319 research outputs found

    Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

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    Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D

    Cancer Res

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    Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and | < 5 7 10| was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, | | = 3.08 7 10|). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (| | = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.R01 CA102765/CA/NCI NIH HHSUnited States/P30 CA016087/CA/NCI NIH HHSUnited States/R01 HL043851/HL/NHLBI NIH HHSUnited States/UG1 CA189974/CA/NCI NIH HHSUnited States/R01 HL034595/HL/NHLBI NIH HHSUnited States/UM1 CA182934/CA/NCI NIH HHSUnited States/P30 ES000260/ES/NIEHS NIH HHSUnited States/P50 CA102701/CA/NCI NIH HHSUnited States/R01 HL026490/HL/NHLBI NIH HHSUnited States/R01 CA154823/CA/NCI NIH HHSUnited States/U58 DP003862/DP/NCCDPHP CDC HHSUnited States/HHSN261200800001C/RC/CCR NIH HHSUnited States/U01 CA247283/CA/NCI NIH HHSUnited States/U10 CA037429/CA/NCI NIH HHSUnited States/HHSN268201600002C/HL/NHLBI NIH HHSUnited States/U01 CA182883/CA/NCI NIH HHSUnited States/R01 HG010480/HG/NHGRI NIH HHSUnited States/P01 CA087969/CA/NCI NIH HHSUnited States/P50 CA062924/CA/NCI NIH HHSUnited States/HHSN268201600018C/HL/NHLBI NIH HHSUnited States/ZIA CP010193/ImNIH/Intramural NIH HHSUnited States/UM1 CA173640/CA/NCI NIH HHSUnited States/R01 CA098870/CA/NCI NIH HHSUnited States/P30 CA008748/CA/NCI NIH HHSUnited States/HHSN268201600003C/HL/NHLBI NIH HHSUnited States/Z99 CA999999/ImNIH/Intramural NIH HHSUnited States/R01 CA098661/CA/NCI NIH HHSUnited States/UM1 CA186107/CA/NCI NIH HHSUnited States/HHSN268201600004C/HL/NHLBI NIH HHSUnited States/UM1 CA182913/CA/NCI NIH HHSUnited States/R01 CA047988/CA/NCI NIH HHSUnited States/R01 CA109767/CA/NCI NIH HHSUnited States/HHSN268201600001C/HL/NHLBI NIH HHSUnited States/R01 HL080467/HL/NHLBI NIH HHSUnited States/UM1 CA167552/CA/NCI NIH HHSUnited States/U01 CA182913/CA/NCI NIH HHSUnited States/R01 CA049449/CA/NCI NIH HHSUnited States/R01 CA040360/CA/NCI NIH HHSUnited States/UM1 CA182910/CA/NCI NIH HHSUnited States/R01 CA097075/CA/NCI NIH HHSUnited States/RC1 HL099355/HL/NHLBI NIH HHSUnited States/UM1 CA182883/CA/NCI NIH HHSUnited States/R01 CA097193/CA/NCI NIH HHSUnited States/R01 CA034944/CA/NCI NIH HHSUnited States/HHSN261200800001E/CA/NCI NIH HHSUnited States/R03 CA123546/CA/NCI NIH HHSUnited States/2021-12-01T00:00:00Z33574088PMC817817510635vault:4055

    Single-Cell RNA-Seq Reveals Developmental Origins and Ontogenetic Stability of Neurexin Alternative Splicing Profiles

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    Neurexins are key synaptic organizers that are expressed in thousands of alternatively spliced isoforms. Because transsynaptic neurexin interactions with different postsynaptic molecules are largely isoform dependent, a cell type-level census of different neurexin isoforms could predict molecular interactions relating to synapse identity and function. Using single-cell transcriptomics to study the origin of neurexin diversity in multiple murine mature and embryonic cell types, we have discovered shared neurexin expression patterns in developmentally related cells. By comparing neurexin profiles in immature embryonic neurons, we show that neurexin profiles are specified during early development and remain unchanged throughout neuronal maturation. Thus, our findings reveal ontogenetic stability and provide a cell type-level census of neurexin isoform expression in the cortex

    Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21

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    Meta-AnalysisThis is the final version of the article. Available from the American Diabetes Association via the DOI in this record.Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.The major funding for this work comes from Council for Scientific and Industrial Research, Government of India, in the form of the grant “Diabetes mellitus—New drug discovery R&D, molecular mechanisms, and genetic and epidemiological factors” (NWP0032-19). R.T. received a postdoctoral fellowship from the Fogarty International Center and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (D43-HD-065249)

    Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

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    Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. / Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. / Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. / Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. / Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. / Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

    Pharmacogenomics and pharmacokinetics of dolutegravir and tenofovir in Southern Africans living with HIV

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    Background The World Health Organization (WHO) recommends dolutegravir in combination with a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people living with HIV (PLWHIV) initiating antiretroviral therapy (ART). Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are both prodrugs of tenofovir. However, plasma tenofovir exposure is higher when given as TDF, and TAF yields lower plasma but higher intracellular tenofovir concentrations. Although generally well tolerated, excessive weight gain has been associated with dolutegravir and (TAF) in PLWHIV initiating ART or those switching from efavirenz- or TDF-containing ART. Interindividual variability in dolutegravir and tenofovir pharmacokinetics or the interindividual differences in host response may, in part, be explained by host genetics. We characterized associations between genetic polymorphisms and dolutegravir exposure, tenofovir clearance and magnitude of weight gain in Southern Africans initiating ART. Methods We collected clinical and laboratory data in adults randomized to initiate TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262). We measured dolutegravir and tenofovir concentrations and developed population pharmacokinetic models for dolutegravir and tenofovir using non-linear mixed-effects modelling. Genome-wide genotyping followed by imputation was performed. Linear regression models examined associations between genetic polymorphisms and unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), unexplained variability in tenofovir clearance, and percentage weight gain from baseline to week 48. Results Considering genetic associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 x 10-4 ), which was also associated with log10 bilirubin (P = 8.6 x 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = 0.02), as were bilirubin concentrations (P = 7.7 x 10-8 ). In the population pharmacokinetic model, compared to C/C, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively. There were no significant genome-wide associations. Considering genetic associations with unexplained variability in tenofovir clearance, we found no significant associations with tenofovir clearance for either TAF or TDF among 5 polymorphisms previously associated with tenofovir pharmacokinetics (lowest P-value > 0.3 for each drug). Among 11 polymorphisms selected based on both prior strong association with any drug phenotype in PharmGKB and any genome-wide association with any trait in the GWAS catalog, IFNL4 rs12979860 T>C was significantly associated with increased tenofovir clearance (TAF: P = 0.003; TDF: P = 0.003). In genome-wide analyses, the lowest P-values for tenofovir clearance in the TAF and TDF arms were with LINC01684 rs9305223 (P = 3.0 x 10-8 ) and intergenic rs142693425 (P = 1.4 x 10-8 ), respectively. Four additional polymorphisms were genome-wide significant. In genome-wide multivariate linear regression analyses adjusting for baseline age, sex, concomitant NRTI, and population stratification, there were no significant associations between 59 polymorphisms relevant to dolutegravir and tenofovir disposition and the percentage weight gain. We found a genome-wide significant association between TMEM163 rs7590091 and percentage weight gain from baseline to week 48 (P = 3.7 x 10-8 ). Conclusion Among Southern African people living with HIV randomized to TAF or TDF, we identified several potential genetic associations with dolutegravir exposure, tenofovir clearance and weight gain. The novel associations between dolutegravir AUCVAR and rs28899168, tenofovir clearance and IFNL4 rs12979860, and weight gain and TMEM163 rs7590091 require independent replication. These findings enhance our understanding of dolutegravir and tenofovir pharmacogenetics among Southern Africans living with HIV

    Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database

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    More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies

    A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial – mesenchymal cell reprogramming and cancer progression

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    Abstract Background Mesenchymal to Epithelial Transition (MET) plasticity is critical to cancer progression, and we recently showed that the OVOL transcription factors (TFs) are critical regulators of MET. Results of that work also posed the hypothesis that the OVOLs impact MET in a range of cancers. We now test this hypothesis by developing a model, OVOL Induced MET (OI-MET), and sub-model (OI-MET-TF), to characterize differential gene expression in MET common to prostate cancer (PC) and breast cancer (BC). Results In the OI-MET model, we identified 739 genes differentially expressed in both the PC and BC models. For this gene set, we found significant enrichment of annotation for BC, PC, cancer, and MET, as well as regulation of gene expression by AP1, STAT1, STAT3, and NFKB1. Focusing on the target genes for these four TFs plus the OVOLs, we produced the OI-MET-TF sub-model, which shows even greater enrichment for these annotations, plus significant evidence of cooperation among these five TFs. Based on known gene/drug interactions, we prioritized targets in the OI-MET-TF network for follow-on analysis, emphasizing the clinical relevance of this work. Reflecting these results back to the OI-MET model, we found that binding motifs for the TF pair AP1/MYC are more frequent than expected and that the AP1/MYC pair is significantly enriched in binding in cancer models, relative to non-cancer models, in these promoters. This effect is seen in both MET models (solid tumors) and in non-MET models (leukemia). These results are consistent with our hypothesis that the OVOLs impact cancer susceptibility by regulating MET, and extend the hypothesis to include mechanisms not specific to MET. Conclusions We find significant evidence of the OVOL, AP1, STAT1, STAT3, and NFKB1 TFs having important roles in MET, and more broadly in cancer. We prioritize known gene/drug targets for follow-up in the clinic, and we show that the AP1/MYC TF pair is a strong candidate for intervention.http://deepblue.lib.umich.edu/bitstream/2027.42/109509/1/12918_2013_Article_1293.pd
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