Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations

Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations

Mapping expression quantitative trait loci (eQTL) has identified genetic variants associated with transcription rates and has provided insight into genotype–phenotype associations obtained from genome-wide association studies (GWAS). Traditional eQTL mapping methods present significant challenges fo...

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Main Authors: Weiser, Matthew, Mukherjee, Sayan, Furey, Terrence S.
Format: Online
Language:English
Published: Genetics Society of America 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224177/
id pubmed-4224177
recordtype oai_dc
spelling pubmed-42241772014-11-10 Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations Weiser, Matthew Mukherjee, Sayan Furey, Terrence S. Investigations Mapping expression quantitative trait loci (eQTL) has identified genetic variants associated with transcription rates and has provided insight into genotype–phenotype associations obtained from genome-wide association studies (GWAS). Traditional eQTL mapping methods present significant challenges for the multiple-testing burden, resulting in a limited ability to detect eQTL that reside distal to the affected gene. To overcome this, we developed a novel eQTL testing approach, “network-based, large-scale identification of distal eQTL” (NetLIFT), which performs eQTL testing based on the pairwise conditional dependencies between genes’ expression levels. When applied to existing data from yeast segregants, NetLIFT replicated most previously identified distal eQTL and identified 46% more genes with distal effects compared to local effects. In liver data from mouse lines derived through the Collaborative Cross project, NetLIFT detected 5744 genes with local eQTL while 3322 genes had distal eQTL. This analysis revealed founder-of-origin effects for a subset of local eQTL that may contribute to previously described phenotypic differences in metabolic traits. In human lymphoblastoid cell lines, NetLIFT was able to detect 1274 transcripts with distal eQTL that had not been reported in previous studies, while 2483 transcripts with local eQTL were identified. In all species, we found no enrichment for transcription factors facilitating eQTL associations; instead, we found that most trans-acting factors were annotated for metabolic function, suggesting that genetic variation may indirectly regulate multigene pathways by targeting key components of feedback processes within regulatory networks. Furthermore, the unique genetic history of each population appears to influence the detection of genes with local and distal eQTL. Genetics Society of America 2014-11 2014-09-16 /pmc/articles/PMC4224177/ /pubmed/25230953 http://dx.doi.org/10.1534/genetics.114.167791 Text en Copyright © 2014 by the Genetics Society of America Available freely online through the author-supported open access option.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Weiser, Matthew
Mukherjee, Sayan
Furey, Terrence S.
spellingShingle Weiser, Matthew
Mukherjee, Sayan
Furey, Terrence S.
Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations
author_facet Weiser, Matthew
Mukherjee, Sayan
Furey, Terrence S.
author_sort Weiser, Matthew
title Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations
title_short Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations
title_full Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations
title_fullStr Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations
title_full_unstemmed Novel Distal eQTL Analysis Demonstrates Effect of Population Genetic Architecture on Detecting and Interpreting Associations
title_sort novel distal eqtl analysis demonstrates effect of population genetic architecture on detecting and interpreting associations
description Mapping expression quantitative trait loci (eQTL) has identified genetic variants associated with transcription rates and has provided insight into genotype–phenotype associations obtained from genome-wide association studies (GWAS). Traditional eQTL mapping methods present significant challenges for the multiple-testing burden, resulting in a limited ability to detect eQTL that reside distal to the affected gene. To overcome this, we developed a novel eQTL testing approach, “network-based, large-scale identification of distal eQTL” (NetLIFT), which performs eQTL testing based on the pairwise conditional dependencies between genes’ expression levels. When applied to existing data from yeast segregants, NetLIFT replicated most previously identified distal eQTL and identified 46% more genes with distal effects compared to local effects. In liver data from mouse lines derived through the Collaborative Cross project, NetLIFT detected 5744 genes with local eQTL while 3322 genes had distal eQTL. This analysis revealed founder-of-origin effects for a subset of local eQTL that may contribute to previously described phenotypic differences in metabolic traits. In human lymphoblastoid cell lines, NetLIFT was able to detect 1274 transcripts with distal eQTL that had not been reported in previous studies, while 2483 transcripts with local eQTL were identified. In all species, we found no enrichment for transcription factors facilitating eQTL associations; instead, we found that most trans-acting factors were annotated for metabolic function, suggesting that genetic variation may indirectly regulate multigene pathways by targeting key components of feedback processes within regulatory networks. Furthermore, the unique genetic history of each population appears to influence the detection of genes with local and distal eQTL.
publisher Genetics Society of America
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224177/
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