Quantitative Trait Locus Association Research Articles

Genome-wide Mendelian randomization mapping the influence of plasma proteome on major depressive disorder.

Plasma proteins play critical roles in a series of biological processes and represent a major source of translational biomarkers and drug targets. In this study, we performed Mendelian randomization (MR) to explore potential causal associations of protein quantitative trait loci (pQTL, n = 54,219) with major depressive disorder (MDD) using summary statistics from the PGC (n = 143,265) and further replicated in FinnGen cohort (n = 406,986). Subsequently, gene expression quantitative trait loci (eQTL) of identified proteins were leveraged to validate the primary findings in both PGC and FinnGen cohorts. We implemented reverse causality detection using bidirectional MR analysis, Steiger test, Bayesian co-localization and phenotype scanning to further strengthen the MR findings. In primary analyses, MR analysis revealed 2 plasma protein significantly associated with MDD risk at Bonferroni correction (P < 3.720 × 10-5), including butyrophilin subfamily 2 member A1 (BTN2A1, OR = 0.860; 95 % CI, 0.825-0.895; P = 1.79 × 10-5) and butyrophilin subfamily 3 member A2 (BTN3A2, OR = 1.071; 95 % CI, 1.056-1.086; P = 3.89 × 10-6). Both the identified proteins had no reverse causality. Bayesian co-localization indicated that BTN2A1 (coloc.abf-PPH4 = 0.620) and BTN3A2 (coloc.abf-PPH4 = 0.872) exhibited a shared variant with MDD, a finding that was subsequently validated by HEIDI test. In the replication stage, BTN2A1 and BTN3A2 were successfully validated in the FinnGen cohort. This study genetically determined BTN2A1 and BTN3A2 were associated with MDD and these findings may have clinical implications for MDD prevention.

Identifying prioritization of therapeutic targets for ankylosing spondylitis: a multi-omics Mendelian randomization study

BackgroundTo investigate the associations of methylation, expression, and protein quantitative trait loci (mQTL, eQTL, and pQTL) with ankylosing spondylitis (AS) and find out genetically supported drug targets for AS.MethodsThe summary-data-based Mendelian randomization (SMR) and Bayesian co-localization analysis were used to assess the potential causality between AS and relevant genes. The GWAS data obtained from the International Genetics of Ankylosing Spondylitis Consortium (IGAS) were set as the discovery stage, and the FinnGen and UK Biobank databases were used to replicate the analysis as an external validation. We further integrated the multi-omics results to screen overlapped genes at different levels. The protein–protein interaction (PPI) network and enrichment analyses were used to explore the biological effect of SMR-identified genes on AS. Drug prediction and molecular docking were used to validate the medicinal value of candidate drug targets.ResultsBased on the results of multi-omics evidence screening, we identified potential associations of TNFRSF1A, B3GNT2, ERAP1, and FCGR2A with AS at different regulatory levels. At the protein level, AIF1, TNXB, APOM, and B3GNT2 were found to be negatively associated with AS risk, whereas higher levels of FCGR2A, FCGR2B, IL12B, TNFRSF1A, and ERAP1 were associated with an increased risk of AS. The bioinformatics analyses showed that the SMR-identified genes were mainly involved in immune response. Molecular docking results displayed stable binding between predicted candidate drugs and these aforementioned proteins.ConclusionOur study found four AS-associated genes with multi-omics evidence and nine promising drug targets for AS, which may contribute to the understanding of the genetic mechanisms of AS and provide innovative perspectives into targeted therapy for AS.

Enhancing aluminium resistance in wheat ( Triticum aestivum L.) by exploring for novel genes in the wheat genome

Abstract Aluminium (Al 3+ ) toxicity is a major constraint to crop production worldwide and is considered second only to drought for its importance as an agronomic challenge. A common practice to manage the impact is the application of lime but this is expensive, and it can take years for the lime to be effective in ameliorating the subsoil acidity. Plant species with a natural ability to adapt to Al 3+ toxicity offer an option to maintain production while amelioration efforts continue, especially in low-rainfall areas where yield responses to lime is less profitable. In wheat ( Triticum aestivum L.), the genes conferring Al 3+ resistance have been extensively researched over the years through classical inheritance, cytogenetic, quantitative trait locus (QTL) and genome-wide association studies, and transcriptional analyses. As a focal point for this discussion, we assembled a total of 212 QTL from research papers published between 2006 and 2024, and their physical positions were projected on the sequenced genome of the moderately Al 3+ -resistant hexaploid wheat variety, Chinese Spring. The markers were distributed across the 21 wheat chromosomes, with the highest numbers on chromosomes 3B, 4D and 7A and the lowest on chromosomes 3D and 5D. The physical mapping of significantly associated markers onto the reference genome map uncovered novel candidate genes. These include wheat aluminium-induced (Wali) genes, the ATP-binding cassette (ABC) transporters, phytosulfokine receptor (PSKR), PIN-formed (PIN, auxin transporter), NAC (NAC domain), WRKY (WRKY domain) and natural resistance-associated macrophage proteins (NRAMP). These were discussed to provide a contextual review of gaps that can be exploited in enhancing Al 3+ resistance in wheat, which can lead to the discovery of novel genes and the development of improved cultivars.

Genetic variants associated with response to anti-CGRP monoclonal antibody therapy in a chronic migraine Han Chinese population

BackgroundAnti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine.MethodsWe conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database.ResultsSix single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10− 7): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10− 9). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure.ConclusionThe identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology.Trial registrationNot applicable.

Concurrently mapping quantitative trait loci associations from multiple subspecies within hybrid populations

Many of the world’s agriculturally important plant and animal populations consist of hybrids of subspecies. Cattle in tropical and sub-tropical regions for example, originate from two subspecies, Bos taurus indicus (Bos indicus) and Bos taurus taurus (Bos taurus). Methods to derive the underlying genetic architecture for these two subspecies are essential to develop accurate genomic predictions in these hybrid populations. We propose a novel method to achieve this. First, we use haplotypes to assign SNP alleles to ancestral subspecies of origin in a multi-breed and multi-subspecies population. Then we use a BayesR framework to allow SNP alleles originating from the different subspecies differing effects. Applying this method in a composite population of B. indicus and B. taurus hybrids, our results show that there are underlying genomic differences between the two subspecies, and these effects are not identified in multi-breed genomic evaluations that do not account for subspecies of origin effects. The method slightly improved the accuracy of genomic prediction. More significantly, by allocating SNP alleles to ancestral subspecies of origin, we were able to identify four SNP with high posterior probabilities of inclusion that have not been previously associated with cattle fertility and were close to genes associated with fertility in other species. These results show that haplotypes can be used to trace subspecies of origin through the genome of this hybrid population and, in conjunction with our novel Bayesian analysis, subspecies SNP allele allocation can be used to increase the accuracy of QTL association mapping in genetically diverse populations.

APOA2: New Target for Molecular Hydrogen Therapy in Sepsis-Related Lung Injury Based on Proteomic and Genomic Analysis.

Target biomarkers for H2 at both the protein and genome levels are still unclear. In this study, quantitative proteomics acquired from a mouse model were first analyzed. At the same time, functional pathway analysis helped identify functional pathways at the protein level. Then, bioinformatics on mRNA sequencing data were conducted between sepsis and normal mouse models. Differential expressional genes with the closest relationship to disease status and development were identified through module correlation analysis. Then, common biomarkers in proteomics and transcriptomics were extracted as target biomarkers. Through analyzing expression quantitative trait locus (eQTL) and genome-wide association studies (GWAS), colocalization analysis on Apoa2 and sepsis phenotype was conducted by summary-data-based Mendelian randomization (SMR). Then, two-sample and drug-target, syndrome Mendelian randomization (MR) analyses were all conducted using the Twosample R package. For protein level, protein quantitative trait loci (pQTLs) of the target biomarker were also included in MR. Animal experiments helped validate these results. As a result, Apoa2 protein or mRNA was identified as a target biomarker for H2 with a protective, causal relationship with sepsis. HDL and type 2 diabetes were proven to possess causal relationships with sepsis. The agitation and inhibition of Apoa2 were indicated to influence sepsis and related syndromes. In conclusion, we first proposed Apoa2 as a target for H2 treatment.

Molecular and functional dissection of LIGULELESS1 (LG1) in plants.

Plant architecture is a culmination of the features necessary for capturing light energy and adapting to the environment. An ideal architecture can promote an increase in planting density, light penetration to the lower canopy, airflow as well as heat distribution to achieve an increase in crop yield. A number of plant architecture-related genes have been identified by map cloning, quantitative trait locus (QTL) and genome-wide association study (GWAS) analysis. LIGULELESS1 (LG1) belongs to the squamosa promoter-binding protein (SBP) family of transcription factors (TFs) that are key regulators for plant growth and development, especially leaf angle (LA) and flower development. The DRL1/2-LG1-RAVL pathway is involved in brassinosteroid (BR) signaling to regulate the LA in maize, which has facilitated the regulation of plant architecture. Therefore, exploring the gene regulatory functions of LG1, especially its relationship with LA genes, can help achieve the precise regulation of plant phenotypes adapted to varied environments, thereby increasing the yield. This review comprehensively summarizes the advances in LG1 research, including its effect on LA and flower development. Finally, we discuss the current challenges and future research goals associate with LG1.

Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

BackgroundTourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. MethodsWe performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. ResultsWe identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. ConclusionsOur work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Combined linkage mapping and association analysis uncovers candidate genes for 25 leaf-related traits across three environments in maize.

Combined linkage and association analysis revealed five co-localized genetic loci across multiple environments. The key gene Zm00001d026491 was further verified to influence leaf length by candidate gene association analysis. Leaf morphology and number determine the canopy structure and thus affect crop yield. Herein, the genetic basis and key genes for 25 leaf-related traits, including leaf lengths (LL), leaf widths (LW), and leaf areas (LA) of eight continuous leaves under the tassel, and the number of leaves above the primary ear (LAE), were dissected by using an association panel and a biparental population. Using an intermated B73 × Mo17 (IBM) Syn10 doubled haploid (DH) population, 290 quantitative trait loci (QTL) controlling these traits were detected across different locations, among which 115 QTL were individually repeatedly identified in at least two environments. Using the association panel, 165 unique significant single-nucleotide polymorphisms (SNPs) were associated with target traits (P < 2.15E-06), of which 35 were separately detected across multiple environments. In total, 42 pleiotropic QTL/SNPs (pQTL/SNPs) were responsible for at least two of the LL, LW, LA, and LAE traits across multiple environments. Combining the QTL mapping and association study, five unique SNPs were located within the confidence intervals of seven QTL, and 77 genes were identified based on the linkage disequilibrium regions of co-localized SNP loci. Gene-based association studies verified that the intragenic variants in the candidate gene Zm00001d026491 influenced LL of the third leaf counted from the top node. These findings will provide vital information to understanding the genetic basis of leaf-related traits and help to cultivate maize varieties with ideal plant architecture.

Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes.

Aim: To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood. Methods: Cross-ancestry (Europeans=302, South Asians=161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from theMoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood. Results & conclusion: cg19888088 (cross-ancestry) in EBF3, cg01952260 (Europeans) and cg07077240 (South Asians) in HERC3 were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants in CASC15. The findings were not replicated and were not significant in cord blood.

Runs of Homozygosity and Quantitative Trait Locus/Association for Semen Parameters in Selected Chinese and South African Beef Cattle.

Simple SummaryGenome-wide runs of homozygosity (ROH) are excellent in understanding population history, estimating genomic inbreeding, and deciphering genetic architecture of complex traits and diseases, as well as identifying genes of agro-economic traits. ROH are defined as continuous region on the chromosome where an individual is homozygous across the genome. This study identified distribution of ROH in the six selected beef cattle breeds, Chinese Simentaler (CSI), Belgian Blue (BEL), and South African Angus (ANG), Nguni (NGU), Bonsmara (BON), and Simentaler (SIM), using Bovine BeadChip markers. Furthermore, nine candidate genes, CDF9, MARCH1, WDR19, SLOICI, ST7, DOP1B, CFAF9, INHBA, and ADAMTS1, were suggested to be associated with semen QTL traits and reported moderate inbreeding in some breeds with high to low correlation inbreeding between breeds. The study findings will allow proper guidelines for breeder’s societies.In this study, runs of homozygosity (ROH) and quantitative trait locus/association (QTL) for semen parameters in selected Chinese and South African beef cattle breed were estimated. The computed results showed 7516 ROH were observed between classes 0–5 Mb with no ROH observed in classes >40 Mb. Distribution of ROH showed high level of genomic coverage for ANG, NGU, CSI, and BEL breeds. Approximately 13 genomic regions with QTL were controlling sperm motility, sperm concentration, semen volume, sperm count, sperm head abnormalities, sperm tail abnormalities, sperm integrity, and percentage of abnormal sperm traits. Nine candidate genes, CDF9, MARCH1, WDR19, SLOICI, ST7, DOP1B, CFAF9, INHBA, and ADAMTS1, were suggested to be associated with above mentioned QTL traits. The results for inbreeding coefficient showed moderate correlation between FROH vs FHOM at 0.603 and high correlation between FROH 0–5 Mb 0.929, and lowest correlation for 0–>40 Mb 0.400. This study suggested recent inbreeding in CSI, BEL, ANG, BON, SIM, and NGU breeds. Furthermore, it highlighted varied inbreeding levels and identified QTL for semen traits and genes of association. These results can assist in implementation of genetic improvement strategies for bulls and provide awareness and proper guidelines in developing breeding programs.

Golgin A7 family member B (GOLGA7B) is a plausible novel gene associating high glycaemic index diet with acne vulgaris.

While the IGF1/FoxO1/mTORC1signalling pathway is a well-established nutrigenomic link between high glycaemic index (GI)/glycaemic load (GL) diet and acne vulgaris, other signalling pathways remain elusive. Therefore, we aimed to investigate other genes that are involved in the high GI/GL diet-acne link, using our Singapore/Malaysia population epidemiological, genomics and transcriptomics data. High GI/GL dietary habit of 3207 acne cases (1869 and 1341 further classified into severity and scarring grades, respectively) and 2521 controls were evaluated based on Quality of Diet based on Glycaemic Index Score (QDGIS). Overlapping concordant differentially expressed genes (DEGs) between acne case-controls and QDGIS poor-moderate/good classes were identified from whole-transcriptome sequencing data of PBMC of a subset of participants. Finally, we assessed the expression quantitative trait loci (eQTL) association of single nucleotide polymorphisms (SNPs) of the concordant DEGs. Daily intake of fruits significantly reduced the risk of acne presentation, severity and scarring by up to 48.5%. Those with good QDGIS had significantly lower risk of mild and moderate/severe acne, and grade 1/2 acne scarring. Sequential filtering identified four overlapping concordant DEGs that were significantly associated with acne and QDGIS, namely GOLGA7B, SNCB, LOC102723849 and LOC283683. Combining transcriptome and genetic association data, we identified intronic SNP rs1953947 in GOLGA7B as an eQTL for acne. In conclusion, we identified GOLGA7B as a plausible novel gene that links high GI/GL with acne, and hence propose a model for the involvement of Golga7b in high GI/GL diet-acne pathogenesis, which includes palmitoyl acyltransferase zDHHC5, fatty acid translocase CD36 and palmitic acid.

Metagenomic and metabolomic remodeling in nonagenarians and centenarians and its association with genetic and socioeconomic factors.

A better understanding of the biological and environmental variables that contribute to exceptional longevity has the potential to inform the treatment of geriatric diseases and help achieve healthy aging. Here, we compared the gut microbiome and blood metabolome of extremely long-lived individuals (94-105 years old) to that of their children (50-79 years old) in 116 Han Chinese families. We found extensive metagenomic and metabolomic remodeling in advanced age and observed a generational divergence in the correlations with socioeconomic factors. An analysis of quantitative trait loci revealed that genetic associations with metagenomic and metabolomic features were largely generation-specific, but we also found 131 plasma metabolic quantitative trait loci associations that were cross-generational with the genetic variants concentrated in six loci. These included associations between FADS1/2 and arachidonate, PTPA and succinylcarnitine and FLVCR1 and choline. Our characterization of the extensive metagenomic and metabolomic remodeling that occurs in people reaching extreme ages may offer new targets for aging-related interventions.

QtlXplorer: an online systems genetics browser in the Eucalyptus Genome Integrative Explorer (EucGenIE)

BackgroundAffordable high-throughput DNA and RNA sequencing technologies are allowing genomic analysis of plant and animal populations and as a result empowering new systems genetics approaches to study complex traits. The availability of intuitive tools to browse and analyze the resulting large-scale genetic and genomic datasets remain a significant challenge. Furthermore, these integrative genomics approaches require innovative methods to dissect the flow and interconnectedness of biological information underlying complex trait variation. The Plant Genome Integrative Explorer (PlantGenIE.org) is a multi-species database and domain that houses online tools for model and woody plant species including Eucalyptus. Since the Eucalyptus Genome Integrative Explorer (EucGenIE) is integrated within PlantGenIE, it shares genome and expression analysis tools previously implemented within the various subdomains (ConGenIE, PopGenIE and AtGenIE). Despite the success in setting up integrative genomics databases, online tools for systems genetics modelling and high-resolution dissection of complex trait variation in plant populations have been lacking.ResultsWe have developed qtlXplorer (https://eucgenie.org/QTLXplorer) for visualizing and exploring systems genetics data from genome-wide association studies including quantitative trait loci (QTLs) and expression-based QTL (eQTL) associations. This module allows users to, for example, find co-located QTLs and eQTLs using an interactive version of Circos, or explore underlying genes using JBrowse. It provides users with a means to build systems genetics models and generate hypotheses from large-scale population genomics data. We also substantially upgraded the EucGenIE resource and show how it enables users to combine genomics and systems genetics approaches to discover candidate genes involved in biotic stress responses and wood formation by focusing on two multigene families, laccases and peroxidases.ConclusionsqtlXplorer adds a new dimension, population genomics, to the EucGenIE and PlantGenIE environment. The resource will be of interest to researchers and molecular breeders working in Eucalyptus and other woody plant species. It provides an example of how systems genetics data can be integrated with functional genetics data to provide biological insight and formulate hypotheses. Importantly, integration within PlantGenIE enables novel comparative genomics analyses to be performed from population-scale data.

Genome-wide association and colocalization analyses identify target genes for brain arteriolosclerosis.

Brain arteriolosclerosis (B-ASC) is a small-vessel cerebrovascular pathologic change involving sclerotic thickening of arterioles in the brain. B-ASC pathology is common in aged autopsy cohorts, is associated with worse cognitive functioning, and is also associated with other neuropathologies. The genetics of dementia and other pathologic changes have been studied extensively, but to date no in-depth study has been conducted on genetic risk of autopsy-proven B-ASC. We performed the first genome-wide association study (GWAS) focusing on B-ASC using multiple cohorts. We then followed up on identified risk variants with functional analysis to investigate potential biological mechanisms. Individual GWAS and mega-analyses were conducted using data from participants in the National Alzheimer's Coordinating Center (NACC) (N = 3318) and the Religious Orders Study and Memory and Aging Project (ROSMAP) (N=1190). In total, 4,577,283 variants (MAF > 5%) were present in both datasets and passed quality control. Variants identified in GWAS were then checked for quantitative trait loci (QTL) associations in the Genotype Tissue Expression (GTEx) project. Colocalization analysis was then performed on identified QTL in brain and vascular tissues. Variants most highly associated with B-ASC were also examined for association with neuroimaging correlates of B-ASC in the Alzheimer's Disease Neuroimaging Initiative. One intergenic locus on Chromosome 6 was significantly associated with B-ASC in NACC (P = 1.4e-08) and colocalized with ELOVL4 gene expression in the brain. Other loci in both cohorts achieved less stringent thresholds of association and colocalized with multiple QTL in GTEx. One intergenic locus on Chromosome 10 near SORCS3 was suggestively associated with B-ASC in NACC and was replicated in ROSMAP. Genetic loci associated with B-ASC pathology were identified using multiple cohorts. Most loci associated with B-ASC in one cohort were not associated in the other. Multiple identified risk loci colocalized with gene expression or splicing QTL, providing evidence for potential biological mechanisms through which variants may influence disease risk. Due to the relatively small sample sizes and heterogeneity between the cohorts used, additional studies are merited to better characterize genetic risk of B-ASC.

Low Temperature Antioxidant Activity QTL Associate with Genomic Regions Involved in Physiological Cold Stress Tolerance Responses in Rice (Oryza sativa L.).

Boosting cold stress tolerance in crop plants can minimize stress-mediated yield losses. Asian rice (Oryza sativa L.), one of the most consumed cereal crops, originated from subtropical regions and is generally sensitive to low temperature environments. Within the two subspecies of rice, JAPONICA, and INDICA, the cold tolerance potential of its accessions is highly variable and depends on their genetic background. Yet, cold stress tolerance response mechanisms are complex and not well understood. This study utilized 370 accessions from the Rice Diversity Panel 1 (RDP1) to investigate and correlate four cold stress tolerance response phenotypes: membrane damage, seedling survivability, and catalase and anthocyanin antioxidative activity. Most JAPONICA accessions, and admixed accessions within JAPONICA, had lower membrane damage, higher antioxidative activity, and overall, higher seedling survivability compared to INDICA accessions. Genome-wide association study (GWAS) mapping was done using the four traits to find novel quantitative trait loci (QTL), and to validate and fine-map previously identified QTL. A total of 20 QTL associated to two or more traits were uncovered by our study. Gene Ontology (GO) term enrichment analyses satisfying four layers of filtering retrieved three potential pathways: signal transduction, maintenance of plasma membrane and cell wall integrity, and nucleic acids metabolism as general mechanisms of cold stress tolerance responses involving antioxidant activity.

Understanding the role of corneal biomechanics-associated genetic variants by bioinformatic analyses.

To analyze functions of corneal biomechanical properties (CBP)-related variants as corneal resistance factor (CRF) and corneal hysteresis (CH). Related single nucleotide polymorphisms (SNPs) and genes were identified from NHGRI-EBI GWAS catalog, GWASdb v2 and possible data in published studies. HaploReg v4.1 was used to find linkage SNPs. Functional annotations were performed by GWAVA, CADD and RegulomeDB. GTEx Portal database was used to find out expression quantitative trait locus (eQTL) association. Enrichr was used to annotate the function of GWAS gene and the associated signal pathway. STING (v11.0) database was utilized for protein interaction and network construction. The integration of 302 CH-associated and 420 CRF-associated lead SNPs has produced 531 CBP-associated lead SNPs. A total of 5,324 proxy variants identified using the HaploReg v4.1 and lead SNPs were functionally annotated. Based on the threshold (CADD ≥ 10, GWAVA ≥ 0.4 and RegulomeDB < rank 3), 23 prioritized putative regulatory SNPs were identified. Eight prioritized eQTL variants (rs75203695, rs34861673, rs846766, rs11024102, rs1377416, rs3829492, rs9934438 and rs197912) were found with strong potential of CBP regulation. It was indicated that CBP-associated genes were significantly enriched in extracellular matrix receptor interaction pathway, closely related to the phenotype of corneal dystrophy and keratoconus. COL1A1, SMAD3, BMP4 and RUNX2 occupied the core position in the co-expression network. Data integrative analysis can evaluate CBP variations and explore collagen and extracellular matrix pathways in CBP regulation, which is a promising tool to investigate biological process of corneal diseases.

A Missense Variant in the IL-6 Receptor and Protection From Peripheral Artery Disease

A Missense Variant in the IL-6 Receptor and Protection From Peripheral Artery Disease

Phenome-wide and expression quantitative trait locus associations of coronavirus disease 2019 genetic risk loci

SummaryWhile several genes and clinical traits have been associated with higher risk of severe coronavirus disease 2019 (COVID-19), how host genetic variants may interact with these parameters and contribute to severe disease is still unclear. Herein, we performed phenome-wide association study, tissue and immune-cell-specific expression quantitative trait locus (eQTL)/splicing quantitative trait locus, and colocalization analyses for genetic risk loci suggestively associated with severe COVID-19 with respiratory failure. Thirteen phenotypes/traits were associated with the severe COVID-19-associated loci at the genome-wide significance threshold, including monocyte counts, fat metabolism traits, and fibrotic idiopathic interstitial pneumonia. In addition, we identified tissue and immune subtype-specific eQTL associations affecting 48 genes, including several ones that may directly impact host immune responses, colocalized with the severe COVID-19 genome-wide association study associations, and showed altered expression in single-cell transcriptomes. Collectively, our work demonstrates that host genetic variations associated with multiple genes and traits show genetic pleiotropy with severe COVID-19 and may inform disease etiology.

Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren's syndrome.

Differential methylation of immune genes has been a consistent theme observed in Sjögren's syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren's International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.