Post-GWAS functional annotation of the RPTOR locus identifies rs12950541 as a candidate regulatory variant for type 2 diabetes and metabolic traits

BackgroundType 2 diabetes (T2D) represents a major global health burden, with over 700 GWAS loci identified. Translation to biological mechanisms remains challenging. This study employs systematic post-GWAS functional annotation to characterize the RPTOR locus, encoding Raptor, a scaffold protein critical for mTORC1 signaling and beta-cell function. MethodsWe analyzed 31 GWAS credible sets containing rs12950541 (chr17:80760693 G>A) using Open Targets Platform v24.12, encompassing 20 metabolic traits. L2G scoring, colocalization analysis, and QTL mapping in GTEx v8 were performed. Independent Variant Effect Predictor (VEP) analysis of the linkage disequilibrium (LD) block was conducted to characterize all variants in LD (D [≥] 0.7) with rs12950541. RNA-protein interaction networks were predicted using RNAct/catRAPID for key RPTOR transcripts and functionally enriched using ToppGene. Drug target and novelty analyses were performed using ChEMBL, PubMed, and ClinicalTrials.gov databases. Phenome-wide associations and regulatory annotations were obtained from the T2D Knowledge Portal. ResultsRPTOR was consistently ranked #1 L2G gene across all 31 credible sets (mean score 0.428, range 0.383-0.503). T2D showed strong GWAS-GWAS colocalizations (H4>0.8) with adiposity traits. Skeletal muscle demonstrated strongest QTL evidence with sQTL at P=1.21x10-16 and multiple eQTLs/tuQTLs. Critically, zero GWAS-QTL colocalizations and zero QTL in pancreatic islets, adipose, or liver highlight an "eQTL gap." VEP analysis of 140 LD partners revealed exclusively non-coding variants (100% MODIFIER impact), including 24 regulatory region variants and 2 transcription factor binding site variants. RNAct analysis revealed that the NMD transcript RPTOR-208 shows stronger RNA-protein interactions than the canonical transcript, with predicted binding partners including sulfonylurea receptors (ABCC8/ABCC9), IGF1R, and chromatin remodelers, enriched for glucose-mediated signaling and SWI/SNF complex pathways. ABCC8 is confirmed as the molecular target of sulfonylurea drugs (ChEMBL: CHEMBL2071), and literature analysis confirms that the RPTOR-ABCC8 RNA-protein interaction is completely novel, with no prior publications linking RPTOR transcript biology to sulfonylurea receptor function. T2DKP PheWAS confirmed 78 significant associations across 18 phenotype groups, revealing effects on acute insulin response, insulin sensitivity, HDL cholesterol, hepatic enzymes, and sleep traits, with transcription factor binding analysis showing that rs12950541 directly enhances p300 enhancer marking while reducing CTCF insulator binding. ConclusionsSeven convergent lines of evidence support rs12950541 as a strong candidate regulatory variant at RPTOR. Integration of post-GWAS annotation, VEP characterization, RNA-protein interaction networks, and translational drug target analysis converges on a regulatory mechanism involving splicing, chromatin remodeling, and metabolic signaling pathways. The novel predicted interaction between RPTOR-208 and ABCC8/ABCC9 suggests a previously unrecognized molecular bridge between mTORC1 signaling and KATP channel-mediated insulin secretion, with potential implications for understanding sulfonylurea-mTOR pathway crosstalk in T2D.