Missing heritability of complex diseases: case solved?

Abstract

About 10 years ago, after the first large-scale genome-wide association studies (GWAS) were conducted to find genes associated with common complex diseases, investigators were surprised to find that the amount of heritability explained by the significant hits was very low for almost all the studied traits. Indeed, when compared to heritability estimates expected from the observed trait concordance within families, the heritability explained by the associated variants was always much smaller, more than ten times smaller for some traits. There was thus a problem of "missing heritability" and different hypotheses were proposed to help find this "missing heritability". These hypotheses involved novel research strategies in which different groups engaged including among others increasing sample sizes of GWAS or looking for rare variants and structural variations that were not captured by the SNP-chips used in GWAS. How successful have these efforts been in finding the "missing heritability"? Could it be that the problem of "missing heritability" was ill-defined? These are the questions that will be addressed in this paper by taking some different examples of complex traits.