Dominance genetic variation contributes little to the missing heritability for human complex traits

Abstract

For human complex traits, non-additive genetic variation has been invoked to explain "missing heritability," but its discovery is often neglected in genome-wide association studies. Here we propose a method of using SNP data to partition and estimate the proportion of phenotypic variance attributed to additive and dominance genetic variation at all SNPs (hSNP(2) and δSNP(2)) in unrelated individuals based on an orthogonal model where the estimate of hSNP(2) is independent of that of δSNP(2). With this method, we analyzed 79 quantitative traits in 6,715 unrelated European Americans. The estimate of δSNP(2) averaged across all the 79 quantitative traits was 0.03, approximately a fifth of that for additive variation (average hSNP(2) = 0.15). There were a few traits that showed substantial estimates of δSNP(2), none of which were replicated in a larger sample of 11,965 individuals. We further performed genome-wide association analyses of the 79 quantitative traits and detected SNPs with genome-wide significant dominance effects only at the ABO locus for factor VIII and von Willebrand factor. All these results suggest that dominance variation at common SNPs explains only a small fraction of phenotypic variation for human complex traits and contributes little to the missing narrow-sense heritability problem.

Figure 1

Off-Diagonal Elements of the Additive GRM against Those of the Dominance GRM The correlation is 3.40 × 10⁻⁴, which is not significantly different from zero (p = 0.11).

Figure 2

Distribution of the Estimates of $h_{SNP}^2$ and ${\delta }_{SNP}^2$ for 79 Traits in the ARIC Cohort To get an unbiased estimate of the mean of $h_{SNP}^2$ or ${\delta }_{SNP}^2$ across all the traits, the estimates of $h_{SNP}^2$ and ${\delta }_{SNP}^2$ for each trait were not constrained to be positive in the REML analysis. The mean estimates of $h_{SNP}^2$ and ${\delta }_{SNP}^2$ are 0.15 and 0.03, respectively.

Figure 3

Estimates of $h_{SNP}^2$ and ${\delta }_{SNP}^2$ in Three Independent Cohorts of ARIC, EGCUT, and LL and in the Combined Dataset of EGCUT and LL for Four Traits Error bar represents the standard error.

Figure 4

Genome-wide Association Tests for Dominance Effects for Factor VIII and von Willebrand Factor (A and B) Manhattan plots of p values for dominance effects from the model of fitting both additive and dominance effects for factor VIII (FVIII) (A) and von Willebrand factor (vWF) (B). SNPs with genome-wide significant dominance effects are located at the ABO gene locus. (C and D) Genotype-phenotype maps at the top SNP rs505922 for FVIII (C) and the top SNP rs612169 for vWF (D). The normalized phenotypic means in the three genotypic classes are −0.57, 0.12, and 0.30 at the SNP rs505922 for FVIII (C), and −0.57, 0.15, and 0.37 at the SNP rs612169 for vWF (D). Bars represent 2.5% and 97.5% quartiles of the phenotype distribution at each of the three genotypic classes.