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Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals

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  • Alkes L Price
  • Agnar Helgason
  • Gudmar Thorleifsson
  • Steven A McCarroll
  • Augustine Kong
  • Kari Stefansson

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 ∼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.Author Summary: An important goal in biology is to understand how genotype affects gene expression. Because gene expression varies across tissues, the relationship between genotype and gene expression may be tissue-specific. In this study, we used heritability approaches to study the regulation of gene expression in two tissue types, blood and adipose tissue, as well as the regulation of gene expression that is shared across these tissues. Heritability can be partitioned into cis and trans effects by assessing identity-by-descent (IBD) at the genomic location close to the expressed gene or genome-wide, respectively, and applying variance-components methods to partition the heritability of each gene. We estimated the proportion of gene expression heritability explained by cis regulation as 37% in blood and 24% in adipose tissue. Notably, the heritability shared across tissue types was primarily due to cis regulation. Thus, the relative contribution of cis versus trans regulation is expected to increase with the number of cell types present in the tissue being assayed, just as observed in our study and in a comparison to previous work on lymphoblastoid cell lines (LCL). We specifically ruled out a substantial contribution of transgenerational epigenetic inheritance to heritability of gene expression in these cohorts by repeating our heritability analyses using segments shared IBD in distantly related Icelanders.

Suggested Citation

  • Alkes L Price & Agnar Helgason & Gudmar Thorleifsson & Steven A McCarroll & Augustine Kong & Kari Stefansson, 2011. "Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals," PLOS Genetics, Public Library of Science, vol. 7(2), pages 1-9, February.
  • Handle: RePEc:plo:pgen00:1001317
    DOI: 10.1371/journal.pgen.1001317
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    1. Valur Emilsson & Gudmar Thorleifsson & Bin Zhang & Amy S. Leonardson & Florian Zink & Jun Zhu & Sonia Carlson & Agnar Helgason & G. Bragi Walters & Steinunn Gunnarsdottir & Magali Mouy & Valgerdur Ste, 2008. "Genetics of gene expression and its effect on disease," Nature, Nature, vol. 452(7186), pages 423-428, March.
    2. Eric E. Schadt & Stephanie A. Monks & Thomas A. Drake & Aldons J. Lusis & Nam Che & Veronica Colinayo & Thomas G. Ruff & Stephen B. Milligan & John R. Lamb & Guy Cavet & Peter S. Linsley & Mao Mao & R, 2003. "Genetics of gene expression surveyed in maize, mouse and man," Nature, Nature, vol. 422(6929), pages 297-302, March.
    3. Enrico Petretto & Leonardo Bottolo & Sarah R Langley & Matthias Heinig & Chris McDermott-Roe & Rizwan Sarwar & Michal Pravenec & Norbert Hübner & Timothy J Aitman & Stuart A Cook & Sylvia Richardson, 2010. "New Insights into the Genetic Control of Gene Expression using a Bayesian Multi-tissue Approach," PLOS Computational Biology, Public Library of Science, vol. 6(4), pages 1-13, April.
    4. Michael Morley & Cliona M. Molony & Teresa M. Weber & James L. Devlin & Kathryn G. Ewens & Richard S. Spielman & Vivian G. Cheung, 2004. "Genetic analysis of genome-wide variation in human gene expression," Nature, Nature, vol. 430(7001), pages 743-747, August.
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    1. Noah Zaitlen & Peter Kraft & Nick Patterson & Bogdan Pasaniuc & Gaurav Bhatia & Samuela Pollack & Alkes L Price, 2013. "Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits," PLOS Genetics, Public Library of Science, vol. 9(5), pages 1-11, May.

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