Identification of novel functional CpG-SNPs associated with Type 2 diabetes and birth weight

Abstract

Genome-wide association studies (GWASs) have identified hundreds of genetic loci for type 2 diabetes (T2D) and birth weight (BW); however, a large proportion of the total trait heritability remains unexplained. The previous studies were generally focused on individual traits and largely failed to identify the majority of the variants that play key functional roles in the etiology of the disease. Here, we aim to identify novel functional loci for T2D, BW and the pleiotropic variants shared between them by performing a targeted conditional false discovery rate (cFDR) analysis that integrates two independent GWASs with summary statistics for T2D ( n = 26,676 cases and 132,532 controls) and BW ( n = 153,781) which entails greater statistical power than individual trait analyses. In this analysis, we considered CpG-SNPs, which are SNPs that may influence DNA methylation status, and are therefore considered to be functionally important. We identified 103 novel CpG-SNPs for T2D, 182 novel CpG-SNPs for BW (cFDR < 0.05), and 52 novel pleiotropic loci for both (conjunction cFDR [ccFDR] < 0.05). Among the identified novel CpG-SNPs, 33 were annotated as methylation quantitative trait loci (meQTLs) in whole blood, and 145 displayed at least some effects on meQTL, metabolic QTL (metaQTL), and/or expression QTL (eQTL). These findings may provide further insights into the shared biological mechanisms and functional genetic determinants that overlap between T2D and BW, thereby providing novel potential targets for treatment/intervention development.

CD80 DNA methylation and single-nucleotide polymorphism associated with clopidogrel response: a whole-genome DNA methylation analysis in acute coronary syndrome

“…[ 65 ] Besides, multiple shared CpG-SNPs of type 2 diabetes risk and birth weight are methylation QTL (me-QTL), metabolic QTL (meta-QTL), or e-QTL. [ 66 ] Our GTEX analysis with the public database showed that CD80 mRNA expression was increased with the number of rs34394661A allele in 9 tissues, which supports the possible tissue-wide influence of the SNP on both CD80_ cg06300880 methylation and CD80 transcriptional activity.…”

EXOC6 (Exocyst Complex Component 6) Is Associated with the Risk of Type 2 Diabetes and Pancreatic β-Cell Dysfunction

“…Moreover, rs947591 was associated with other traits, including triglyceride and total cholesterol levels in the Chinese population [46]. rs2488071 was identified as a novel functional locus shared between T2D and birth weight in Chinese populations [47]. It seems that rs947591 is an important genetic variant that requires replication in different ethnic populations as biomarkers for the risk of T2D.…”

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

“…DNA methylation can also be altered as a result of genetic variants: epigenome-wide approaches on human islets have identified hypo- and hyper-methylated regions in T2D, some of these mapping to GWAS loci such as ADYC5 or KCNQ1 [ 316 , 317 ]. T2D-risk SNPs at potential sites of methylation (CpG dinucleotides) have also been mapped [ 318 , 319 ]. There are other underexplored DNA modifications such as 5-hydroxymethylcytosine (5hmC) that have an impact in chromatin architecture and gene expression.…”