying genome-wide SNPs in allopolyploid Brassica napus (rapeseed, canola) by resequencing many accessions has become feasible, due to the availability of reference genomes of Brassica rapa (2n = AA) and Brassica oleracea (2n = CC), which are the progenitor species of B. napus (2n = AACC). Although many SNPs in B. napus have been released, the objective in the present study was to produce a larger, more informative set of SNPs for large-scale and efficient genotypic screening. Hence, short-read genome sequencing was conducted on ten elite B. napus accessions for SNP discovery. A subset of these SNPs was randomly selected for sequence validation and for genotyping efficiency testing using the Illumina GoldenGate assay. RESULTS: A total of 892,536 bi-allelic SNPs were discovered throughout the B. napus genome. A total of 36,458 putative amino acid variants were located in 13,552 protein-coding genes, which were predicted to have enriched binding and catalytic activity as a result. Using the GoldenGate genotyping platform, 94 of 96 SNPs sampled could effectively distinguish genotypes of 130 lines from two mapping populations, with an average call rate of 92%. CONCLUSIONS: Despite the polyploid nature of B. napus, nearly 900,000 simple SNPs were identified by whole genome resequencing. These SNPs were predicted to be effective in high-throughput genotyping assays (51% polymorphic SNPs, 92% average call rate using the GoldenGate assay, leading to an estimated >450 000 useful SNPs). Hence, the development of a much larger genotyping array of informative SNPs is feasible. SNPs identified in this study to cause non-synonymous amino acid substitutions can also be utilized to directly identify causal genes in association studies.

Dataset Information

Effect of population stratification on the identification of significant single-nucleotide polymorphisms in genome-wide association studies.

Publications

Effect of population stratification on the identification of significant single-nucleotide polymorphisms in genome-wide association studies.

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