Impact of rare and common genetic variants on diabetes diagnosis by hemoglobin A1c in multi-ancestry cohorts: The Trans-Omics for Precision Medicine Program

Abstract

93Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in 94 patients with diabetes. However, nonglycemic determinants, including genetic variation, may 95 influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-96 Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies 97 and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics and 407 East 98 Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-99 Americans, HK1 in Europeans and Hispanics, FN3K/FN3KRP in Europeans and G6PD in 100 African-Americans and Hispanics) and discovered a new African-ancestry specific low-101 frequency variant (rs1039215 in HBG2/HBE1, minor allele frequency (MAF)=0.03). The most 102 associated G6PD variant (p.Val98Met, rs1050828-T, MAF=12% in African-Americans, 103 MAF=2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous 104 females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics.105Additionally, we identified a rare distinct G6PD coding variant (rs76723693 -p.Leu353Pro, 106 MAF=0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected 107 significant association with HbA1c when aggregating rare missense variants in G6PD. We 108 observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 109 (G6PD) in the two largest TOPMed African-American cohorts and replicated the rs76723693 110 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 111 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals 112 carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, 113 assessment of these variants should be considered for incorporation into precision medicine 114 approaches for diabetes diagnosis.115 116 6 157We included in our analyses 10,338 TOPMed participants without diabetes from five

Rare Non-coding Variation Identified by Large Scale Whole Genome Sequencing Reveals Unexplained Heritability of Type 2 Diabetes

“…In this large-scale multi-ancestry association study within TOPMed, we observed common variant heritability estimates that were consistent with common variant GWAS 10 , but identified a remarkably larger contribution of rare, non-coding variation to T2D heritability estimates. These data revise prior T2D heritability estimates that used just a few thousand low-pass sequences to model heritability and concluded that rare variation contributes relatively little to T2D heritability 13,14,16 . Although the large amount of rare variant heritability for T2D seems outsized, this has now been seen in TOPMed WGS for height and BMI 27 , and may be a genetic architecture characteristic of polygenic traits and phenotypes in general.…”

“…Analyses of FG and logtransformed FI were examined in individuals without T2D; and adjusted for age, age-squared, BMI, sex, and study-ancestry (study and ancestry combined into a single variable), and accounting for relatedness using a genetic relatedness matrix (GRM). Association analysis with HbA1c was stratified by ancestry and meta-analyzed for pooled estimates across ancestries, adjusting for age, sex, and study, and included a random effect for study and a GRM to account for relatedness 16 . Association analysis with BMI was performed by creating BMI residuals, adjusted for age, age squared, study and 10 PCs; and were created within ancestry and sex strata, then rank-normal transformed and rescaled by strata variance.…”

“…Twin studies in Europeans suggest genetic contributions to T2D risk (heritability) estimates of up to 72% 9 , but the discovered variants from GWAS in the same ancestry account for just 18% of T2D heritability 10 some of which localizes to specific classes of pancreatic islet-specific enhancers 6 . "Missing heritability" may reside among the rare variants that make up the vast majority of human genetic variation and that are not interrogated by GWAS, despite initial suggestions from small samples of exome and low-pass whole genome sequencing [11][12][13][14][15][16] that rare variants make a limited contribution to T2D heritability 13 . Here, we analyzed large-scale, multi-ancestry, high-coverage whole genome sequencing (WGS) from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program 2 and show that rare, non-coding variation contributes to T2D heritability.…”

Analyses of Biomarker Traits in Diverse UK Biobank Participants Identify Associations Missed by European-centric Analysis Strategies

“…Unlike the G6PD deficiency variant common in African Americans (rs1050828, reported here for bilirubin), which has been reported to strongly influence HbA1c in this population, [15] this variant is not previously reported in the GWAS catalog. Other G6PD coding variants (rs76723693 in African Americans, [16] rs72554665 and rs72554664 in East Asians [17]) have also been reported to influence HbA1c. Our results are concordant with this previous literature, and add to concerns that use of HbA1c as a laboratory test in populations with a high prevalence of G6PD deficiency may lead to underdiagnosis of diabetes and poor management and prevention of complications in those with diagnosed diabetes.…”

A system for phenotype harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

“…The harmonization system described in this report has been used to harmonize 63 phenotypes for several WGs, members of which are using them in many different analyses, primarily genotype-phenotype association studies. Some of these studies have been published (e.g., [12][13][14][15] and many others are in preparation.…”