The Trans-Ancestral Genomic Architecture of Glycemic Traits

Laura J Corbin; Nicholas John  Timpson; Debbie A Lawlor; Ines Barroso; et al.

doi:10.1038/s41588-021-00852-9

The Trans-Ancestral Genomic Architecture of Glycemic Traits

Laura J Corbin, Nicholas John Timpson, Debbie A Lawlor, Ines Barroso^*, et al.

^*Corresponding author for this work

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

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Abstract

Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To 462 date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, 463 we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% 464 non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and 465 fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; 466 P<5x10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted 467 to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. 468 Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of 469 estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression 470 and gene-set analyses revealed distinct biological signatures for each trait, highlighting different 471 underlying biological pathways. Our results increase understanding of diabetes pathophysiology by 472 use of trans-ancestry studies for improved power and resolution.

Original language	English
Pages (from-to)	840-860
Number of pages	21
Journal	Nature Genetics
Volume	53
Issue number	6
Early online date	31 May 2021
DOIs	https://doi.org/10.1038/s41588-021-00852-9
Publication status	Published - Jun 2021

Bibliographical note

Funding Information:
A.A. is the recipient of honoraria as a speaker for a wide range of Danish and international concerns and receives royalties from textbooks, and from popular diet and cookery books. A.A. is also co-inventor of a number of patents, including methods of inducing weight loss, treating obesity and preventing weight gain (licensee Gelesis) and biomarkers for predicting the degree of weight loss (licensee Nestec), owned by the University of Copenhagen, in accordance with Danish law. I.B. and spouse own stock in GlaxoSmithKline and Incyte Corporation. B.H.C. is now an employee of Life Epigenetics; all work was completed before employment by Life Epigenetics. A.Y.C. is now an employee of Merck & Co.; all work was completed before employment by Merck & Co. J.C.F. has received consulting honoraria from Janssen. J.G. is now an employee of F. Hoffmann-La Roche, and owns stock in Roche and GlaxoSmithKline. A.L.G. has received honoraria from Merck and Novo Nordisk. As of June 2019, A.L.G. discloses that her spouse is an employee of Genentech and hold stock options in Roche. E.I. is now an employee of GlaxoSmithKline; all work was completed before his employment by GlaxoSmithKline. W.M. has received grants and/ or personal fees from the following companies/corporations: Siemens Healthineers, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Sanofi, Alexion Pharmaceuticals, BASF, Abbott Diagnostics Numares, Berlin-Chemie, Akzea Therapeutics, Bayer Vital, Bestbion dx, Boehringer Ingelheim Pharma, Immundiagnostik, Merck Chemicals, MSD Sharp and Dohme, Novartis Pharma, Olink Proteomics and Synlab Holding Deutschland. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, and has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly. He holds stock options in Zoe Global and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. He is now an employee of Genentech and a holder of Roche stock. J.B.M. has consulted for Quest Diagnostics, who is a manufacturer of an HbA1c assay. M.E.M. has received grant funding from Regeneron Pharmaceuticals. M.E.M. is also an inventor on a patent that was published by the US Patent and Trademark Office on 6December 2018 under Publication Number US 2018-0346888, and international patent application that was published on 13December 2018 under Publication Number WO-2018/226560; all work was completed before these competing interests arose, and are unrelated to this work. D.O.M.-K. is a part-time clinical research consultant for Metabolon. J.L.N. is a member of the Scientific Advisory Board for Veralox Therapeutics. C.N.A.P. has received research support from GlaxoSmithKline and AstraZeneca unrelated to this project. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. N. Sattar has consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Napp and Sanofi, and received grant support from Boehringer Ingelheim. R.A.S. is an employee and shareholder of GlaxoSmithKline. T.D.S. is the founder of Zoe Global. J. Tuomilehto receives research support from Bayer, is a consultant for Eli Lily and holds stock in Orion Pharma and Aktivolabs.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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10.1038/s41588-021-00852-9

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title = "The Trans-Ancestral Genomic Architecture of Glycemic Traits",

abstract = "Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To 462 date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, 463 we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% 464 non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and 465 fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; 466 P<5x10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted 467 to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. 468 Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of 469 estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression 470 and gene-set analyses revealed distinct biological signatures for each trait, highlighting different 471 underlying biological pathways. Our results increase understanding of diabetes pathophysiology by 472 use of trans-ancestry studies for improved power and resolution.",

author = "Corbin, {Laura J} and Timpson, {Nicholas John} and Lawlor, {Debbie A} and Ines Barroso and {et al.}",

note = "Funding Information: A.A. is the recipient of honoraria as a speaker for a wide range of Danish and international concerns and receives royalties from textbooks, and from popular diet and cookery books. A.A. is also co-inventor of a number of patents, including methods of inducing weight loss, treating obesity and preventing weight gain (licensee Gelesis) and biomarkers for predicting the degree of weight loss (licensee Nestec), owned by the University of Copenhagen, in accordance with Danish law. I.B. and spouse own stock in GlaxoSmithKline and Incyte Corporation. B.H.C. is now an employee of Life Epigenetics; all work was completed before employment by Life Epigenetics. A.Y.C. is now an employee of Merck & Co.; all work was completed before employment by Merck & Co. J.C.F. has received consulting honoraria from Janssen. J.G. is now an employee of F. Hoffmann-La Roche, and owns stock in Roche and GlaxoSmithKline. A.L.G. has received honoraria from Merck and Novo Nordisk. As of June 2019, A.L.G. discloses that her spouse is an employee of Genentech and hold stock options in Roche. E.I. is now an employee of GlaxoSmithKline; all work was completed before his employment by GlaxoSmithKline. W.M. has received grants and/ or personal fees from the following companies/corporations: Siemens Healthineers, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Sanofi, Alexion Pharmaceuticals, BASF, Abbott Diagnostics Numares, Berlin-Chemie, Akzea Therapeutics, Bayer Vital, Bestbion dx, Boehringer Ingelheim Pharma, Immundiagnostik, Merck Chemicals, MSD Sharp and Dohme, Novartis Pharma, Olink Proteomics and Synlab Holding Deutschland. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, and has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly. He holds stock options in Zoe Global and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. He is now an employee of Genentech and a holder of Roche stock. J.B.M. has consulted for Quest Diagnostics, who is a manufacturer of an HbA1c assay. M.E.M. has received grant funding from Regeneron Pharmaceuticals. M.E.M. is also an inventor on a patent that was published by the US Patent and Trademark Office on 6December 2018 under Publication Number US 2018-0346888, and international patent application that was published on 13December 2018 under Publication Number WO-2018/226560; all work was completed before these competing interests arose, and are unrelated to this work. D.O.M.-K. is a part-time clinical research consultant for Metabolon. J.L.N. is a member of the Scientific Advisory Board for Veralox Therapeutics. C.N.A.P. has received research support from GlaxoSmithKline and AstraZeneca unrelated to this project. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. N. Sattar has consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Napp and Sanofi, and received grant support from Boehringer Ingelheim. R.A.S. is an employee and shareholder of GlaxoSmithKline. T.D.S. is the founder of Zoe Global. J. Tuomilehto receives research support from Bayer, is a consultant for Eli Lily and holds stock in Orion Pharma and Aktivolabs. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

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doi = "10.1038/s41588-021-00852-9",

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AU - Timpson, Nicholas John

AU - Lawlor, Debbie A

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N1 - Funding Information: A.A. is the recipient of honoraria as a speaker for a wide range of Danish and international concerns and receives royalties from textbooks, and from popular diet and cookery books. A.A. is also co-inventor of a number of patents, including methods of inducing weight loss, treating obesity and preventing weight gain (licensee Gelesis) and biomarkers for predicting the degree of weight loss (licensee Nestec), owned by the University of Copenhagen, in accordance with Danish law. I.B. and spouse own stock in GlaxoSmithKline and Incyte Corporation. B.H.C. is now an employee of Life Epigenetics; all work was completed before employment by Life Epigenetics. A.Y.C. is now an employee of Merck & Co.; all work was completed before employment by Merck & Co. J.C.F. has received consulting honoraria from Janssen. J.G. is now an employee of F. Hoffmann-La Roche, and owns stock in Roche and GlaxoSmithKline. A.L.G. has received honoraria from Merck and Novo Nordisk. As of June 2019, A.L.G. discloses that her spouse is an employee of Genentech and hold stock options in Roche. E.I. is now an employee of GlaxoSmithKline; all work was completed before his employment by GlaxoSmithKline. W.M. has received grants and/ or personal fees from the following companies/corporations: Siemens Healthineers, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Sanofi, Alexion Pharmaceuticals, BASF, Abbott Diagnostics Numares, Berlin-Chemie, Akzea Therapeutics, Bayer Vital, Bestbion dx, Boehringer Ingelheim Pharma, Immundiagnostik, Merck Chemicals, MSD Sharp and Dohme, Novartis Pharma, Olink Proteomics and Synlab Holding Deutschland. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, and has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly. He holds stock options in Zoe Global and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. He is now an employee of Genentech and a holder of Roche stock. J.B.M. has consulted for Quest Diagnostics, who is a manufacturer of an HbA1c assay. M.E.M. has received grant funding from Regeneron Pharmaceuticals. M.E.M. is also an inventor on a patent that was published by the US Patent and Trademark Office on 6December 2018 under Publication Number US 2018-0346888, and international patent application that was published on 13December 2018 under Publication Number WO-2018/226560; all work was completed before these competing interests arose, and are unrelated to this work. D.O.M.-K. is a part-time clinical research consultant for Metabolon. J.L.N. is a member of the Scientific Advisory Board for Veralox Therapeutics. C.N.A.P. has received research support from GlaxoSmithKline and AstraZeneca unrelated to this project. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. N. Sattar has consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Napp and Sanofi, and received grant support from Boehringer Ingelheim. R.A.S. is an employee and shareholder of GlaxoSmithKline. T.D.S. is the founder of Zoe Global. J. Tuomilehto receives research support from Bayer, is a consultant for Eli Lily and holds stock in Orion Pharma and Aktivolabs. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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N2 - Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To 462 date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, 463 we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% 464 non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and 465 fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; 466 P<5x10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted 467 to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. 468 Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of 469 estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression 470 and gene-set analyses revealed distinct biological signatures for each trait, highlighting different 471 underlying biological pathways. Our results increase understanding of diabetes pathophysiology by 472 use of trans-ancestry studies for improved power and resolution.

AB - Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To 462 date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, 463 we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% 464 non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and 465 fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; 466 P<5x10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted 467 to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. 468 Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of 469 estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression 470 and gene-set analyses revealed distinct biological signatures for each trait, highlighting different 471 underlying biological pathways. Our results increase understanding of diabetes pathophysiology by 472 use of trans-ancestry studies for improved power and resolution.

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DO - 10.1038/s41588-021-00852-9

M3 - Article (Academic Journal)

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VL - 53

SP - 840

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JO - Nature Genetics

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The Trans-Ancestral Genomic Architecture of Glycemic Traits

Abstract

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UN SDGs

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