The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30...

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Published in:	Nature genetics Vol. 53; no. 6; pp. 840 - 860
Main Authors:	Marenne, Gaëlle, Horikoshi, Momoko, Chu, Audrey Y., Hong, Jaeyoung, Hottenga, Jouke-Jan, Kaakinen, Marika A., Moreno-Macias, Hortensia, Nolte, Ilja M., Raulerson, Chelsea K., Chen, Brian H., Hai, Yang, He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Jensen, Richard A., Lange, Leslie A., Langefeld, Carl D., Li, Man, Nag, Abhishek, Pistis, Giorgio, Raffield, Laura, Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Saxena, Richa, van der Most, Peter J., Wang, Nan, Warren, Helen R., Wilsgaard, Tom, Wong, Andrew, Zafarmand, Mohammad Hadi, Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bornstein, Stefan R., Campbell, Archie, Chang, Yi Cheng, Eiriksdottir, Gudny, Han, Sohee, Hartman, Catharina A., Ichihara, Sahoko, Katsuya, Tomohiro, Khor, Chiea Chuen, Kolcic, Ivana, Kuulasmaa, Teemu, Lemaitre, Rozenn N., Lin, Shih-Yi, Linneberg, Allan, Matsuda, Fumihiko, Moon, Sanghoon, Ohyagi, Yasumasa, Qi, Qibin, Sandow, Kevin, Thuesen, Betina, van Dam, Rob M., Willems van Dijk, Ko, Adair, Linda S., Boehnke, Michael, Bønnelykke, Klaus, Boomsma, D. I., Buchanan, Thomas A., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Collins, Francis S., Cucca, Francesco, de Silva, H. Janaka, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Grimsgaard, Sameline, Guo, Xiuqing, Huang, Wei, Kato, Norihiro, Koistinen, Heikki A., Kuh, Diana, Kumari, Meena, Launer, Lenore J., Mook-Kanamori, Dennis O., Pedersen, Oluf, Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Rosendaal, Frits R., Shu, Xiao-ou, Tai, E. Shyong, Timpson, Nicholas J., Tusie, Teresa, Uusitupa, Matti, Vrijkotte, Tanja G. M., Wei, Wen B., Willemsen, Gonneke, Wong, Tien-Yin, Xiang, Anny H., Yokota, Mitsuhiro, Zeggini, Eleftheria, McCarthy, Mark I., Dupuis, Josée, Parker, Stephen C. J.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.06.2021 Nature Publishing Group
Subjects:	45/43 631/208 692/699 African Americans Agriculture Alleles Animal Genetics and Genomics Biological effects Biomedical and Life Sciences Biomedicine Blood Glucose - genetics Cancer Research Clinical Medicine Demographic aspects Diabetes Diabetes mellitus (non-insulin dependent) Endocrinology and Diabetes Endokrinologi och diabetes Epigenesis, Genetic Equivalence Europeans Fasting Gene expression Gene Expression Profiling Gene Function Gene mapping Genetic aspects Genome, Human Genome-wide association studies Genome-Wide Association Study Genomes Genomics Glucose Glycated Hemoglobin - metabolism Glycemic index Health aspects Hemoglobin Heterogeneity Hispanic people Human Genetics Humans Insulin Insulin resistance Klinisk medicin Laboratory testing Life Sciences Medical and Health Sciences Medicin och hälsovetenskap Meta-analysis Multifactorial Inheritance - genetics Pathophysiology Physical Chromosome Mapping Quantitative Trait Loci - genetics Quantitative Trait, Heritable White People - genetics Europe
ISSN:	1061-4036, 1546-1718, 1546-1718
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Summary:	Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10 −8 ), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7610958 Denote shared authorship contributions Current address: Genentech, South San Francisco, CA
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-00852-9