Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Dorret Boomsma; Michel G. Nivard; eQTLGen Consortium

doi:10.1038/s41467-018-04951-w

Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Dorret Boomsma
, Michel G. Nivard
, eQTLGen Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

Original language	English
Article number	2941
Number of pages	14
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04951-w
Publication status	Published - 27 Jul 2018

Funding

This research was supported by the Australian National Health and Medical Research Council (1107258, 1083656, 1078037, and 1113400), Australian Research Council grants (DP160101056, DP160103860, and DP160102400), the US National Institutes of Health (R01 MH100141, P01 GM099568, R01 GM075091, R01 AG042568, and R21 ES025052), and the Sylvia & Charles Viertel Charitable Foundation. Yeda Wu is supported by the F.G. Meade Scholarship and UQ Research Training Scholarship from the University of Queensland. This study makes use of data from dbGaP (accession: phs000674.v2.p2) and UK Biobank (project ID: 12505). A full list of acknowledgments of these data sets can be found in Supplementary Note 13.

Funders	Funder number
Australian National Health and Medical Research Council	1107258, 1083656, 1113400, 1078037
US National Institutes of Health	R21 ES025052, R01 AG042568, P01 GM099568, R01 GM075091, R01 MH100141
National Institute on Aging	R01AG042568
Sylvia and Charles Viertel Charitable Foundation
Australian Research Council	DP160102400, DP160101056, DP160103860
University of Queensland

UN SDGs

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

SDG 3 Good Health and Well-being

Cohort Studies

Netherlands Twin Register (NTR)

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10.1038/s41467-018-04951-w

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title = "Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes",

abstract = "Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with \textasciitilde{}16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.",

author = "Angli Xue and Yang Wu and Zhihong Zhu and Futao Zhang and Kemper, \{Kathryn E.\} and Zhili Zheng and Loic Yengo and Lloyd-Jones, \{Luke R.\} and Julia Sidorenko and Yeda Wu and Mawuss{\'e} Agbessi and Habibul Ahsan and Isabel Alves and Anand Andiappan and Philip Awadalla and Alexis Battle and Frank Beutner and Bonder, \{Marc Jan J.\} and Dorret Boomsma and Mark Christiansen and Annique Claringbould and Patrick Deelen and T{\~o}nu Esko and Fav{\'e}, \{Marie Julie\} and Lude Franke and Timothy Frayling and Sina Gharib and Gregory Gibson and Gibran Hemani and Rick Jansen and Mika K{\"a}h{\"o}nen and Anette Kalnapenkis and Silva Kasela and Johannes Kettunen and Yungil Kim and Holger Kirsten and Peter Kovacs and Knut Krohn and Jaanika Kronberg-Guzman and Viktorija Kukushkina and Zoltan Kutalik and Bernett Lee and Terho Lehtim{\"a}ki and Markus Loeffler and Marigorta, \{Urko M.\} and Andres Metspalu and Lili Milani and Martina M{\"u}ller-Nurasyid and Matthias Nauck and Nivard, \{Michel G.\} and \{eQTLGen Consortium\}",

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AU - Xue, Angli

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AU - Zhu, Zhihong

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AU - Zheng, Zhili

AU - Yengo, Loic

AU - Lloyd-Jones, Luke R.

AU - Sidorenko, Julia

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AU - Agbessi, Mawussé

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AU - Alves, Isabel

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AU - Awadalla, Philip

AU - Battle, Alexis

AU - Beutner, Frank

AU - Bonder, Marc Jan J.

AU - Boomsma, Dorret

AU - Christiansen, Mark

AU - Claringbould, Annique

AU - Deelen, Patrick

AU - Esko, Tõnu

AU - Favé, Marie Julie

AU - Franke, Lude

AU - Frayling, Timothy

AU - Gharib, Sina

AU - Gibson, Gregory

AU - Hemani, Gibran

AU - Jansen, Rick

AU - Kähönen, Mika

AU - Kalnapenkis, Anette

AU - Kasela, Silva

AU - Kettunen, Johannes

AU - Kim, Yungil

AU - Kirsten, Holger

AU - Kovacs, Peter

AU - Krohn, Knut

AU - Kronberg-Guzman, Jaanika

AU - Kukushkina, Viktorija

AU - Kutalik, Zoltan

AU - Lee, Bernett

AU - Lehtimäki, Terho

AU - Loeffler, Markus

AU - Marigorta, Urko M.

AU - Metspalu, Andres

AU - Milani, Lili

AU - Müller-Nurasyid, Martina

AU - Nauck, Matthias

AU - Nivard, Michel G.

AU - eQTLGen Consortium

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JF - Nature Communications

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Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Abstract

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