Estimation of the multiple testing burden for genomewide association studies of nearly all common variants

TLDR

Genome‑wide association studies (GWAS) have become feasible and identified many novel genes linked to diverse phenotypes, yet determining significance amid millions of noisy tests remains a challenge. The authors aim to establish standardized genome‑wide significance thresholds rather than relying on study‑specific evaluations. They derive these thresholds using data from the International Haplotype Map Consortium. They estimate roughly one million independent tests in Europeans and twice that in Africans, and show that the testing burden varies with the chosen significance level, affecting staged study designs. © 2008 Wiley‑Liss, Inc., Genet Epidemiol 2008.

Abstract

Abstract Genomewide association studies are an exciting strategy in genetics, recently becoming feasible and harvesting many novel genes linked to multiple phenotypes. Determining the significance of results in the face of testing a genomewide set of multiple hypotheses, most of which are producing noisy, null‐distributed association signals, presents a challenge to the wide community of association researchers. Rather than each study engaging in independent evaluation of significance standards, we have undertaken the task of developing such standards for genomewide significance, based on data collected by the International Haplotype Map Consortium. We report an estimated testing burden of a million independent tests genomewide in Europeans, and twice that number in Africans. We further identify the sensitivity of the testing burden to the required significance level, with implications to staged design of association studies. Genet. Epidemiol. 2008. © 2008 Wiley‐Liss, Inc.