An integrative approach to identifying NPC1 as a susceptibility gene for gestational diabetes mellitus.

Abstract

Objective: The objective of this study was to identify a novel gene and its potential mechanisms associated with susceptibility to gestational diabetes mellitus (GDM) through an integrative approach.

Methods: We analyzed data from genome-wide association studies (GWAS) of GDM in the FinnGen R11 dataset (16,802 GDM cases and 237,816 controls) and Genotype Tissue Expression v8 expression quantitative trait locus data. We used summary-data-based Mendelian randomization to determine associations between transcript levels and phenotypes, transcriptome-wide association studies to provide insights into gene-trait associations, multi-marker analysis of genomic annotation to perform gene-based analysis, genome-wide complex trait analysis-multivariate set-based association test-combo to determine gene prioritization, and polygenic priority scores to prioritize the causal genes to screen candidate genes. Subsequent Mendelian randomization analysis was performed to infer causality between the candidate genes and GDM and phenome-wide association study (PheWAS) analysis was used to explore the associations between selected genes and other characteristics. Furthermore, to gain a deeper understanding of the functional implications of these susceptibility genes, GeneMANIA analysis was used to determine the fundamental biological functions of the therapeutic targets and protein-protein interaction network analysis was performed to identify intracellular protein interactions.

Results: We identified two novel susceptibility genes associated with GDM: NPC1 and KIAA1191. Magnetic resonance imaging revealed a strong correlation between NPC1 expression levels and a lower incidence of GDM (odds ratio: 0.922, 95% confidence interval: 0.866-0.981, p = 0.011). PheWAS at the gene level indicated that NPC1 was not associated with any other trait. The biological significance of this gene was evidenced by its strong association with sterol metabolism.

Conclusion: Our study identified NPC1 as a novel gene whose predicted expression level is linked to a reduced risk of GDM, providing new insights into the genetic framework of this disease.