Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program

TOPMed Diabetes Working Group, TOPMed Hematology Working Group, TOPMed Hemostasis Working Group, National Heart, Lung, and Blood Institute TOPMed Consortium

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)706-718
Number of pages13
JournalAmerican Journal of Human Genetics
Volume105
Issue number4
DOIs
StatePublished - Oct 3 2019

Fingerprint

Precision Medicine
Hispanic Americans
African Americans
Hemoglobins
Gene Frequency
National Heart, Lung, and Blood Institute (U.S.)

Keywords

  • hemoglobin A1c
  • multi-ancestry sample
  • The Trans-Omics for Precision Medicine (TOPMed) program
  • whole-genome sequence association analyses

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

TOPMed Diabetes Working Group, TOPMed Hematology Working Group, TOPMed Hemostasis Working Group, & National Heart, Lung, and Blood Institute TOPMed Consortium (2019). Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. American Journal of Human Genetics, 105(4), 706-718. https://doi.org/10.1016/j.ajhg.2019.08.010

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts : The Trans-Omics for Precision Medicine Program. / TOPMed Diabetes Working Group; TOPMed Hematology Working Group; TOPMed Hemostasis Working Group; National Heart, Lung, and Blood Institute TOPMed Consortium.

In: American Journal of Human Genetics, Vol. 105, No. 4, 03.10.2019, p. 706-718.

Research output: Contribution to journalArticle

TOPMed Diabetes Working Group, TOPMed Hematology Working Group, TOPMed Hemostasis Working Group & National Heart, Lung, and Blood Institute TOPMed Consortium 2019, 'Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program', American Journal of Human Genetics, vol. 105, no. 4, pp. 706-718. https://doi.org/10.1016/j.ajhg.2019.08.010
TOPMed Diabetes Working Group, TOPMed Hematology Working Group, TOPMed Hemostasis Working Group, National Heart, Lung, and Blood Institute TOPMed Consortium. Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. American Journal of Human Genetics. 2019 Oct 3;105(4):706-718. https://doi.org/10.1016/j.ajhg.2019.08.010
TOPMed Diabetes Working Group ; TOPMed Hematology Working Group ; TOPMed Hemostasis Working Group ; National Heart, Lung, and Blood Institute TOPMed Consortium. / Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts : The Trans-Omics for Precision Medicine Program. In: American Journal of Human Genetics. 2019 ; Vol. 105, No. 4. pp. 706-718.
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abstract = "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.",
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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

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AU - TOPMed Hematology Working Group

AU - TOPMed Hemostasis Working Group

AU - National Heart, Lung, and Blood Institute TOPMed Consortium

AU - Sarnowski, Chloé

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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.

PY - 2019/10/3

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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.

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KW - multi-ancestry sample

KW - The Trans-Omics for Precision Medicine (TOPMed) program

KW - whole-genome sequence association analyses

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