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Nat Genet DOI:10.1038/ng.2852

Meta-analysis of gene-level tests for rare variant association.

Publication TypeJournal Article
Year of Publication2014
AuthorsLiu, DJ, Peloso, GM, Zhan, X, Holmen, OL, Zawistowski, M, Feng, S, Nikpay, M, Auer, PL, Goel, A, Zhang, H, Peters, U, Farrall, M, Orho-Melander, M, Kooperberg, C, McPherson, R, Watkins, H, Willer, CJ, Hveem, K, Melander, O, Kathiresan, S, Abecasis, GR
JournalNat Genet
Volume46
Issue2
Pages200-4
Date Published2014 Feb
ISSN1546-1718
KeywordsData Interpretation, Statistical, Exome, Genetic Association Studies, Genetic Variation, Genetics, Population, Genotype, Humans, Lipids, Meta-Analysis as Topic, Models, Genetic, Monte Carlo Method, Research Design
Abstract

The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.

URLhttp://dx.doi.org/10.1038/ng.2852
DOI10.1038/ng.2852
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24336170?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID24336170
PubMed Central IDPMC3939031
Grant ListN01WH42129-32 / WH / WHI NIH HHS / United States
R01 HL107816 / HL / NHLBI NIH HHS / United States
R01 HL109946 / HL / NHLBI NIH HHS / United States
R01HL117626 / HL / NHLBI NIH HHS / United States
R01HL107816 / HL / NHLBI NIH HHS / United States
N01WH32100-2 / WH / WHI NIH HHS / United States
N01WH32108-9 / WH / WHI NIH HHS / United States
MOP-77682 / / Canadian Institutes of Health Research / Canada
N01WH42107-26 / WH / WHI NIH HHS / United States
R01EY022005 / EY / NEI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
N01WH32122 / WH / WHI NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
MOP-82810 / / Canadian Institutes of Health Research / Canada
N01WH32105-6 / WH / WHI NIH HHS / United States
R01HG007022 / HG / NHGRI NIH HHS / United States
N01WH32111-13 / WH / WHI NIH HHS / United States
N01WH32118-32119 / WH / WHI NIH HHS / United States
282255 / / European Research Council / International
T32HL007208 / HL / NHLBI NIH HHS / United States
R01 HG007022 / HG / NHGRI NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
MOP-2380941 / / Canadian Institutes of Health Research / Canada
N01WH32115 / WH / WHI NIH HHS / United States
N01WH44221 / WH / WHI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
N01WH24152 / WH / WHI NIH HHS / United States
R01 EY022005 / EY / NEI NIH HHS / United States