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

Ana Viñuela; Arushi Varshney; Martijn van de Bunt; Rashmi B. Prasad; Olof Asplund; Amanda Bennett; Michael Boehnke; Andrew A. 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:10.1038/s41467-020-18581-8

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

Ana Viñuela (Lead / Corresponding author), Arushi Varshney, Martijn van de Bunt, Rashmi B. Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew A. 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 NarisuVibe 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

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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 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.

Original language	English
Article number	4912
Number of pages	14
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-18581-8
Publication status	Published - 30 Sept 2020

Keywords

Data acquisition
Gene regulation
Genetic association study
Type 2 diabetes

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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

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10.1038/s41467-020-18581-8

Final Published VersionFinal published version, 4.33 MBLicence: CC BY

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Viñuela, A., 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., ... McCarthy, M. I. (2020). Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D. Nature Communications, 11, Article 4912. https://doi.org/10.1038/s41467-020-18581-8

@article{68d00a3252214571a37664b34f86acca,

title = "Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D",

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 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.",

keywords = "Data acquisition, Gene regulation, Genetic association study, Type 2 diabetes",

author = "Ana Vi{\~n}uela and Arushi Varshney and {van de Bunt}, Martijn and Prasad, {Rashmi B.} and Olof Asplund and Amanda Bennett and Michael Boehnke and Brown, {Andrew A.} 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 {Manning Fox}, {Jocelyn E.} 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.}",

note = "Funding Information: A.Vi. and E.T.D. were supported by EU IMI program (UE7-DIRECT-115317-1), NIH (NIH-R01-MH101814), and FNS funded project RNA1 (31003A_149984). A.Va. was supported by the American Association for University Women International Doctoral Fellowship, Barbour Doctoral Scholarship, and the University of Michigan Rackham Predoctoral Fellowship. M.v.d.B. was supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. R.B.P. was supported by the EFSD/Novo Nordisk Programme for Diabetes Research in Europe, Diabetes Wellness (720-858-16 JDWG), {\AA}ke Wiberg Foundation (M18-0216). L.G. was supported by the Swedish Research Council project grant (2015-2558) Swedish Research Council, Astra Zeneca (10033731), Strategic Research Area Exodiab, Dnr 2009-1039, Swedish Foundation for Strategic Research Dnr IRC15-0067, and the Swedish Research Council, Linnaeus grant, Dnr 349-2006-237. F.S.C., M.R.E., and N.N. were supported by NHGRI-ZIA HG000024. A.K.I., S.V., and K.L.M. were supported by NIH R01 DK072193 and NIH U01 DK105561. S.C.J.P., L.J.S., and M.B. were supported by U01DK062370. M.L.S. was supported by K99/R00DK092251. P.O. was supported by grant T32 HG00040 from the National Human Genome Research Institute of the NIH. P.E.M. was supported by a Foundation grant from the Canadian Institutes of Health Research (CIHR: 148451). S.C. J.P. was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R00 DK-099240 and R01 DK-117960, American Diabetes Association Pathway to Stop Diabetes grant 1–14-INI-7. The Alberta Diabetes Institute IsletCore was supported by the Alberta Diabetes Foundation. We thank the Human Organ Procurement and Exchange (HOPE) program and the Trillium Gift of Life Network (TGLN) for their efforts in obtaining human organs for research. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. This work was funded in Oxford by the Wellcome Trust (095101, 200837, 106130, 203141, Medical Research Council (MR/L020149/1), European Union Horizon 2020 Programme (T2D Systems), NIH (U01-DK105535; U01-DK085545) and by the EU IMI program (UE7-DIRECT-115317-1). M.I.Mc.C was a Wellcome Senior Investigator and an NIHR Senior Investigator. He was supported by the Wellcome Trust (grants nos. 090532, 106130, 098381, 203141, and 212259); Medical Research Council grant no. MR/L020149/1; NIDDK (U01-DK105535, R01-MH101814, and R01-MH090941); NIHR (NF-SI-0617-10090). This work was also supported by the Oxford NIHR Biomedical Research Centre. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly; and received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, he is an employee of Genentech, and a holder of Roche stock. M.v.d.B. is an employee of Novo Nordisk A/S, although all experimental work was carried out under employment at the University of Oxford. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = sep,

day = "30",

doi = "10.1038/s41467-020-18581-8",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Viñuela, A, Varshney, A, van de Bunt, M, Prasad, RB, Asplund, O, Bennett, A, Boehnke, M, Brown, AA, Erdos, MR, Fadista, J, Hansson, O, Hatem, G, Howald, C, Iyengar, AK, Johnson, P, Krus, U, MacDonald, PE, Mahajan, A, Manning Fox, JE, 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 2020, 'Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D', Nature Communications, vol. 11, 4912. https://doi.org/10.1038/s41467-020-18581-8

TY - JOUR

T1 - Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

AU - Viñuela, Ana

AU - Varshney, Arushi

AU - van de Bunt, Martijn

AU - Prasad, Rashmi B.

AU - Asplund, Olof

AU - Bennett, Amanda

AU - Boehnke, Michael

AU - Brown, Andrew A.

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 - Manning Fox, Jocelyn E.

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.

N1 - Funding Information: A.Vi. and E.T.D. were supported by EU IMI program (UE7-DIRECT-115317-1), NIH (NIH-R01-MH101814), and FNS funded project RNA1 (31003A_149984). A.Va. was supported by the American Association for University Women International Doctoral Fellowship, Barbour Doctoral Scholarship, and the University of Michigan Rackham Predoctoral Fellowship. M.v.d.B. was supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. R.B.P. was supported by the EFSD/Novo Nordisk Programme for Diabetes Research in Europe, Diabetes Wellness (720-858-16 JDWG), Åke Wiberg Foundation (M18-0216). L.G. was supported by the Swedish Research Council project grant (2015-2558) Swedish Research Council, Astra Zeneca (10033731), Strategic Research Area Exodiab, Dnr 2009-1039, Swedish Foundation for Strategic Research Dnr IRC15-0067, and the Swedish Research Council, Linnaeus grant, Dnr 349-2006-237. F.S.C., M.R.E., and N.N. were supported by NHGRI-ZIA HG000024. A.K.I., S.V., and K.L.M. were supported by NIH R01 DK072193 and NIH U01 DK105561. S.C.J.P., L.J.S., and M.B. were supported by U01DK062370. M.L.S. was supported by K99/R00DK092251. P.O. was supported by grant T32 HG00040 from the National Human Genome Research Institute of the NIH. P.E.M. was supported by a Foundation grant from the Canadian Institutes of Health Research (CIHR: 148451). S.C. J.P. was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R00 DK-099240 and R01 DK-117960, American Diabetes Association Pathway to Stop Diabetes grant 1–14-INI-7. The Alberta Diabetes Institute IsletCore was supported by the Alberta Diabetes Foundation. We thank the Human Organ Procurement and Exchange (HOPE) program and the Trillium Gift of Life Network (TGLN) for their efforts in obtaining human organs for research. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. This work was funded in Oxford by the Wellcome Trust (095101, 200837, 106130, 203141, Medical Research Council (MR/L020149/1), European Union Horizon 2020 Programme (T2D Systems), NIH (U01-DK105535; U01-DK085545) and by the EU IMI program (UE7-DIRECT-115317-1). M.I.Mc.C was a Wellcome Senior Investigator and an NIHR Senior Investigator. He was supported by the Wellcome Trust (grants nos. 090532, 106130, 098381, 203141, and 212259); Medical Research Council grant no. MR/L020149/1; NIDDK (U01-DK105535, R01-MH101814, and R01-MH090941); NIHR (NF-SI-0617-10090). This work was also supported by the Oxford NIHR Biomedical Research Centre. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly; and received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, he is an employee of Genentech, and a holder of Roche stock. M.v.d.B. is an employee of Novo Nordisk A/S, although all experimental work was carried out under employment at the University of Oxford. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/9/30

Y1 - 2020/9/30

N2 - 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.

AB - 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.

KW - Data acquisition

KW - Gene regulation

KW - Genetic association study

KW - Type 2 diabetes

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U2 - 10.1038/s41467-020-18581-8

DO - 10.1038/s41467-020-18581-8

M3 - Article

C2 - 32999275

AN - SCOPUS:85091718759

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 4912

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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

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