Pooled Association Tests for Rare Genetic Variants: A Review and Some New Results

TL;DR

This paper reviews and introduces new results on pooled association tests for rare genetic variants, highlighting their performance, limitations, and the importance of biological information in study design.

Contribution

It provides a comprehensive review, new power formulas, simulation results, and practical recommendations for testing rare variants in genetic association studies.

Findings

Power is low for medium-sized studies unless many variants are causal.

Performance varies depending on the genetic model and data type.

Biological information is crucial for selecting variants to improve detection.

Abstract

In the search for genetic factors that are associated with complex heritable human traits, considerable attention is now being focused on rare variants that individually have small effects. In response, numerous recent papers have proposed testing strategies to assess association between a group of rare variants and a trait, with competing claims about the performance of various tests. The power of a given test in fact depends on the nature of any association and on the rareness of the variants in question. We review such tests within a general framework that covers a wide range of genetic models and types of data. We study the performance of specific tests through exact or asymptotic power formulas and through novel simulation studies of over 10,000 different models. The tests considered are also applied to real sequence data from the 1000 Genomes project and provided by the GAW17. We recommend a testing strategy, but our results show that power to detect association in plausible genetic scenarios is low for studies of medium size unless a high proportion of the chosen variants are causal. Consequently, considerable attention must be given to relevant biological information that can guide the selection of variants for testing.