eQTL Analysis Research Articles

Deciphering cell-specific genetic insights: Unraveling the immunogenetic landscape of systemic lupus erythematosus

Functional genes within genomic loci associated with systemic lupus erythematosus (SLE), as identified by genome-wide association studies, exhibit cell-specific characteristics. This study delves into the impact of genetic variants within SLE loci on gene expression in different types of immune cells, unraveling the complex interplay between genetics and immunopathogenesis. Through the integration of genetic association and single-cell transcriptomic sequencing data, we identified potential cell-specific susceptibility genes for SLE across diverse immune cell subsets. The single-cell eQTL analysis revealed 30,409 associations involving 3583 SLE-associated SNPs. These SNPs exhibited associations with expression levels of 147 genes across 14 distinct cell types. The single-cell summary data-based Mendelian randomization (SMR) analysis identified 119 significant associations between the expression levels of 44 genes and SLE. Notably, myeloid cells exhibited associations solely within the MHC region, while T, B, and natural killer cells showed associations with both MHC and non-MHC genes in relation to SLE. Analysis of single-cell transcriptomic data from 33 children SLE cases and 11 match controls (227,303 cells), as well as 7 adult SLE cases and 5 match controls (78,414 cells) highlights differential expression of key genes. Notably, genetic variants within HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, IRF7, IRF5, BLK and HLA-DPA1 play a pivotal role in mediating immune dysregulation in specific immune cell types. Our study contributes to a comprehensive understanding of the intricate relationships between genetics, gene expression and SLE susceptibility. The findings shed light on the cell-specific impacts of genetic variants within SLE-associated genomic loci.

EQTL in diseased colon tissue identifies novel target genes associated with IBD.

Genome-wide association studies (GWAS) have identified over 300 loci associated with the inflammatory bowel diseases (IBD), but putative causal genes for most are unknown. We conducted the largest disease-focused expression quantitative trait loci (eQTL) analysis using colon tissue from 252 IBD patients to determine genetic effects on gene expression and potential contribution to IBD. Combined with two non-IBD colon eQTL studies, we identified 194 potential target genes for 108 GWAS loci. eQTL in IBD tissue were enriched for IBD GWAS loci colocalizations, provided novel evidence for IBD-associated genes such as ABO and TNFRSF14 , and identified additional target genes compared to non-IBD tissue eQTL. IBD-associated eQTL unique to diseased tissue had distinct regulatory and functional characteristics with increased effect sizes. Together, these highlight the importance of eQTL studies in diseased tissue for understanding functional consequences of genetic variants, and elucidating molecular mechanisms and regulation of key genes involved in IBD.

Genetic variations in NER pathway gene polymorphisms and Wilms tumor risk: A six-center case-control study in East China.

The nucleotide excision repair (NER) system is one of the main ways to protect organisms from DNA damage caused by endogenous and exogenous carcinogens. NER deficiency increases genome mutations, chromosomal aberrations, and cancer viability. However, the genetic association between Wilms tumor and NER pathway gene polymorphisms needs to be further validated. We assessed the associations between 19 NER gene polymorphisms and Wilms tumor susceptibility in 416 cases and 936 controls from East China via the TaqMan method. We found that xeroderma pigmentosum group D (XPD) rs238406 and rs13181 significantly decreased the risk of Wilms tumor [adjusted odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.46-0.75, p <.0001; adjusted OR = 0.63, 95% CI = 0.44-0.89, p = .009, respectively]. Furthermore, the rs751402 and rs2296147 polymorphisms in the xeroderma pigmentosum group G (XPG) gene were significantly correlated with an increased risk for Wilms tumor (adjusted OR = 1.47, 95% CI = 1.03-2.09, p = .034; adjusted OR = 2.14, 95% CI = 1.29-3.56, p = .003, respectively). Expression quantitative trait loci (eQTL) analysis revealed that these four polymorphisms may affect the expression of genes that are adjacent to XPD and XPG. Our study provides evidence that XPD and XPG gene polymorphisms are associated with Wilms tumor risk. Nonetheless, these findings should be confirmed in a larger sample size.

Peripheral mononuclear cells and systemic lupus erythematosus association: Integrated study of single-cell sequencing and mendelian randomization analysis.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease predominantly affecting women. Despite advances in treatment, recent developments in single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) continue to facilitate the need for precision medicine. Data obtained from the GSE135779 dataset underwent quality control, normalization, and dimensionality reduction using Seurat and MonacoImmuneData. Marker genes identified subgroups for analysis with CellChat and ClusterProfilerR. MR analysis of these genes' eQTLs was performed to establish causal relationships with SLE using IEU Open GWAS project data. Single-cell analysis revealed distinct cellular subtypes and highlighted increased monocyte levels in patients with SLE. MR analysis revealed 12 genes, particularly interferon induced protein with tetratricopeptide repeats 3 (IFIT3), causally related to SLE. Gene ontology and the Kyoto encyclopedia of genes and genomes analyses identified pathways significant to SLE pathogenesis. Visualization of these genes at the single-cell level revealed their role in disease progression. Cell communication differences between IFIT3-positive and -negative groups were also observed. This study demonstrates the potential of scRNA-seq and MR in identifying critical factors in SLE pathogenesis, thereby supporting the need for targeted therapies. Identifying IFIT3, among other genes, as central to SLE progression opens new avenues for precision medicine approaches in SLE management.

SNP-Based and Kmer-Based eQTL Analysis Using Transcriptome Data.

Traditional expression quantitative trait locus (eQTL) mapping associates single nucleotide polymorphisms (SNPs) with gene expression, where the SNPs are derived from large-scale whole-genome sequencing (WGS) data or transcriptome data. While WGS provides a high SNP density, it also incurs substantial sequencing costs. In contrast, RNA-seq data, which are more accessible and less expensive, can simultaneously yield gene expressions and SNPs. Thus, eQTL analysis based on RNA-seq offers significant potential applications. Two primary strategies were employed for eQTL in this study. The first involved analyzing expression levels in relation to variant sites detected between populations from RNA-seq data. The second approach utilized kmers, which are sequences of length k derived from RNA-seq reads, to represent variant sites and associated these kmer genotypes with gene expression. We discovered 87 significant association signals involving eGene on the basis of the SNP-based eQTL analysis. These genes include DYNLT1, NMNAT1, and MRLC2, which are closely related to neurological functions such as motor coordination and homeostasis, play a role in cellular energy metabolism, and function in regulating calcium-dependent signaling in muscle contraction, respectively. This study compared the results obtained from eQTL mapping using RNA-seq identified SNPs and gene expression with those derived from kmers. We found that the vast majority (23/30) of the association signals overlapping the two methods could be verified by haplotype block analysis. This comparison elucidates the strengths and limitations of each method, providing insights into their relative efficacy for eQTL identification.

Research progress on single-cell expression quantitative trait loci.

Expression quantitative trait loci (eQTL) represent genetic variants that regulate gene expression levels. eQTL analysis has become a crucial method for identifying the functional roles of disease-associated genetic variants in the post-genome-wide association study (GWAS) era, yielding numerous significant discoveries. Traditional eQTL analysis relies on whole-genome sequencing combined with bulk RNA-seq, which obscures gene expression differences between cells and thus fails to identify cell type- or state-dependent eQTL. This limitation makes it challenging to elucidate the roles of disease-associated genetic variants under specific conditions. In recent years, with the development and widespread application of single-cell RNA sequencing (scRNA-seq) technology, scRNA-seq-based eQTL (sc-eQTL) research has emerged as a focal point. The advantage of this approach lies in its ability to leverage the resolution and granularity of single-cell sequencing to uncover eQTL that are dependent on cell type, cell state, and cellular dynamics. This significantly enhances our ability to analyze genetic variants associated with gene expression. Consequently, it holds substantial significance for advancing our understanding of the formation of complex organs and the mechanisms underlying disease onset, progression, intervention, and treatment. This review comprehensively examines the recent advancements in sc-eQTL studies, focusing on their development, experimental design strategies, modeling approaches, and current challenges. The aim is to offer researchers novel perspectives for identifying disease-associated loci and elucidating gene regulatory mechanisms.

Genetic Variants in METTL16 Affect the Risk of Non-Syndromic Orofacial Clefts.

N6-methyladenosine (m6A) is the most prevalent modification of RNA in eukaryotes which is associated with many cellular processes and diseases. Here, our objective is to explore whether genetic variants in m6A modification genes are associated with the risk of non-syndrome orofacial clefts (NSOCs). The transmission disequilibrium test (TDT) was performed to calculate the association between single nucleotide polymorphisms (SNPs) in m6A modification genes and NSOCs risk in 944 case-parent trios. The function of SNP was predicted by HaploReg, RegulomeDB and histone enrichment data. The expression quantitative trait locus (eQTL) analysis was examined using Genotype-Tissue Expression (GTEx) and eQTLGen. The role of gene in the development of NSOCs was assessed with correlation and enrichment analysis based on gene expression data in mice craniofacial tissue and zebrafish embryo. We identified that rs8078195 (A > C) in METTL16 was suggestively associated with the increased risk of NSOCs (OR = 1.32, p = 1.80E - 03). The region surrounding rs8078195 was subjected to deoxyribonuclease hypersensitivity and enriched with multiple histone modifications. In addition, it had a significant eQTL effect with METTL16 in skin tissue and human peripheral blood, which played an important role in NSOCs development. Bioinformatic analysis indicated that METTL16 contributed to the development of NSOCs probably by regulating cell cycle process. Rs8078195 in METTL16 was associated with the occurrence of NSOCs.

Multi-omics analysis of the molecular response to glucocorticoids - insights into shared genetic risk from psychiatric to medical disorders

BackgroundAlterations in the effects of glucocorticoids have been implicated in mediating some of the negative health effects associated with chronic stress, including increased risk for psychiatric disorders as well as cardiovascular and metabolic diseases. This study investigates how genetic variants influence gene expression and DNA methylation (DNAm) in response to glucocorticoid receptor (GR)-activation, and their association with disease risk. MethodsWe measured DNAm (n=199) and gene expression (n=297) in peripheral blood before and after GR-activation with dexamethasone, with matched genotype data available for all samples. A comprehensive molecular quantitative trait locus (QTL) analysis was conducted, mapping GR-response methylation (me)QTLs, GR-response expression (e)QTLs, and GR-response expression quantitative trait methylation (eQTM). A multi-level network analysis was employed to map the complex relationships between the transcriptome, epigenome, and genetic variation. ResultsWe identified 3,772 GR-response meCpGs corresponding to 104,828 local GR-response meQTLs that did not strongly overlap with baseline meQTLs. eQTM and eQTL analyses revealed distinct genetic influences on gene expression and DNAm. Multi-level network analysis uncovered GR-response network trio QTLs, characterized by SNP-CpG-transcript combinations where meQTLs act as both eQTLs and eQTMs. GR-response trio variants were enriched in GWAS for psychiatric, respiratory, autoimmune and cardiovascular diseases and conferred a higher relative heritability per SNP than GR-response meQTL and baseline QTL SNP. ConclusionsGenetic variants modulating the molecular effects of glucocorticoids are associated with psychiatric as well as medical diseases and not uncovered in baseline QTL analyses.

Allelic effects on KLHL17 expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33.

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at 1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine-mapped SNPs, rs13303160 (r2=0.93 in 1000G EUR samples, OR=1.23, P value=2.74x10-9) demonstrated allele-preferential gene regulatory activity in vitro and allele-preferential binding of JunB and JunD in vitro and in vivo. Expression Quantitative Trait Locus (eQTL) analysis identified KLHL17 as a likely target gene underlying the signal. Proteomic analysis identified KLHL17 as a member of the Cullin-E3 ubiquitin ligase complex in PDAC-derived cells. In silico differential gene expression analysis of the GTExv8 pancreas data suggested an association between lower KLHL17 (risk associated) and pro-inflammatory pathways. We hypothesize that KLHL17 may mitigate inflammation by recruiting pro-inflammatory proteins for ubiquitination and degradation thereby influencing PDAC risk.

Genomic study of taste perception genes in African Americans reveals SNPs linked to Alzheimer’s disease

While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer’s disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer’s disease. This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer’s Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel. The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer’s disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.

PSV-8 Investigation of a haplotype and eQTL analysis of the LCORL-NCAPG locus associated with increased lean growth in beef cattle

Abstract Numerous studies have shown genetic variation at the LCORL-NCAPG locus is strongly associated with growth traits in beef cattle. However, a causative molecular variant has yet to be identified. To define all possible candidate variants, Charolais-sired calves (n = 34) were whole genome sequenced including 17 homozygous for a long-range haplotype associated with increased growth (QQ), and 17 homozygous for potential ancestral haplotypes for this region (qq). The Q haplotype was refined to an 814-kb region between chr6:37,199,897-38,014,080 and contained 218 variants not found in qq individuals. These variants include an insertion in an intron of NCAPG, a previously documented mutation in NCAPG (rs109570900), two coding sequence mutations in LCORL (rs109696064 and rs384548488), and 15 variants located within ATAC peaks that were predicted to affect transcription factor binding. Notably, rs384548488 is a frameshift variant likely resulting in loss of function for long isoforms of LCORL. To test the association of the coding sequence variants of LCORL with phenotype, 405 cattle from five populations were genotyped. The two variants were in complete linkage disequilibrium. Statistical analysis of the three populations that contained QQ animals revealed significant (P &amp;lt; 0.05) associations with genotype and birth weight, body weight, carcass weight, hip height, and average daily gain. Additionally, an RNAseq analysis was performed using 22 of the Charolais-sired calves. This, in conjunction with the WGS data, was used to run an eQTL analysis, which revealed 256 genes whose expression were impacted by eQTL in the region (FDR &amp;lt; 0.05). These findings affirm the link between this locus and growth in beef cattle and describe DNA variants that define the haplotype. However, further studies will be required to define the true causative mutation.

Transcriptome analysis reveals genetic regulation of growth diversity in F2 intergeneric hybrids of Megalobrama amblycephala and Culter alburnus

Hybridization between different genera can greatly shape the genotype and phenotype of individuals. It is possible to sporadically obtain individuals or populations with heterosis through conducting multiple rounds and stages of hybridization, backcrossing, and self-crossing. Investigating the regulatory relationship between allelic combinations from different species and specific economic traits in hybrid individuals will help us understand the genetic mechanism of heterosis. In this study, we conducted a transcriptomic analysis of 25 individuals from the F2 population obtained from the intergeneric hybridization of blunt snout bream (Megalobrama amblycephala, BSB) and topmouth culter (Culter alburnus, TC). We identified 94,897 SNPs on the subgenome BSB (originating from species BSB) and 26,372 SNPs on the subgenome TC (originating from species TC). By utilizing WGCNA to construct a co-expression network, we successfully identified 54 key genes involved in growth regulation. Of these, 8 genes from subgenome BSB show 7 positively influencing and 1 negatively influencing growth rate. Additionally, 46 genes in subgenome TC include 24 with positive and 22 with negative correlations to growth rate. Using eQTL analysis, we assessed associations between SNPs and gene expression levels for 3736 cis- and 7683 trans-regulatory events. In comparative analyses of eQTL and WGCNA, we detected 2 cis- and 16 trans-regulatory genes shared in them, indicating their potential regulatory network in growth diversity in the hybrid. These results help us understand the complex regulatory network of growth traits in intergeneric hybrids. It represents a significant advancement in molecular-assisted breeding, offering valuable insights for developing effective hybrid breeding strategies and achieving heterosis in populations or individuals.

Genetic polymorphism in untranslated regions of PRKCZ influences mRNA structure, stability and binding sites

BackgroundVariations in untranslated regions (UTR) alter regulatory pathways impacting phenotype, disease onset, and course of disease. Protein kinase C Zeta (PRKCZ), a serine-threonine kinase, is implicated in cardiovascular, neurological and oncological disorders. Due to limited research on PRKCZ, this study aimed to investigate the impact of UTR genetic variants’ on binding sites for transcription factors and miRNA. RNA secondary structure, eQTLs, and variation tolerance analysis were also part of the study.MethodsThe data related to PRKCZ gene variants was downloaded from the Ensembl genome browser, COSMIC and gnomAD. The RegulomeDB database was used to assess the functional impact of 5’ UTR and 3’UTR variants. The analysis of the transcription binding sites (TFBS) was done through the Alibaba tool, and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) was employed to identify pathways associated with PRKCZ. To predict the effect of variants on microRNA binding sites, PolymiRTS was utilized for 3’ UTR variants, and the SNPinfo tool was used for 5’ UTR variants.ResultsThe results obtained indicated that a total of 24 variants present in the 3’ UTR and 25 variants present in the 5’ UTR were most detrimental. TFBS analysis revealed that 5’ UTR variants added YY1, repressor, and Oct1, whereas 3’ UTR variants added AP-2alpha, AhR, Da, GR, and USF binding sites. The study predicted TFs that influenced PRKCZ expression. RNA secondary structure analysis showed that eight 5’ UTR and six 3’ UTR altered the RNA structure by either removal or addition of the stem-loop. The microRNA binding site analysis highlighted that seven 3’ UTR and one 5’ UTR variant altered the conserved site and also created new binding sites. eQTLs analysis showed that one variant was associated with PRKCZ expression in the lung and thyroid. The variation tolerance analysis revealed that PRKCZ was an intolerant gene.ConclusionThis study laid the groundwork for future studies aimed at targeting PRKCZ as a therapeutic target.

Genome-Wide Analysis Reveals Copy Number Variant Gene TGFBR3 Regulates Pig Back Fat Deposition.

BFT is closely related to meat quality and lean meat percentage in pigs. The BFT traits of European LW pigs significantly differ from those of Chinese indigenous fatty MZ pigs. CNV is a prevalent genetic variation that plays an important role in economically important traits in pigs. However, the potential contribution of CNV to BFT in LW and MZ pigs remains unclear. In this study, whole-genome CNV detection was performed using next-generation sequencing data from LW and MZ pigs, and transcriptome data from back fat tissue of 180-day-old LW and MZ pigs were integrated for expression quantitative trait loci (eQTL) analysis. We identified a copy number variation in the TGFBR3 gene associated with BFT, showing a dose effect between the genome and transcriptome levels of the TGFBR3 gene. In porcine preadipocytes, TGFBR3 expression continuously increased during differentiation. Knockdown of TGFBR3 using specific siRNA inhibited preadipocyte differentiation and proliferation. Our study provides insights into the genetic regulation of pork quality and offers a theoretical basis for improving carcass quality by modulating BFT in pigs.

An observational and genetic investigation into the association between psoriasis and risk of malignancy

The relationship between psoriasis and site-specific cancers remains unclear. Here, we aim to investigate whether psoriasis is causally associated with site-specific cancers. We use observational and genetic data from the UK Biobank, obtaining GWAS summary data, eQTL analysis data, TCGA data, and GTEx data from public datasets. We perform PheWAS, polygenic risk score analysis, and one-sample and two-sample Mendelian randomization analyses to investigate the potential causal associations between psoriasis and cancers. In the unselected PheWAS analysis, psoriasis is associated with higher risks of 16 types of cancer. Using one-sample Mendelian randomization analyses, it is found that genetically predicted psoriasis is associated with higher risks of anal canal cancer, breast cancer, follicular non-Hodgkin’s lymphoma and nonmelanoma skin cancer in women; and lung cancer and kidney cancer in men. Our two-sample Mendelian randomization analysis indicates that psoriasis is causally associated with breast cancer and lung cancer. Gene annotation shows that psoriasis-related genes, such as ERAP1, are significantly different in lung and breast cancer tissues. Taken together, clinical attention to lung cancer and breast cancer may be warranted among patients with psoriasis.

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10−8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson’s disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.

A functional variant rs912304 for late-onset T1D risk contributes to islet dysfunction by regulating proinflammatory cytokine-responsive gene STXBP6 expression

BackgroundOur previous genome‑wide association studies (GWAS) have suggested rs912304 in 14q12 as a suggestive risk variant for type 1 diabetes (T1D). However, the association between this risk region and T1D subgroups and related clinical risk features, the underlying causal functional variant(s), putative candidate gene(s), and related mechanisms are yet to be elucidated.MethodsWe assessed the association between variant rs912304 and T1D, as well as islet autoimmunity and islet function, stratified by the diagnosed age of 12. We used epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to prioritize the most likely functional variant and potential causal gene. We also performed functional experiments to evaluate the role of the causal gene on islet function and its related mechanisms.ResultsWe identified rs912304 as a risk variant for T1D subgroups with diagnosed age ≥ 12 but not < 12. This variant is associated with residual islet function but not islet-specific autoantibody positivity in T1D individuals. Bioinformatics analysis indicated that rs912304 is a functional variant exhibiting spatial overlaps with enhancer active histone marks (H3K27ac and H3K4me1) and open chromatin status (ATAC-seq) in the human pancreas and islet tissues. Luciferase reporter gene assays and eQTL analyses demonstrated that the biallelic sites of rs912304 had differential allele-specific enhancer activity in beta cell lines and regulated STXBP6 expression, which was defined as the most putative causal gene based on Open Targets Genetics, GTEx v8 and Tiger database. Moreover, Stxbp6 was upregulated by T1D-related proinflammatory cytokines but not high glucose/fat. Notably, Stxbp6 over-expressed INS-1E cells exhibited decreasing insulin secretion and increasing cell apoptosis through Glut1 and Gadd45β, respectively.ConclusionsThis study expanded the genomic landscape regarding late-onset T1D risk and supported islet function mechanistically connected to T1D pathogenesis.

Gene expression and splicing QTL analysis of blood cells in African American participants from the Jackson Heart Study.

Most gene expression and alternative splicing quantitative trait loci (eQTL/sQTL) studies have been biased toward European ancestry individuals. Here, we performed eQTL and sQTL analyses using TOPMed whole-genome sequencing-derived genotype data and RNA-sequencing data from stored peripheral blood mononuclear cells in 1,012 African American participants from the Jackson Heart Study (JHS). At a false discovery rate of 5%, we identified 17,630 unique eQTL credible sets covering 16,538 unique genes; and 24,525 unique sQTL credible sets covering 9,605 unique genes, with lead QTL at P < 5e-8. About 24% of independent eQTLs and independent sQTLs with a minor allele frequency > 1% in JHS were rare (minor allele frequency < 0.1%), and therefore unlikely to be detected, in European ancestry individuals. Finally, we created an open database, which is freely available online, allowing fast query and bulk download of our QTL results.

Enhlink infers distal and context-specific enhancer–promoter linkages

Enhlink is a computational tool for scATAC-seq data analysis, facilitating precise interrogation of enhancer function at the single-cell level. It employs an ensemble approach incorporating technical and biological covariates to infer condition-specific regulatory DNA linkages. Enhlink can integrate multi-omic data for enhanced specificity, when available. Evaluation with simulated and real data, including multi-omic datasets from the mouse striatum and novel promoter capture Hi-C data, demonstrate that Enhlink outperfoms alternative methods. Coupled with eQTL analysis, it identified a putative super-enhancer in striatal neurons. Overall, Enhlink offers accuracy, power, and potential for revealing novel biological insights in gene regulation.

Impact of putatively beneficial genomic loci on gene expression in little brown bats (Myotis lucifugus, Le Conte, 1831) affected by white-nose syndrome.

Genome-wide scans for selection have become a popular tool for investigating evolutionary responses in wildlife to emerging diseases. However, genome scans are susceptible to false positives and do little to demonstrate specific mechanisms by which loci impact survival. Linking putatively resistant genotypes to observable phenotypes increases confidence in genome scan results and provides evidence of survival mechanisms that can guide conservation and management efforts. Here we used an expression quantitative trait loci (eQTL) analysis to uncover relationships between gene expression and alleles associated with the survival of little brown bats (Myotis lucifugus) despite infection with the causative agent of white-nose syndrome. We found that 25 of the 63 single-nucleotide polymorphisms (SNPs) associated with survival were related to gene expression in wing tissue. The differentially expressed genes have functional annotations associated with the innate immune system, metabolism, circadian rhythms, and the cellular response to stress. In addition, we observed differential expression of multiple genes with survival implications related to loci in linkage disequilibrium with focal SNPs. Together, these findings support the selective function of these loci and suggest that part of the mechanism driving survival may be the alteration of immune and other responses in epithelial tissue.