Discovering Genetic Variation that Affects Expression in Multiple Tissues

Over the past several years, Genome Wide Association Studies (GWAS) have discovered hundreds of genetic variants involved in complex diseases(10.1056/NEJMra0905980).  The vast majority of these variants do not lie in the protein coding regions of genes and thus do not affect what the gene produces, but instead likely affect how the genes are regulated.  For this reason, the study of how genetic variation affect gene activity levels (referred to as expression levels) has been a major focus of research for many years.  Genetic variation that affects gene expression are referred to as expression quantitative trait loci (eQTL)(10.1038/nrg2969).

Several studies collect expression from multiple tissues which leads to the question of whether or not the same genetic variants affect expression in multiple tissues(10.1038/ng.2653).  Another way to ask this question is: Are eQTLs tissue specific or not tissue specific?

A challenge in this type of analysis is that an eQTL may affect expression in multiple tissues, but because of small sample sizes, the eQTL will only be detected in one of the tissues.  Thus, traditional techniques for eQTLs will systematically be biased against detecting eQTLs in multiple tissues.

Jae-Hoon Sul and Buhm Han in our group developed a method to address this issue which builds upon recent methods in random effects meta-analysis(10.1016/j.ajhg.2011.04.014),(10.1371/journal.pgen.1002555).  To apply these methods we first analyze each tissue separately and then use the meta-analysis method to combine the results of each tissue.  Since our methods are specifically designed to handle “heterogeneity” which is that the effect size can be different in each study, our method is able to perform well when the effect is present in all of the tissues or just some of the tissues.  More information about our meta-analysis research is here.

The full citation of our paper is here:

Sul, Jae Hoon; Han, Buhm ; Ye, Chun ; Choi, Ted ; Eskin, Eleazar

Effectively Identifying eQTLs from Multiple Tissues by Combining Mixed Model and Meta-analytic Approaches Journal Article

In: PLoS Genet, 9 (6), pp. e1003491, 2013, ISSN: 1553-7404.

Abstract | Links | BibTeX

Over the past few years, our group has published several papers on methods for eQTL analysis.  Our other paper on eQTL analysis include:


Gamazon, Eric R; Segrè, Ayellet V; van de Bunt, Martijn; Wen, Xiaoquan; Xi, Hualin S; Hormozdiari, Farhad; Ongen, Halit; Konkashbaev, Anuar; Derks, Eske M; Aguet, François; Quan, Jie; Nicolae, Dan L; Eskin, Eleazar; Kellis, Manolis; Getz, Gad; McCarthy, Mark I; Dermitzakis, Emmanouil T; Cox, Nancy J; Ardlie, Kristin G

Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Journal Article

In: Nat Genet, 50 (7), pp. 956-967, 2018, ISSN: 1546-1718.

Abstract | Links | BibTeX


Duong, Dat; Gai, Lisa; Snir, Sagi; Kang, Eun Yong; Han, Buhm; Sul, Jae Hoon; Eskin, Eleazar

Applying meta-analysis to genotype-tissue expression data from multiple tissues to identify eQTLs and increase the number of eGenes. Journal Article

In: Bioinformatics, 33 (14), pp. i67-i74, 2017, ISSN: 1367-4811.

Abstract | Links | BibTeX


Duong, Dat ; Zou, Jennifer ; Hormozdiari, Farhad ; Sul, Jae Hoon ; Ernst, Jason ; Han, Buhm ; Eskin, Eleazar

Using genomic annotations increases statistical power to detect eGenes. Journal Article

In: Bioinformatics, 32 (12), pp. i156-i163, 2016, ISSN: 1367-4811.

Abstract | Links | BibTeX

Kang, Eun Yong; Martin, Lisa; Mangul, Serghei; Isvilanonda, Warin; Zou, Jennifer; Ben-David, Eyal; Han, Buhm; Lusis, Aldons J; Shifman, Sagiv; Eskin, Eleazar

Discovering SNPs Regulating Human Gene Expression Using Allele Specific Expression from RNA-Seq Data. Journal Article

In: Genetics, 2016, ISSN: 1943-2631.

Abstract | Links | BibTeX

Hormozdiari, Farhad; van de Bunt, Martijn; Segrè, Ayellet V; Li, Xiao; Joo, Jong Wha J; Bilow, Michael; Sul, Jae Hoon; Sankararaman, Sriram; Pasaniuc, Bogdan; Eskin, Eleazar

Colocalization of GWAS and eQTL Signals Detects Target Genes. Journal Article

In: Am J Hum Genet, 2016, ISSN: 1537-6605.

Abstract | Links | BibTeX

Peterson, Christine B; Service, Susan K; Jasinska, Anna J; Gao, Fuying; Zelaya, Ivette; Teshiba, Terri M; Bearden, Carrie E; Cantor, Rita M; Reus, Victor I; Macaya, Gabriel; López-Jaramillo, Carlos; Bogomolov, Marina; Benjamini, Yoav; Eskin, Eleazar; Coppola, Giovanni; Freimer, Nelson B; Sabatti, Chiara

Characterization of Expression Quantitative Trait Loci in Pedigrees from Colombia and Costa Rica Ascertained for Bipolar Disorder. Journal Article

In: PLoS Genet, 12 (5), pp. e1006046, 2016, ISSN: 1553-7404.

Abstract | Links | BibTeX

Hasin-Brumshtein, Yehudit; Khan, Arshad H; Hormozdiari, Farhad; Pan, Calvin; Parks, Brian W; Petyuk, Vladislav A; Piehowski, Paul D; Brümmer, Anneke; Pellegrini, Matteo; Xiao, Xinshu; Eskin, Eleazar; Smith, Richard D; Lusis, Aldons J; Smith, Desmond J

Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes. Journal Article

In: Elife, 5 , 2016, ISSN: 2050-084X.

Abstract | Links | BibTeX


Sul, Jae Hoon; Raj, Towfique; de Jong, Simone; de Bakker, Paul I W; Raychaudhuri, Soumya; Ophoff, Roel A; Stranger, Barbara E; Eskin, Eleazar; Han, Buhm

Accurate and Fast Multiple-Testing Correction in eQTL Studies. Journal Article

In: Am J Hum Genet, 96 (6), pp. 857-68, 2015, ISSN: 1537-6605.

Abstract | Links | BibTeX


Joo, Jong Wha J; Sul, Jae Hoon ; Han, Buhm ; Ye, Chun ; Eskin, Eleazar

Effectively identifying regulatory hotspots while capturing expression heterogeneity in gene expression studies. Journal Article

In: Genome Biol, 15 (4), pp. R61, 2014, ISSN: 1465-6914.

Abstract | Links | BibTeX


Kostem, Emrah; Eskin, Eleazar

Efficiently Identifying Significant Associations in Genome-Wide Association Studies Conference

Research in Computational Molecular Biology, University of California Springer Berlin Heidelberg, 2013.

Abstract | Links | BibTeX

Kostem, Emrah; Eskin, Eleazar

Efficiently Identifying Significant Associations in Genome-wide Association Studies. Journal Article

In: J Comput Biol, 20 (10), pp. 817-30, 2013, ISSN: 1557-8666.

Abstract | Links | BibTeX


Kang, Eun Yong; Ye, Chun ; Shpitser, Ilya ; Eskin, Eleazar

Detecting the presence and absence of causal relationships between expression of yeast genes with very few samples. Journal Article

In: J Comput Biol, 17 (3), pp. 533-46, 2010, ISSN: 1557-8666.

Abstract | Links | BibTeX


Ye, Chun; Galbraith, Simon J; Liao, James C; Eskin, Eleazar

Using network component analysis to dissect regulatory networks mediated by transcription factors in yeast. Journal Article

In: PLoS Comput Biol, 5 (3), pp. e1000311, 2009, ISSN: 1553-7358.

Abstract | Links | BibTeX


Kang, Hyun Min; Ye, Chun ; Eskin, Eleazar

Accurate discovery of expression quantitative trait loci under confounding from spurious and genuine regulatory hotspots. Journal Article

In: Genetics, 180 (4), pp. 1909-25, 2008, ISSN: 0016-6731.

Abstract | Links | BibTeX