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, 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

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

Sammanfattning

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.

Originalspråk	engelska
Sidor (från-till)	4912
Tidskrift	Nature Communications
Volym	11
Nummer	1
DOI	https://doi.org/10.1038/s41467-020-18581-8
Status	Published - 2020 sep. 30

FN:s Globala mål

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SDG 3 – God hälsa och välbefinnande

Ämnesklassifikation (UKÄ)

Endokrinologi och diabetes

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10.1038/s41467-020-18581-8Licens: CC BY

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Data integration and visualization in type 2 diabetes research and care: From biological mechanisms to precision medicine.
Asplund, O., 2021, Lund: Lund University, Faculty of Medicine. 63 s.
Forskningsoutput: Avhandling › Doktorsavhandling (sammanläggning)

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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(1), 4912. https://doi.org/10.1038/s41467-020-18581-8

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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.",

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\}",

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month = sep,

day = "30",

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

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journal = "Nature Communications",

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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, nr. 1, s. 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

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.

UR - https://www.scopus.com/pages/publications/85091718759

U2 - 10.1038/s41467-020-18581-8

DO - 10.1038/s41467-020-18581-8

M3 - Article

C2 - 32999275

SN - 2041-1723

VL - 11

SP - 4912

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Sammanfattning

FN:s Globala mål

Ämnesklassifikation (UKÄ)

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Forskningsoutput

Data integration and visualization in type 2 diabetes research and care: From biological mechanisms to precision medicine.

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