Meta-Analysis

. 2022 Apr 7;5(1):329.

doi: 10.1038/s42003-022-03248-5.

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Marie Loh^#^{1

2}, Weihua Zhang^#^{2

3}, Hong Kiat Ng¹, Katharina Schmid^{4

5}, Amel Lamri^{6

7}, Lin Tong⁸, Meraj Ahmad⁹, Jung-Jin Lee^{10

11}, Maggie C Y Ng^{12

13}, Lauren E Petty^{13

14}, Cassandra N Spracklen^{15

16}, Fumihiko Takeuchi¹⁷, Md Tariqul Islam¹⁸, Farzana Jasmine⁸, Anuradhani Kasturiratne¹⁹, Muhammad Kibriya⁸, Karen L Mohlke¹⁵, Guillaume Paré^{7

20}, Gauri Prasad^{21

22}, Mohammad Shahriar⁸, Miao Ling Chee²³, H Janaka de Silva²⁴, James C Engert^{25

26}, Hertzel C Gerstein^{6

7

27}, K Radha Mani⁹, Charumathi Sabanayagam^{23

28}, Marijana Vujkovic²⁹, Ananda R Wickremasinghe¹⁹, Tien Yin Wong^{23

28

30}, Chittaranjan S Yajnik³¹, Salim Yusuf^{6

7

27}, Habibul Ahsan⁸, Dwaipayan Bharadwaj^{21

22}, Sonia S Anand^{6

7

27}, Jennifer E Below^{13

14}, Michael Boehnke³², Donald W Bowden^{11

33}, Giriraj R Chandak^{9

34

35}, Ching-Yu Cheng^{23

28

30}, Norihiro Kato¹⁷, Anubha Mahajan^{36

37}, Xueling Sim³⁸, Mark I McCarthy^{36

37

39}, Andrew P Morris^{40

41

42}, Jaspal S Kooner^#^{43

44

45

46}, Danish Saleheen^#^{47

48

49}, John C Chambers^#^{50

51

52

53

54}

Affiliations

¹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.
² Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK.
³ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK.
⁴ Institute of Computational Biology, Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
⁵ Department of Informatics, Technical University of Munich, 85748, Garching bei München, Neuherberg, Germany.
⁶ Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁷ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
⁸ The University of Chicago, Biological Sciences Division, Public Health Sciences, 5841 South Maryland Avenue, MC2000, Chicago, IL, 60637, USA.
⁹ Genomic Research on Complex diseases, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India.
¹⁰ Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹¹ Department of Medicine, Mayo Hospital, Lahore, Pakistan.
¹² Center for Genomics and Personalized Medicine Research, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, 37215, USA.
¹³ Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
¹⁴ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
¹⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
¹⁶ Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA, 01003, USA.
¹⁷ Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
¹⁸ U Chicago Research Bangladesh, House#4, Road#2b, Sector#4, Uttara, Dhaka, 1230, Bangladesh.
¹⁹ Department of Public Health, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka.
²⁰ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
²¹ Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110020, India.
²² Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
²³ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
²⁴ Department of Medicine, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka.
²⁵ Department of Medicine, McGill University, Montreal, QC, Canada.
²⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada.
²⁷ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
²⁸ Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
²⁹ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.
³⁰ Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³¹ Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India.
³² Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, 48109, USA.
³³ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 37215, USA.
³⁴ JSS Academy of Health Education of Research, Mysuru, India.
³⁵ Science and Engineering Research Board, Department of Science and Technology, Ministry of Science and technology, Government of India, New Delhi, India.
³⁶ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
³⁷ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
³⁸ Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
³⁹ Oxford NIHR Biomedical Research Centre, Churchill Hosptial, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK.
⁴⁰ Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK.
⁴¹ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
⁴³ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK. j.kooner@ic.ac.uk.
⁴⁴ Imperial College Healthcare NHS Trust, Imperial College London, London, W12 0HS, UK. j.kooner@ic.ac.uk.
⁴⁵ MRC-PHE Centre for Enviroment and Health, Imperial College London, London, W2 1PG, UK. j.kooner@ic.ac.uk.
⁴⁶ National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK. j.kooner@ic.ac.uk.
⁴⁷ Center for Non-Communicable Diseases, Karachi, Pakistan. ds3792@cumc.columbia.edu.
⁴⁸ Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA. ds3792@cumc.columbia.edu.
⁴⁹ Department of Cardiology, Columbia University Irving Medical Center, New York, NY, 10032, USA. ds3792@cumc.columbia.edu.
⁵⁰ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore. john.chambers@ntu.edu.sg.
⁵¹ Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK. john.chambers@ntu.edu.sg.
⁵² Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK. john.chambers@ntu.edu.sg.
⁵³ Imperial College Healthcare NHS Trust, Imperial College London, London, W12 0HS, UK. john.chambers@ntu.edu.sg.
⁵⁴ MRC-PHE Centre for Enviroment and Health, Imperial College London, London, W2 1PG, UK. john.chambers@ntu.edu.sg.

^# Contributed equally.

PMID: 35393509
PMCID: PMC8991226
DOI: 10.1038/s42003-022-03248-5

Meta-Analysis

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Marie Loh et al. Commun Biol. 2022.

. 2022 Apr 7;5(1):329.

doi: 10.1038/s42003-022-03248-5.

Authors

Affiliations

¹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.
² Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK.
³ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK.
⁴ Institute of Computational Biology, Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
⁵ Department of Informatics, Technical University of Munich, 85748, Garching bei München, Neuherberg, Germany.
⁶ Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁷ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
⁸ The University of Chicago, Biological Sciences Division, Public Health Sciences, 5841 South Maryland Avenue, MC2000, Chicago, IL, 60637, USA.
⁹ Genomic Research on Complex diseases, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India.
¹⁰ Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹¹ Department of Medicine, Mayo Hospital, Lahore, Pakistan.
¹² Center for Genomics and Personalized Medicine Research, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, 37215, USA.
¹³ Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
¹⁴ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
¹⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
¹⁶ Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA, 01003, USA.
¹⁷ Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
¹⁸ U Chicago Research Bangladesh, House#4, Road#2b, Sector#4, Uttara, Dhaka, 1230, Bangladesh.
¹⁹ Department of Public Health, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka.
²⁰ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
²¹ Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110020, India.
²² Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
²³ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
²⁴ Department of Medicine, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka.
²⁵ Department of Medicine, McGill University, Montreal, QC, Canada.
²⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada.
²⁷ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
²⁸ Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
²⁹ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.
³⁰ Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³¹ Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India.
³² Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, 48109, USA.
³³ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 37215, USA.
³⁴ JSS Academy of Health Education of Research, Mysuru, India.
³⁵ Science and Engineering Research Board, Department of Science and Technology, Ministry of Science and technology, Government of India, New Delhi, India.
³⁶ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
³⁷ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
³⁸ Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
³⁹ Oxford NIHR Biomedical Research Centre, Churchill Hosptial, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK.
⁴⁰ Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK.
⁴¹ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
⁴³ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK. j.kooner@ic.ac.uk.
⁴⁴ Imperial College Healthcare NHS Trust, Imperial College London, London, W12 0HS, UK. j.kooner@ic.ac.uk.
⁴⁵ MRC-PHE Centre for Enviroment and Health, Imperial College London, London, W2 1PG, UK. j.kooner@ic.ac.uk.
⁴⁶ National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK. j.kooner@ic.ac.uk.
⁴⁷ Center for Non-Communicable Diseases, Karachi, Pakistan. ds3792@cumc.columbia.edu.
⁴⁸ Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA. ds3792@cumc.columbia.edu.
⁴⁹ Department of Cardiology, Columbia University Irving Medical Center, New York, NY, 10032, USA. ds3792@cumc.columbia.edu.
⁵⁰ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore. john.chambers@ntu.edu.sg.
⁵¹ Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK. john.chambers@ntu.edu.sg.
⁵² Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK. john.chambers@ntu.edu.sg.
⁵³ Imperial College Healthcare NHS Trust, Imperial College London, London, W12 0HS, UK. john.chambers@ntu.edu.sg.
⁵⁴ MRC-PHE Centre for Enviroment and Health, Imperial College London, London, W2 1PG, UK. john.chambers@ntu.edu.sg.

^# Contributed equally.

PMID: 35393509
PMCID: PMC8991226
DOI: 10.1038/s42003-022-03248-5

Erratum in

Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.
Loh M, Zhang W, Ng HK, Schmid K, Lamri A, Tong L, Ahmad M, Lee JJ, Ng MCY, Petty LE, Spracklen CN, Takeuchi F, Islam MT, Jasmine F, Kasturiratne A, Kibriya M, Mohlke KL, Paré G, Prasad G, Shahriar M, Chee ML, de Silva HJ, Engert JC, Gerstein HC, Mani KR, Sabanayagam C, Vujkovic M, Wickremasinghe AR, Wong TY, Yajnik CS, Yusuf S, Ahsan H, Bharadwaj D, Anand SS, Below JE, Boehnke M, Bowden DW, Chandak GR, Cheng CY, Kato N, Mahajan A, Sim X, McCarthy MI, Morris AP, Kooner JS, Saleheen D, Chambers JC. Loh M, et al. Commun Biol. 2022 May 5;5(1):441. doi: 10.1038/s42003-022-03404-x. Commun Biol. 2022. PMID: 35513483 Free PMC article. No abstract available.

Abstract

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (n_eff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10^-8 to 5.2 × 10^-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.

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Conflict of interest statement

The authors declare no competing interests.

References

1. International Diabetes Federation. IDF Diabetes Atlas 8th edn. (International Diabetes Federation, 2017).
1. United Nations. World Population Prospects: The 2019 Revision (United Nations, 2019).
1. Kooner JS, et al. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat. Genet. 2011;43:984–989. - PMC - PubMed
1. Sattar N, Gill JM. Type 2 diabetes in migrant south Asians: mechanisms, mitigation, and management. Lancet Diabetes Endocrinol. 2015;3:1004–1016. - PubMed
1. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 2018;14:88–98. - PubMed

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Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Affiliations

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous