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Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

Viñuela, Ana ; Varshney, Arushi ; van de Bunt, Martijn ; Prasad, Rashmi B LU ; Asplund, Olof LU ; Bennett, Amanda ; Boehnke, Michael ; Brown, Andrew A ; Erdos, Michael R and Fadista, João LU , et al. (2020) In Nature Communications 11(1). p.4912-4912
Abstract

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most... (More)

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
11
issue
1
pages
4912 - 4912
publisher
Nature Publishing Group
external identifiers
  • pmid:32999275
  • scopus:85091718759
ISSN
2041-1723
DOI
10.1038/s41467-020-18581-8
language
English
LU publication?
yes
id
0c14af81-5316-4d3f-b1cf-c300b2581719
date added to LUP
2020-10-10 12:32:02
date last changed
2021-01-26 01:26:58
@article{0c14af81-5316-4d3f-b1cf-c300b2581719,
  abstract     = {<p>Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.</p>},
  author       = {Viñuela, Ana and Varshney, Arushi and van de Bunt, Martijn and Prasad, Rashmi B and Asplund, Olof and Bennett, Amanda and Boehnke, Michael and Brown, Andrew A and Erdos, Michael R and Fadista, João and Hansson, Ola and Hatem, Gad and Howald, Cédric and Iyengar, Apoorva K and Johnson, Paul and Krus, Ulrika and MacDonald, Patrick E and Mahajan, Anubha and Manning Fox, Jocelyn E and Narisu, Narisu and Nylander, Vibe and Orchard, Peter and Oskolkov, Nikolay and Panousis, Nikolaos I and Payne, Anthony and Stitzel, Michael L and Vadlamudi, Swarooparani and Welch, Ryan and Collins, Francis S and Mohlke, Karen L and Gloyn, Anna L and Scott, Laura J and Dermitzakis, Emmanouil T and Groop, Leif and Parker, Stephen C J and McCarthy, Mark I},
  issn         = {2041-1723},
  language     = {eng},
  month        = {09},
  number       = {1},
  pages        = {4912--4912},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D},
  url          = {http://dx.doi.org/10.1038/s41467-020-18581-8},
  doi          = {10.1038/s41467-020-18581-8},
  volume       = {11},
  year         = {2020},
}