Blood Expression Quantitative Trait Loci Research Articles

Proteome-Wide Mendelian Randomization and Colocalization Analysis Identify Therapeutic Targets for Knee and Hip Osteoarthritis.

Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still exist in the targeted therapy of OA. Mendelian randomization (MR) analysis has been regarded as a reliable analytic method to identify effective therapeutic targets. Thus, we aimed to identify novel therapeutic targets for OA and investigate their potential side effects based on MR analysis. In this study, two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR) and Mendelian randomization phenome-wide association study (MR-PheWAS) were conducted. We firstly analyzed data from 4907 plasma proteins to identify potential therapeutic targets associated with OA. In addition, blood expression quantitative trait loci (eQTLs) data sources were used to perform additional validation. A protein-protein interaction (PPI) network was also constructed to delve into the interactions among identified proteins. Then, MR-PheWASs were utilized to assess the potential side effects of core therapeutic targets. After MR analysis and FDR correction, we identified twelve proteins as potential therapeutic targets for knee OA or hip OA. Colocalization analysis and additional validation supported our findings, and PPI networks revealed the interactions among identified proteins. Finally, we identified MAPK3 (OR = 0.855, 95% CI: 0.791-0.923, p = 6.88 × 10-5) and GZMK (OR = 1.278, 95% CI: 1.131-1.444, p = 8.58 × 10-5) as the core therapeutic targets for knee OA, and ITIH1 (OR = 0.847, 95% CI: 0.784-0.915, p = 2.44 × 10-5) for hip OA. A further MR phenome-wide association study revealed the potential side effects of treatments targeting MAPK3, GZMK, and ITIH1. This comprehensive study indicates twelve plasma proteins with potential roles in knee and hip OA as therapeutic targets. This advancement holds promise for the progression of OA drug development, and paves the way for more efficacious treatments of OA.

Modeling of horizontal pleiotropy identifies possible causal gene expression in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with complex causes involving genetic and environmental factors. While genome-wide association studies (GWASs) have identified genetic loci associated with SLE, the functional genomic elements responsible for disease development remain largely unknown. Mendelian Randomization (MR) is an instrumental variable approach to causal inference based on data from observational studies, where genetic variants are employed as instrumental variables (IVs). This study utilized a two-step strategy to identify causal genes for SLE. In the first step, the classical MR method was employed, assuming the absence of horizontal pleiotropy, to estimate the causal effect of gene expression on SLE. In the second step, advanced probabilistic MR methods (PMR-Egger, MRAID, and MR-MtRobin) were applied to the genes identified in the first step, considering horizontal pleiotropy, to filter out false positives. PMR-Egger and MRAID analyses utilized whole blood expression quantitative trait loci (eQTL) and SLE GWAS summary data, while MR-MtRobin analysis used an independent eQTL dataset from multiple immune cell types along with the same SLE GWAS data. The initial MR analysis identified 142 genes, including 43 outside of chromosome 6. Subsequently, applying the advanced MR methods reduced the number of genes with significant causal effects on SLE to 66. PMR-Egger, MRAID, and MR-MtRobin, respectively, identified 13, 7, and 16 non-chromosome 6 genes with significant causal effects. All methods identified expression of PHRF1 gene as causal for SLE. A comprehensive literature review was conducted to enhance understanding of the functional roles and mechanisms of the identified genes in SLE development. The findings from the three MR methods exhibited overlapping genes with causal effects on SLE, demonstrating consistent results. However, each method also uncovered unique genes due to different modelling assumptions and technical factors, highlighting the complementary nature of the approaches. Importantly, MRAID demonstrated a reduced percentage of causal genes from the Major Histocompatibility complex (MHC) region on chromosome 6, indicating its potential in minimizing false positive findings. This study contributes to unraveling the mechanisms underlying SLE by employing advanced probabilistic MR methods to identify causal genes, thereby enhancing our understanding of SLE pathogenesis.

PIK3R3 is a candidate regulator of platelet count in people of Bangladeshi ancestry

BackgroundBlood platelets are mediators of atherothrombotic disease and are regulated by complex sets of genes. Association studies in European ancestry populations have already detected informative platelet regulatory loci. Studies in other ancestries can potentially reveal new associations because of different allele frequencies, linkage structures, and variant effects. ObjectivesTo reveal new regulatory genes for platelet count (PLT). MethodsGenome-wide association studies (GWAS) were performed in 20,218 Bangladeshi and 9198 Pakistani individuals from the Genes & Health study. Loci significantly associated with PLT underwent fine-mapping to identify candidate genes. ResultsOf 1588 significantly associated variants (P < 5 × 10−8) at 20 loci in the Bangladeshi analysis, most replicated findings in prior transancestry GWAS and in the Pakistani analysis. However, the Bangladeshi locus defined by rs946528 (chr1:46019890) did not associate with PLT in the Pakistani analysis but was in the same linkage disequilibrium block (r2 ≥ 0.5) as PLT-associated variants in prior East Asian GWAS. The single independent association signal was refined to a 95% credible set of 343 variants spanning 8 coding genes. Functional annotation, mapping to megakaryocyte regulatory regions, and colocalization with blood expression quantitative trait loci identified the likely mediator of the PLT phenotype to be PIK3R3 encoding a regulator of phosphoinositol 3-kinase (PI3K). ConclusionAbnormal PI3K activity in the vessel wall is already implicated in the pathogenesis of atherothrombosis. Our identification of a new association between PIK3R3 and PLT provides further mechanistic insights into the contribution of the PI3K pathway to platelet biology.

Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE.

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

Single-cell expression and Mendelian randomization analyses identify blood genes associated with lifespan and chronic diseases

The human lifespan is a heritable trait, which is intricately linked to the development of disorders. Here, we show that genetic associations for the parental lifespan are enriched in open chromatin of blood cells. By using blood expression quantitative trait loci (eQTL) derived from 31,684 samples, we identified for the lifespan 125 cis- and 559 trans-regulated expressed genes (eGenes) enriched in adaptive and innate responses. Analysis of blood single-cell expression data showed that eGenes were enriched in dendritic cells (DCs) and the modelling of cell ligand-receptor interactions predicted crosstalk between DCs and a cluster of monocytes with a signature of cytotoxicity. In two-sample Mendelian randomization (MR), we identified 16 blood cis-eGenes causally associated with the lifespan. In MR, the majority of cis-eGene-disorder association pairs had concordant effects with the lifespan. The present work underlined that the lifespan is linked with the immune response and identifies eGenes associated with the lifespan and disorders.

Integration of genome-wide association study and expression quantitative trait loci data identifies AIM2 as a risk gene of periodontitis.

To identify risk variants associated with gene expression in peripheral blood and to identify genes whose expression change may contribute to the susceptibility to periodontitis. We systematically integrated the genetic associations from a recent large-scale periodontitis GWAS and blood expression quantitative trait loci (eQTL) data using Sherlock, a Bayesian statistical framework. We then validated the potential causal genes in independent gene expression data sets. Gene co-expression analysis was used to explore the functional relationship for the identified causal genes. Sherlock analysis identified 10 genes (rs7403881 for MT1L, rs12459542 for SIGLEC5, rs12459542 for SIGLEC14, rs6680386 for S100A12, rs10489524 for TRIM33, rs11962642 for HIST1H3E, rs2814770 for AIM2, rs7593959 for FASTKD2, rs10416904 for PKN1, and rs10508204 for WDR37) whose expression may influence periodontitis. Among these genes, AIM2 was consistent significantly upregulated in periodontium of periodontitis patients across four data sets. The cis-eQTL (rs2814770, ~16kb upstream of AIM2) showed significant association with AIM2 (p=6.63×10-6 ) and suggestive association with periodontitis (p=7.52×10-4 ). We also validated the significant association between rs2814770 and AIM2 expression in independent expression data set. Pathway analysis revealed that genes co-expressed with AIM2 were significantly enriched in immune- and inflammation-related pathways. Our findings implicate that AIM2 is a susceptibility gene, expression of which in gingiva may influence periodontitis risk. Further functional investigation of AIM2 may provide new insight for periodontitis pathogenesis.

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer

BackgroundBreast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers.MethodsWe selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR), and the ribonucleotide reductase M1 gene (RRM1) in 342 MBC patients treated with capecitabine-based chemotherapy. The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson’s χ2 test, and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis. The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci (eQTL) browser online tools.ResultsWe found 4 positive sites for HFS in the TYMS and MTHFR genes: TYMS rs2606241 (P = 0.022), TYMS rs2853741 (P = 0.019), MTHFR rs3737964 (P = 0.029), and MTHFR rs4846048 (P = 0.030). Logistic regression analyses showed that the genotype AG of MTHFR rs3737964 [odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.31–0.97, P = 0.038] and MTHFR rs4846048 (OR = 0.54, 95% CI 0.30–0.98, P = 0.042) were protective factors of HFS, whereas the genotype CT of TYMS rs2853741 (OR = 2.25, 95% CI 1.31–3.87, P = 0.012) increased the risk of HFS. The association between the genotype GT of TYMS rs2606241 (OR = 1.27, 95% CI 0.73–2.23, P = 0.012) and HFS was uncertain. Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis.ConclusionsWe have identified four potentially useful pharmacogenetic markers, TYMS rs2606241, TYMS rs2853741, MTHFR rs3737964, and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.

IL1B polymorphism is associated with essential tremor in Chinese population

BackgroundThe aim of the study was to investigate the genetic risk factors of essential tremor (ET) in Chinese Population.MethodsA total of 225 ET patients (25 ET patients also had restless legs syndrome (RLS) and were excluded from final analysis) and 229 controls were recruited. The diagnosis of ET was based on the Consensus Statement of the Movement Disorders Society on tremor. Polymerase chain reaction (PCR) and sequencing were used to detect 12 single nucleotide polymorphisms (SNPs) in seven candidate genes for RLS (HMOX1, HMOX2, VDR, IL17A, IL1B, NOS1 and ADH1B).ResultsWe found that one SNP was associated with the risk of ET in Chinese population after adjusting for age and gender: rs1143633 of IL1B (odds ratio [OR] =2.57, p = 0.003, recessive model), and the statistical result remained significant after Bonferroni correction. Then, we performed a query in Genotype-tissue Expression (GTEx), Brain eQTL Almanac (Braineac) databases and Blood expression quantitative trait loci (eQTL) browser. The significant association was only found between genotype at rs1143633 and IL1B expression level of putamen and white matter in Braineac database, which was more prominent with homozygous (GG) carriers.ConclusionsOur study firstly reported the association of IL1B polymorphism with the risk of ET in Chinese population. However, the association might only suggest a marker of IL1B SNP associated with ET instead of the casual variant. Further studies are needed to confirm our finding.

Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

Exploring hepsin functional genetic variation association with disease specific protein expression in bipolar disorder: Applications of a proteomic informed genomic approach

In a prior discovery study, increased levels of serum Growth Differentiation Factor 15 (GDF15), Hepsin (HPN), and Matrix Metalloproteinase-7 (MMP7) were observed in bipolar depressed patients vs controls. This exploratory post-hoc analysis applied a proteomic-informed genomic research strategy to study the potential functional role of these proteins in bipolar disorder (BP). Utilizing the Genotype-Tissue Expression (GTEx) database to identify cis-acting blood expression quantitative trait loci (cis-eQTLs), five eQTL variants from the HPN gene were analyzed for association with BP cases using genotype data of cases from the discovery study (n = 58) versus healthy controls (n = 777). After adjusting for relevant covariates, we analyzed the relationship between these 5 cis-eQTLs and HPN serum level in the BP cases. All 5 cis-eQTL minor alleles were significantly more frequent in BP cases vs controls [(rs62122114, OR = 1.6, p = 0.02), (rs67003112, OR = 1.6, p = 0.02), (rs4997929, OR = 1.7, p = 0.01), (rs12610663, OR = 1.7, p = 0.01), (rs62122148, OR = 1.7, P = 0.01)]. The minor allele (A) in rs62122114 was significantly associated with increased serum HPN level in BP cases (Beta = 0.12, P = 0.049). However, this same minor allele was associated with reduced gene expression in GTEx controls. These exploratory analyses suggest that genetic variation in/near the gene encoding for hepsin protein may influence risk of bipolar disorder. This genetic variation, at least for the rs62122114-A allele, may have functional impact (i.e. differential expression) as evidenced by serum HPN protein expression. Although limited by small sample size, this study highlights the merits of proteomic informed functional genomic studies as a tool to investigate with greater precision the genetic risk of bipolar disorder and secondary relationships to protein expression recognizing, and encouraging in subsequent studies, high likelihood of epigenetic modification of genetic disease risk.

Integration of expression quantitative trait loci and pleiotropy identifies a novel psoriasis susceptibility gene, PTPN1.

Psoriasis is a common inflammatory skin disease, whereas schizophrenia is a psychiatric disorder with substantial comorbidity. Although these two disorders manifest with apparently unrelated phenotypes, there is some evidence suggesting that they share common genetic factors. We implemented a genetic analysis incorporating pleiotropy and annotation to genome-wide association summary statistics data for approximately 120 000 psoriasis and schizophrenia samples, as well as whole blood expression quantitative trait loci in 5311 samples. We observed a significant pleiotropic effect between psoriasis and schizophrenia (p=5.92×10-43 ). We characterized an enrichment of whole blood expression quantitative trait loci in genome-wide association data for psoriasis and schizophrenia (q1 /q0 >1.5, p<10-77 ) and we revealed that common variants for both diseases were more likely to confer expression quantitative trait loci effects (q1 /q0 =4.197, SE=0.183). Through joint analysis of the associations in the combined psoriasis and schizophrenia data set, we identified a potential susceptibility PTPN1 gene for psoriasis, which may affect the risk of psoriasis through modulation of the function of TYK2 kinase. The results of the present study highlight the expression quantitative trait loci enrichment and pleiotropy in psoriasis and schizophrenia, and also suggest a possible key role of the PTPN1 gene in the etiology of psoriasis.