Searching for missing heritability: Designing rare variant association studies

Abstract

Significance Discovering the genetic basis of common diseases, such as diabetes, heart disease, and schizophrenia, is a key goal in biomedicine. Genomic studies have revealed thousands of common genetic variants underlying disease, but these variants explain only a portion of the heritability. Rare variants are also likely to play an important role, but few examples are known thus far, and initial discovery efforts with small sample sizes have had only limited success. In this paper, we describe an analytical framework for the design of rare variant association studies of disease. It provides guidance with respect to sample size, as well as the roles of selection, disruptive and missense alleles, gene-specific allele frequency thresholds, isolated populations, gene sets, and coding vs. noncoding regions.

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Affiliated Institutions

• Brigham and Women's Hospital US
• Massachusetts General Hospital US
• Center for Systems Biology US
• Harvard University US
• Center for Human Genetics US
• Toyota Technological Institute at Chicago US
• Massachusetts Institute of Technology US

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