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Meta‐Analysis of Rare Variant Association Tests in Multiethnic Populations
Author(s) -
MensahAblorh Akweley,
Lindstrom Sara,
Haiman Christopher A.,
Henderson Brian E.,
Marchand Loic Le,
Lee Seunngeun,
Stram Daniel O.,
Eliassen A. Heather,
Price Alkes,
Kraft Peter
Publication year - 2016
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.21939
Subject(s) - ethnic group , association test , sample size determination , meta analysis , statistical power , multiple comparisons problem , association (psychology) , demography , genetics , medicine , biology , psychology , statistics , single nucleotide polymorphism , genotype , gene , mathematics , sociology , anthropology , psychotherapist
ABSTRACT Several methods have been proposed to increase power in rare variant association testing by aggregating information from individual rare variants (MAF < 0.005). However, how to best combine rare variants across multiple ethnicities and the relative performance of designs using different ethnic sampling fractions remains unknown. In this study, we compare the performance of several statistical approaches for assessing rare variant associations across multiple ethnicities. We also explore how different ethnic sampling fractions perform, including single‐ethnicity studies and studies that sample up to four ethnicities. We conducted simulations based on targeted sequencing data from 4,611 women in four ethnicities (African, European, Japanese American, and Latina). As with single‐ethnicity studies, burden tests had greater power when all causal rare variants were deleterious, and variance component‐based tests had greater power when some causal rare variants were deleterious and some were protective. Multiethnic studies had greater power than single‐ethnicity studies at many loci, with inclusion of African Americans providing the largest impact. On average, studies including African Americans had as much as 20% greater power than equivalently sized studies without African Americans. This suggests that association studies between rare variants and complex disease should consider including subjects from multiple ethnicities, with preference given to genetically diverse groups.