Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals

Abstract

Family studies of individual tissues have shown that gene expression traits are genetically heritable. Here, we investigate cis and trans components of heritability both within and across tissues by applying variance-components methods to 722 Icelanders from family cohorts, using identity-by-descent (IBD) estimates from long-range phased genome-wide SNP data and gene expression measurements for approximately 19,000 genes in blood and adipose tissue. We estimate the proportion of gene expression heritability attributable to cis regulation as 37% in blood and 24% in adipose tissue. Our results indicate that the correlation in gene expression measurements across these tissues is primarily due to heritability at cis loci, whereas there is little sharing of trans regulation across tissues. One implication of this finding is that heritability in tissues composed of heterogeneous cell types is expected to be more dominated by cis regulation than in tissues composed of more homogeneous cell types, consistent with our blood versus adipose results as well as results of previous studies in lymphoblastoid cell lines. Finally, we obtained similar estimates of the cis components of heritability using IBD between unrelated individuals, indicating that transgenerational epigenetic inheritance does not contribute substantially to the "missing heritability" of gene expression in these tissue types.

Figure 1. Local and genome-wide IBD.

We plot the local relatedness (0, 1 or 2 copies IBD) between two siblings from the IFB cohort at each 2cM block on chromosome 1. The dotted line represents their genome-wide relatedness of 0.568, which is within the expected range for siblings .

Figure 2. Family heritability in the IFB and IFA cohorts.

(A) Gene expression covariance (average value of product of normalized gene expression measurements) between related individuals in the IFB cohort varies with genome-wide IBD. Each point represents one pair of related individuals. The slope of this plot corresponds to the regression-based estimate of h². (B) Same as (A), for IFA cohort. (C) Gene expression covariance between siblings for genes with 0, 1 or 2 copies IBD at the cis locus, minus total covariance as displayed above. The slope of this plot corresponds to the regression-based estimate of h_cis². The signal to noise ratio is higher in this plot due to reduced effects of systematic noise covariance. (D) Same as (C), for IFA cohort.

Figure 3. Cross-tissue heritability in the IFB and IFA cohorts.

Plots are analogous to those in Figure 2, except that we analyze the covariance between related individuals in different tissues, instead of between related individuals in the same tissue. (A) Cross-tissue covariance between related individuals in the intersection of IFB and IFA varies with genome-wide IBD. The slope of this plot corresponds to the regression-based estimate of ξ². (B) Cross-tissue covariance between siblings in the intersection of IFB and IFA with 0, 1 or 2 copies IBD at the cis locus, minus total covariance as displayed in (A). The slope of this plot corresponds to ξ_cis².