Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

Ana Viñuela; Arushi Varshney; Martijn van de Bunt; Rashmi B. Prasad; Olof Asplund; Amanda Bennett; Michael Boehnke; Andrew Brown; Michael R. Erdos; João Fadista; Ola Hansson; Gad Hatem; Cédric Howald; Apoorva K. Iyengar; Paul Johnson; Ulrika Krus; Patrick E. MacDonald; Anubha Mahajan; Jocelyn E. Manning Fox; Narisu Narisu; Vibe Nylander; Peter Orchard; Nikolay Oskolkov; Nikolaos I. Panousis; Anthony Payne; Michael L. Stitzel; Swarooparani Vadlamudi; Ryan Welch; Francis S. Collins; Karen L. Mohlke; Anna L. Gloyn; Laura J. Scott; Emmanouil T. Dermitzakis; Leif Groop; Stephen C.J. Parker; Mark I. McCarthy

doi:10.1101/655670

Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

Ana Viñuela (Lead / Corresponding author)
, Arushi Varshney
, Martijn van de Bunt
, Rashmi B. Prasad
, Olof Asplund
, Amanda Bennett
, Michael Boehnke
, Andrew Brown
, Michael R. Erdos
, João Fadista
, Ola Hansson
, Gad Hatem
, Cédric Howald
, Apoorva K. Iyengar
, Paul Johnson
, Ulrika Krus
, Patrick E. MacDonald
, Anubha Mahajan
, Jocelyn E. Manning Fox
, Narisu Narisu

Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I. Panousis, Anthony Payne, Michael L. Stitzel, Swarooparani Vadlamudi, Ryan Welch, Francis S. Collins, Karen L. Mohlke, Anna L. Gloyn, Laura J. Scott, Emmanouil T. Dermitzakis, Leif Groop, Stephen C.J. Parker, Mark I. McCarthy (Lead / Corresponding author)

Population Health and Genomics

Research output: Working paper/Preprint › Preprint

64 Downloads (Pure)

Abstract

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.

Original language	English
Publisher	BioRxiv
Number of pages	39
DOIs	https://doi.org/10.1101/655670
Publication status	Published - 31 May 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1101/655670Licence: CC BY

Submitted manuscriptSubmitted manuscript, 1.84 MBLicence: CC BY

1 Article

Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D
Viñuela, A. (Lead / Corresponding author), Varshney, A., van de Bunt, M., Prasad, R. B., Asplund, O., Bennett, A., Boehnke, M., Brown, A. A., Erdos, M. R., Fadista, J., Hansson, O., Hatem, G., Howald, C., Iyengar, A. K., Johnson, P., Krus, U., MacDonald, P. E., Mahajan, A., Manning Fox, J. E. & Narisu, N. & 16 others, Nylander, V., Orchard, P., Oskolkov, N., Panousis, N. I., Payne, A., Stitzel, M. L., Vadlamudi, S., Welch, R., Collins, F. S., Mohlke, K. L., Gloyn, A. L., Scott, L. J., Dermitzakis, E. T., Groop, L., Parker, S. C. J. & McCarthy, M. I. (Lead / Corresponding author), 30 Sept 2020, In: Nature Communications. 11, 14 p., 4912.
Research output: Contribution to journal › Article › peer-review

Open Access
File
107 Link opens in a new tab Citations (Scopus)

213 Downloads (Pure)

Summary statistics for the InsPIRE consortium (pancreatic islets eQTLs)
Viñuela, A. (Creator), Varshney, A. (Creator), van de Bunt, M. (Creator), Prasad, R. B. (Creator), Asplund, O. (Creator), Bennett, A. J. (Creator), Boehnke, M. (Creator), Brown, A. (Creator), Erdos, M. R. (Creator), Fadista, J. (Creator), Hansson, O. (Creator), Hatem, G. (Creator), Howald, C. (Creator), Iyengar, A. K. (Creator), Johnston, P. (Creator), Krus, U. (Creator), MacDonald, P. E. (Creator), Mahajan, A. (Creator), Manning Fox, J. E. (Creator), Narisu, N. (Creator), Nylander, V. (Creator), Orchard, P. (Creator), Panousis, N. I. (Creator), Payne, A. J. (Creator), Stitzel, M. L. (Creator), Vadlamudi, S. (Creator), Welch, R. P. (Creator), Collins, F. S. (Creator), Mohlke, K. L. (Creator), Gloyn, A. L. (Creator), Scott, L. J. (Creator), Dermitzakis, E. T. (Creator), Groop, L. (Creator), Parker, S. C. J. (Creator) & McCarthy, M. I. (Creator), Zenodo, 14 Sept 2019
DOI: 10.5281/zenodo.3408355, https://zenodo.org/records/3408356
Dataset

Cite this

Viñuela, A., Varshney, A., Bunt, M. V. D., Prasad, R. B., Asplund, O., Bennett, A., Boehnke, M., Brown, A., Erdos, M. R., Fadista, J., Hansson, O., Hatem, G., Howald, C., Iyengar, A. K., Johnson, P., Krus, U., MacDonald, P. E., Mahajan, A., Fox, J. E. M., ... McCarthy, M. I. (2019). Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes. BioRxiv. https://doi.org/10.1101/655670

@techreport{c5ec8f486367490596132e3506f329ee,

title = "Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes",

abstract = "Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73\%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.",

author = "Ana Vi{\~n}uela and Arushi Varshney and Bunt, \{Martijn van de\} and Prasad, \{Rashmi B.\} and Olof Asplund and Amanda Bennett and Michael Boehnke and Andrew Brown and Erdos, \{Michael R.\} and Jo{\~a}o Fadista and Ola Hansson and Gad Hatem and C{\'e}dric Howald and Iyengar, \{Apoorva K.\} and Paul Johnson and Ulrika Krus and MacDonald, \{Patrick E.\} and Anubha Mahajan and Fox, \{Jocelyn E. Manning\} and Narisu Narisu and Vibe Nylander and Peter Orchard and Nikolay Oskolkov and Panousis, \{Nikolaos I.\} and Anthony Payne and Stitzel, \{Michael L.\} and Swarooparani Vadlamudi and Ryan Welch and Collins, \{Francis S.\} and Mohlke, \{Karen L.\} and Gloyn, \{Anna L.\} and Scott, \{Laura J.\} and Dermitzakis, \{Emmanouil T.\} and Leif Groop and Parker, \{Stephen C.J.\} and McCarthy, \{Mark I.\}",

year = "2019",

month = may,

day = "31",

doi = "10.1101/655670",

language = "English",

publisher = "BioRxiv",

address = "United States",

type = "WorkingPaper",

institution = "BioRxiv",

}

Viñuela, A, Varshney, A, Bunt, MVD, Prasad, RB, Asplund, O, Bennett, A, Boehnke, M, Brown, A, Erdos, MR, Fadista, J, Hansson, O, Hatem, G, Howald, C, Iyengar, AK, Johnson, P, Krus, U, MacDonald, PE, Mahajan, A, Fox, JEM, Narisu, N, Nylander, V, Orchard, P, Oskolkov, N, Panousis, NI, Payne, A, Stitzel, ML, Vadlamudi, S, Welch, R, Collins, FS, Mohlke, KL, Gloyn, AL, Scott, LJ, Dermitzakis, ET, Groop, L, Parker, SCJ & McCarthy, MI 2019 'Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes' BioRxiv. https://doi.org/10.1101/655670

TY - UNPB

T1 - Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

AU - Viñuela, Ana

AU - Varshney, Arushi

AU - Bunt, Martijn van de

AU - Prasad, Rashmi B.

AU - Asplund, Olof

AU - Bennett, Amanda

AU - Boehnke, Michael

AU - Brown, Andrew

AU - Erdos, Michael R.

AU - Fadista, João

AU - Hansson, Ola

AU - Hatem, Gad

AU - Howald, Cédric

AU - Iyengar, Apoorva K.

AU - Johnson, Paul

AU - Krus, Ulrika

AU - MacDonald, Patrick E.

AU - Mahajan, Anubha

AU - Fox, Jocelyn E. Manning

AU - Narisu, Narisu

AU - Nylander, Vibe

AU - Orchard, Peter

AU - Oskolkov, Nikolay

AU - Panousis, Nikolaos I.

AU - Payne, Anthony

AU - Stitzel, Michael L.

AU - Vadlamudi, Swarooparani

AU - Welch, Ryan

AU - Collins, Francis S.

AU - Mohlke, Karen L.

AU - Gloyn, Anna L.

AU - Scott, Laura J.

AU - Dermitzakis, Emmanouil T.

AU - Groop, Leif

AU - Parker, Stephen C.J.

AU - McCarthy, Mark I.

PY - 2019/5/31

Y1 - 2019/5/31

N2 - Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.

AB - Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.

U2 - 10.1101/655670

DO - 10.1101/655670

M3 - Preprint

BT - Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

PB - BioRxiv

ER -

Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

Abstract

UN SDGs

Access to Document

Fingerprint

Research output

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

Datasets

Summary statistics for the InsPIRE consortium (pancreatic islets eQTLs)

Cite this