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

Price AL, Helgason A, Thorleifsson G, McCarroll SA, Kong A, Stefansson K - PLoS Genet. (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America. aprice@hsph.harvard.edu

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.

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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 hcis2. 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.
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pgen-1001317-g002: 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 hcis2. 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.

Mentions: We estimated the overall heritability hg2 for each gene g using variance-component methods [14] (see Methods). Although estimates for each gene g are statistically noisy at these sample sizes, histograms show a clear positive bias for both IFB and IFA cohorts (Figure S1 and Table S1), and hg2>0 was nominally significant (P = 0.05; see Methods) for an excess of genes: 42% for IFB and 63% for IFA. We computed the average h2 as the average of hg2 across genes g. A relevant question is whether or not to allow negative values of hg2 when computing this average [26]. Such values have no biological interpretation (except in the case of negative correlation among siblings in traits that depend on birth order). However, because values close to zero may be either increased or decreased by statistical noise—leading to negative estimates of hg2 for 3,031 of 18,735 genes for IFB and 1,038 of 19,099 genes for IFA—we elected to allow negative values in our main computations so as to produce an unbiased estimate of average h2. We obtained estimates of h2 = 0.150 for blood and h2 = 0.234 for adipose tissue. We obtained similar results when using a regression-based approach to estimate average h2 (Text S1), which more readily lends itself to visualization (Figure 2A and 2B). (When clipping negative hg2 values to zero, we obtained h2 = 0.159 for blood and h2 = 0.237 for adipose tissue.) Our results are consistent with previous analyses reporting that expression levels of a substantial fraction of genes are significantly heritable at the level of h2 = 0.3 or higher [10]-[13], [26].


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

Price AL, Helgason A, Thorleifsson G, McCarroll SA, Kong A, Stefansson K - PLoS Genet. (2011)

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 hcis2. 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.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044684&req=5

pgen-1001317-g002: 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 hcis2. 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.
Mentions: We estimated the overall heritability hg2 for each gene g using variance-component methods [14] (see Methods). Although estimates for each gene g are statistically noisy at these sample sizes, histograms show a clear positive bias for both IFB and IFA cohorts (Figure S1 and Table S1), and hg2>0 was nominally significant (P = 0.05; see Methods) for an excess of genes: 42% for IFB and 63% for IFA. We computed the average h2 as the average of hg2 across genes g. A relevant question is whether or not to allow negative values of hg2 when computing this average [26]. Such values have no biological interpretation (except in the case of negative correlation among siblings in traits that depend on birth order). However, because values close to zero may be either increased or decreased by statistical noise—leading to negative estimates of hg2 for 3,031 of 18,735 genes for IFB and 1,038 of 19,099 genes for IFA—we elected to allow negative values in our main computations so as to produce an unbiased estimate of average h2. We obtained estimates of h2 = 0.150 for blood and h2 = 0.234 for adipose tissue. We obtained similar results when using a regression-based approach to estimate average h2 (Text S1), which more readily lends itself to visualization (Figure 2A and 2B). (When clipping negative hg2 values to zero, we obtained h2 = 0.159 for blood and h2 = 0.237 for adipose tissue.) Our results are consistent with previous analyses reporting that expression levels of a substantial fraction of genes are significantly heritable at the level of h2 = 0.3 or higher [10]-[13], [26].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America. aprice@hsph.harvard.edu

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.

Show MeSH
Related in: MedlinePlus