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Meta-analysis in genome-wide association studies.

ABSTRACT: The advent of genome-wide association studies has allowed considerable progress in the identification and robust replication of common gene variants that confer susceptibility to common diseases and other phenotypes of interest. These genetic effect sizes are almost invariably moderate to small in magnitude and single studies, even if large, are underpowered to detect them with confidence. Meta-analysis of many genome-wide association studies improves the power to detect more associations, and to investigate the consistency or heterogeneity of these associations across diverse datasets and study populations. In this review, we discuss the key methodological issues in the set-up, information gathering and processing, and analysis of meta-analyses of genome-wide association datasets. We illustrate, as an example, the application of meta-analysis methods in the elucidation of common genetic variants associated with Type 2 diabetes. Finally, we discuss the prospects and caveats for future application of meta-analysis methods in the genome-wide setting.

SUBMITTER: Zeggini E

PROVIDER: S-EPMC2695132 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Meta-analysis in genome-wide association studies.

Zeggini Eleftheria E Ioannidis John P A JP

Pharmacogenomics 20090201 2

The advent of genome-wide association studies has allowed considerable progress in the identification and robust replication of common gene variants that confer susceptibility to common diseases and other phenotypes of interest. These genetic effect sizes are almost invariably moderate to small in magnitude and single studies, even if large, are underpowered to detect them with confidence. Meta-analysis of many genome-wide association studies improves the power to detect more associations, and t ...[more]

PMID: 19207020

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Project description:Poor vitamin K status is linked to greater risk of several chronic diseases. Age, sex, and diet are determinants of circulating vitamin K; however, there is still large unexplained interindividual variability in vitamin K status. Although a strong genetic component has been hypothesized, this has yet to be examined by a genome-wide association (GWA) study.The objective was to identify common genetic variants associated with concentrations of circulating phylloquinone, the primary circulating form of vitamin K.We conducted a 2-stage GWA meta-analysis of circulating phylloquinone in 2 populations of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Nutrition Working Group. Circulating phylloquinone was measured by using reversed-phase high-performance liquid chromatography. Results from adjusted cohort-specific discovery GWA analyses were meta-analyzed with inverse variance weights (n = 2138). Associations with circulating phylloquinone at P < 1 × 10(-6) were then evaluated in a second-stage analysis consisting of one independent cohort (n = 265).No significant association was observed for circulating phylloquinone at the genome-wide significance level of 5 × 10(-8). However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P < 1 × 10(-6), including a functional variant previously associated with warfarin dose and altered phylloquinone metabolism. These SNPs are on 5 independent loci on 11q23.3, 8q24.3, 5q22.3, 2p12, and 19p13.12, and they fall within or near the candidate genes APOA1/C3/A4/A5 cluster (involved in lipoprotein metabolism), COL22A1, CDO1, CTNAA2, and CYP4F2 (a phylloquinone oxidase), respectively. Second-stage analysis in an independent cohort further suggests the association of the 5q22.3 locus with circulating phylloquinone (P < 0.05).Multiple candidate genes related to lipoprotein and vitamin K metabolism were identified as potential determinants of circulating phylloquinone. Further investigation with a larger sample is warranted to verify our initial findings and identify other loci contributing to circulating phylloquinone. Trials related to this study were registered at clinicaltrials.gov as NCT00005121 (Framingham Offspring Study) and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Project description:BackgroundBovine paratuberculosis (ParaTB) also known as Johne's disease, is a contagious fatal disease resulting from infection by Mycobacterium avium subspecies paratuberculosis (MAP). Previous studies have identified loci associated with ParaTB using different measurements to define cases and controls. The objective of this study was to combine the data from two recent studies to identify genetic loci associated with MAP tissue infection and humoral immune response, defined by MAP ELISA-positive cattle, by comparing cases and control animals for one or both measures of infection.Methodology/principal findingsThe two populations used for the association analyses were a cohort of MAP tissue infected animals and control Holstein cows from the USA and the second cohort composed of ELISA-positive and ELISA-negative Holstein cows from Italy. Altogether 1190 cattle were genotyped with the Illumina BovineSNP50 BeadChip. SNP markers were removed if the minor allele frequency <0.01 or genotyping failure was >5%. Animals were removed with >5% genotyping failure. Whole genome association analyses were conducted with the GRAMMAR-CG method using two different definitions of control populations.Conclusion/significanceThe analyses identified several loci (P<5 e-05) associated with ParaTB, defined by positive ELISA and presence of bacteria in tissue compared to ELISA and tissue negative animals, on chromosomes 1, 12 and 15 and one unassigned SNP. These results confirmed associations on chromosome 12 and the unassigned SNP with ParaTB which had been found in the Italian population alone. Furthermore, several additional genomic regions were found associated with ParaTB when ELISA and tissue positive animals were compared with tissue negative samples. These loci were on chromosomes 1, 6, 7, 13, 16, 21,23 and 25 (P<5 e-05). The results clearly indicate the importance of the phenotype definition when seeking to identify markers associated with different disease responses.

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Meta-analysis in genome-wide association studies.

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Meta-analysis in genome-wide association studies.

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