Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

Abstract

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

Global perspectives on CYP2D6 associations with primaquine metabolism and Plasmodium vivax radical cure

“…As a result of these efforts, capacity to perform complex genotyping has advanced in fields of knowledge, attitudes and practice (KAP) ( Muzoriana et al, 2017 ; Rahma et al, 2021 ; Koufaki et al, 2022 ), pharmacogenomics ( Marsh et al, 2006 ), diabetes and hematology ( Kountouris et al, 2021 ) globally. Additionally, studies focused on understanding patterns of genetic variation are advancing and will expand capacity to resolve their health implications in diverse populations ( Taliun et al, 2021 ; DiCorpo et al, 2022 ). Given what we are observing across human genomics investigations, efforts are well underway to extend the breakthroughs available through genomics technologies as a global health mission and must be included as part of malaria elimination strategies.…”