Identification of 489 Type 2 Diabetes Shared and Tissue-Specific Effector Genes by Integrating eQTL Data with a Multiancestry GWAS of 2.5 Million Individuals

Linking type 2 diabetes (T2D) associated loci with effector genes remains a challenge. To identify new T2D effector transcripts, we performed the largest, most ancestrally diverse T2D genome-wide association meta-analysis including 428,452 cases and 2,107,149 controls, as part of the Type 2 Diabetes Global Genomic Initiative. We identified 859 associated regions, which we evaluated for colocalization with expression quantitative trait loci (eQTL) datasets from tissues relevant for T2D including pancreatic islets, subcutaneous and visceral adipose tissue (SAT, VAT), liver, skeletal muscle, and hypothalamus. We found 492 colocalizations with eQTL signals across all tissues, comprising 489 genes, including 18 genes in previously unreported loci. Pancreatic islets had the highest percentage (50.9%) of tissue-specific colocalizations. For example, a lead variant associated with higher T2D risk colocalized with higher expression of secretin receptor (SCTR), a gene expressed primarily in pancreatic islets and involved in glucagon secretion, only in pancreatic islets. Another T2D-associated signal colocalized with increased expression of the insulin receptor substrate 2 (IRS2) in skeletal muscle only. Colocalizations were assessed for enrichment with clusters previously defined from associations with 37 other cardiometabolic traits. Genes from islet-specific colocalizations showed significant enrichment with insulin secretion-associated genetic clusters with negative (adj p=1.1×10-4) and positive (adj p=8.1×10-4) effects on proinsulin and impaired fasting glucose (adj p=3.7×10-4). Genes from SAT-specific colocalizations were also enriched with a cluster related to lipodystrophy (adj p=1.9×10-2). Overall, this work identified putative molecular pathways and 489 effector transcripts underlying T2D and may inform future therapeutic strategies. Disclosure R.Mandla: None. Diamante consortium: n/a. Va million veteran program: n/a. J.B.Meigs: Consultant; Quest Diagnostics. M.I.Mccarthy: Employee; Genentech, Inc., Stock/Shareholder; Roche Pharmaceuticals. A.Mahajan: Employee; Genentech, Inc. C.Spracklen: None. M.Boehnke: None. M.Vujkovic: None. J.I.Rotter: None. B.F.Voight: None. K.Lorenz: None. E.Zeggini: None. A.Morris: None. J.M.Mercader: None. Type 2 diabetes global genomics initiative: n/a. X.Yin: None. L.Southam: None. K.Suzuki: None. K.Hatzikotoulas: None. H.J.Taylor: None. A.Huerta: None. N.W.Rayner: None. Funding American Diabetes Association (11-22-ICTSPM-16 to J.M.M.); National Human Genome Research Institute (U01HG011723)