Rare-variant Association Analysis: Study Designs and Statistical Tests

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2014 Jul 5

PMID 24995866

Citations 540

Authors

Seunggeung Lee

Goncalo R Abecasis

Michael Boehnke

Xihong Lin

Affiliations

Soon will be listed here.

Abstract

Despite the extensive discovery of trait- and disease-associated common variants, much of the genetic contribution to complex traits remains unexplained. Rare variants can explain additional disease risk or trait variability. An increasing number of studies are underway to identify trait- and disease-associated rare variants. In this review, we provide an overview of statistical issues in rare-variant association studies with a focus on study designs and statistical tests. We present the design and analysis pipeline of rare-variant studies and review cost-effective sequencing designs and genotyping platforms. We compare various gene- or region-based association tests, including burden tests, variance-component tests, and combined omnibus tests, in terms of their assumptions and performance. Also discussed are the related topics of meta-analysis, population-stratification adjustment, genotype imputation, follow-up studies, and heritability due to rare variants. We provide guidelines for analysis and discuss some of the challenges inherent in these studies and future research directions.

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