TY - JOUR
T1 - Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts
T2 - The Trans-Omics for Precision Medicine Program
AU - TOPMed Diabetes Working Group
AU - TOPMed Hematology Working Group
AU - TOPMed Hemostasis Working Group
AU - National Heart, Lung, and Blood Institute TOPMed Consortium
AU - Sarnowski, Chloé
AU - Leong, Aaron
AU - Raffield, Laura M.
AU - Wu, Peitao
AU - de Vries, Paul S.
AU - DiCorpo, Daniel
AU - Guo, Xiuqing
AU - Xu, Huichun
AU - Liu, Yongmei
AU - Zheng, Xiuwen
AU - Hu, Yao
AU - Brody, Jennifer A.
AU - Goodarzi, Mark O.
AU - Hidalgo, Bertha A.
AU - Highland, Heather M.
AU - Jain, Deepti
AU - Liu, Ching Ti
AU - Naik, Rakhi P.
AU - O'Connell, Jeffrey R.
AU - Perry, James A.
AU - Porneala, Bianca C.
AU - Selvin, Elizabeth
AU - Wessel, Jennifer
AU - Psaty, Bruce M.
AU - Curran, Joanne E.
AU - Peralta, Juan M.
AU - Blangero, John
AU - Kooperberg, Charles
AU - Mathias, Rasika
AU - Johnson, Andrew D.
AU - Reiner, Alexander P.
AU - Mitchell, Braxton D.
AU - Cupples, L. Adrienne
AU - Vasan, Ramachandran S.
AU - Correa, Adolfo
AU - Morrison, Alanna C.
AU - Boerwinkle, Eric
AU - Rotter, Jerome I.
AU - Rich, Stephen S.
AU - Manning, Alisa K.
AU - Dupuis, Josée
AU - Meigs, James B.
N1 - Funding Information:
Whole-genome sequencing: Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute ( NHLBI ). Acknowledgments and funding information for each study are available in the Supplemental Data . Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center ( 3R01HL-117626-02S1 ). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center ( 3R01HL-120393-02S1 ). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The contributions of the investigators of the NHLBI TOPMed Consortium are gratefully acknowledged. Full authorship list is available in the Supplemental Data .
Funding Information:
Funding: L.M.R. is funded by NHLBI grant T32 HL129982 . A.K.M. is supported by National Institutes of Health ( NIH ) National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) grants K01 DK107836 and R03 DK118305 . P.S.dV. is supported by American Heart Association grant 18CDA34110116 . J.B.M. and the project are supported by NIH NIDDK grants K24 DK080140 , U01 DK078616 , and U01 DK105554 Opportunity Pool OP6 . The Analysis Commons was funded by R01HL131136 . H.M.H. was supported by NHLBI training grants T32 HL007055 and T32 HL129982 and American Diabetes Association grant 1-19-PDF-045 . J.R.O. is supported by the TOPMed grant U01 HL137181 .
Funding Information:
Whole-genome sequencing: Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Acknowledgments and funding information for each study are available in the Supplemental Data. Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The contributions of the investigators of the NHLBI TOPMed Consortium are gratefully acknowledged. Full authorship list is available in the Supplemental Data. Funding: L.M.R. is funded by NHLBI grant T32 HL129982. A.K.M. is supported by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants K01 DK107836 and R03 DK118305. P.S.dV. is supported by American Heart Association grant 18CDA34110116. J.B.M. and the project are supported by NIH NIDDK grants K24 DK080140, U01 DK078616, and U01 DK105554 Opportunity Pool OP6. The Analysis Commons was funded by R01HL131136. H.M.H. was supported by NHLBI training grants T32 HL007055 and T32 HL129982 and American Diabetes Association grant 1-19-PDF-045. J.R.O. is supported by the TOPMed grant U01 HL137181.
Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2019/10/3
Y1 - 2019/10/3
N2 - Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
AB - Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
KW - The Trans-Omics for Precision Medicine (TOPMed) program
KW - hemoglobin A1c
KW - multi-ancestry sample
KW - whole-genome sequence association analyses
UR - http://www.scopus.com/inward/record.url?scp=85072829736&partnerID=8YFLogxK
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U2 - 10.1016/j.ajhg.2019.08.010
DO - 10.1016/j.ajhg.2019.08.010
M3 - Article
C2 - 31564435
AN - SCOPUS:85072829736
SN - 0002-9297
VL - 105
SP - 706
EP - 718
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -