Measuring missing heritability: Inferring the contribution of common variants

TLDR

Studies have identified thousands of common genetic variants linked to many diseases, yet they explain only a minority of heritability—a problem known as missing heritability—prompting indirect methods to estimate total common‑variant heritability. The authors aim to describe a method that provides unbiased estimates of common‑variant heritability. The method is a framework that can be applied to case‑control, extreme‑phenotype, and other study designs to estimate heritability. The authors demonstrate that existing methods underestimate heritability in case‑control studies and, using their method on six diseases, find that common variants explain on average 60 % of heritability.

Abstract

Significance Studies have identified thousands of common genetic variants associated with hundreds of diseases. Yet, these common variants typically account for a minority of the heritability, a problem known as “missing heritability.” Geneticists recently proposed indirect methods for estimating the total heritability attributable to common variants, including those whose effects are too small to allow identification in current studies. Here, we show that these methods seriously underestimate the true heritability when applied to case–control studies of disease. We describe a method that provides unbiased estimates. Applying it to six diseases, we estimate that common variants explain an average of 60% of the heritability for these diseases. The framework also may be applied to case–control studies, extreme-phenotype studies, and other settings.