Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study

Abstract

Aims/hypothesis Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA 1c , that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA 1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study. Methods We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA 1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS metaanalyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci. Results Four novel associations were identified (p < 5 × 10 −9 ), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis. Conclusions/interpretation Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations. Data availability Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics).

Genetic heterogeneity in cardiovascular disease across ancestries: Insights for mechanisms and therapeutic intervention

“…Notable allele frequency distribution has been observed in BMI-associated variants which consequently confers ancestral differences in BMI. For example, in a transancestry meta-analysis by Downie et al, wide variation of minor allele frequency (MAF) was seen across populations for sentinel variants ranging from 0.12-0.36 for VEGFA locus and 0.10-0.37 for PTEN locus (Downie et al, 2022). A population specific locus (LRRC37A5P) was found in individuals that self-identify as African Americans (Downie et al, 2022).…”

“…For example, in a transancestry meta-analysis by Downie et al, wide variation of minor allele frequency (MAF) was seen across populations for sentinel variants ranging from 0.12-0.36 for VEGFA locus and 0.10-0.37 for PTEN locus (Downie et al, 2022). A population specific locus (LRRC37A5P) was found in individuals that self-identify as African Americans (Downie et al, 2022). The identification of these ancestry specific loci underscores the significance of undertaking genetic studies in diverse populations.…”

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

“…Over the last years, consortium-driven genome-wide association studies (GWAS) have successfully identified common variants at genomic loci associated with an increased risk of T2D [ 36 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ]. A few of the coding variants identified in these studies result in hypomorphic variants [ 9 , 190 ].…”

Insight into genetic, biological, and environmental determinants of sexual-dimorphism in type 2 diabetes and glucose-related traits

“…In sex-combined studies, SNPs in the adenylate cyclase 5 (ADCY5 ) gene are associated with multiple T2D-related traits including FG ( 23 , 28 – 32 ), FI ( 21 ), glycated hemoglobin ( 33 ), HOMA-B (i.e., index of insulin secretion) and T2D ( 34 – 43 ), anthropometric and body fat distribution traits, such as WHR ( 44 , 45 ), body fat percentage ( 46 ), BMI ( 47 ), inflammation phenotypes such as C-reactive protein ( 48 ), early life factors including gestation duration ( 49 ), birth weight ( 50 – 56 ), blood lipid levels, including total cholesterol ( 57 , 58 ), HDL-cholesterol, apolipoprotein A1 ( 59 ), and blood pressure measures ( 60 ). SNPs in the vicinity of ADCY5 showed sex-dimorphic effects in association to FG.…”

“…The melatonin receptor 1B ( MTNR1B ) gene is a well-established T2D locus with significant associations with multiple glucose-related traits including FG ( 21 , 23 , 28 – 30 , 67 , 94 – 101 ), glycated hemoglobin ( 31 – 33 , 102 , 103 ), insulin levels, insulin disposition index and insulin secretion rates ( 104 , 105 ), acute insulin response, HOMA-B ( 21 ), and T2D ( 27 , 34 , 35 , 37 – 40 , 42 , 43 , 106 , 107 ). The gene is also associated with various sleep and circadian rhythm-related phenotypes ( 108 , 109 ).…”