High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans

Abstract

Interpretation of results from genome-wide association studies for T2D is challenging. Only very few loci have been replicated in African ancestry populations and the identification of the implicated functional genes remain largely undefined. We used genetic maps that capture detailed linkage disequilibrium information in European and African Americans and applied these to large T2D case-control samples in order to estimate locations for putative functional variants in both populations. Replicated T2D locations were tested for evidence of being regulatory hotspots using adipose expression. We validated a sample of our co-location intervals using next generation sequencing and functional annotation, including enhancers, transcription, and chromatin modifications. We identified 111 additional diseasesusceptibility locations, 93 of which are cosmopolitan and 18 of which are European specific. We show that many previously known signals are also risk loci in African Americans. The majority of the disease locations appear to confer risk of T2D via the regulation of expression levels for a large number (266) of cis-regulated genes, the majority of which are not the nearest genes to the disease loci. Sequencing three cosmopolitan locations provided candidate functional variants that precisely co-locate with cell-specific chromatin domains and pancreatic islet enhancers. These variants have large effect sizes and are common across populations. Results show that disease-associated loci in different populations, gene expression, and cell-specific regulatory annotation can be effectively integrated by localizing these effects on high-resolution genetic maps. The cis-regulated genes provide insights into the complex molecular pathways involved and can be used as targets for sequencing and functional molecular studies.

Single-cell transcriptomics–based MacSpectrum reveals macrophage activation signatures in diseases

“…Gene ontology analyses of these genes indicated roles in both inflammatory and metabolic regulation of monocytes/macrophages (Supplemental Figure 9C). Among this set of genes, several were previously reported as diabetes-associated genes by different studies, such as Ercc1 (42)(43)(44), Comt (45), Clic1, Gpx1 (46)(47)(48), Rnaset2 (49), Tkt (50, 51), Sparc (52), Gpc3 (53), Prrx1 (54,55), and Bdh2 (56,57). In addition to these known diabetes-related genes, we also identified 13 genes that potentially contribute to T2DM development in obese populations.…”

Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS

“…Two pairs from the liver data identified by the full model involve rs12221064 in the promoter of CNNM2 . This gene is among those associated with T2D (Lau et al 2017). The enhancer SNP in one of the pairs (rs2297786) is in high LD with rs11191438 (r 2 =1 from http://raggr.usc.edu/ across Europeans), which has an eQTL p-value=0.02 with CNNM2 in liver from GTEx.…”

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

“…Like TMTC4, both TMTC1 and TMTC2 are enriched in the ER and coimmunoprecipitate with SERCA2B (38). There is preliminary large-scale evidence from genome-wide association study linking TMTC1, TMTC2, and TMTC4 to type 2 diabetes, a disease whose pathogenesis has been linked strongly to ER stress and the UPR (39,40). Separately, a recent study suggested that the Tmtc class of proteins may also function as components of an O-mannosylation pathway that selectively glycosylates cadherins and protocadherins, many of which, especially Cdh23, play critical roles in hair cell function and have also been tied to ER stress and the UPR (41,42).…”