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

Nat Genet
Authors
Keywords
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.

Year of Publication
2014
Journal
Nat Genet
Volume
46
Issue
2
Pages
200-4
Date Published
2014 Feb
ISSN
1546-1718
URL
DOI
10.1038/ng.2852
PubMed ID
24336170
PubMed Central ID
PMC3939031
Links
Grant list
N01WH42129-32 / 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