eqtl analysis
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2022 ◽  
Author(s):  
Martin Broberg ◽  
Minna Ampuja ◽  
Samuel Jones ◽  
Tiina Ojala ◽  
Otto Rahkonen ◽  
...  

AbstractCongenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. CHDs exhibit a complex inheritance pattern. While genetic factors are known to play an important role in the development of CHD, relatively few variants have been discovered so far and very few genome-wide association studies (GWAS) have been conducted. We performed a GWAS of general CHD and five CHD subgroups in FinnGen followed by functional fine-mapping through eQTL analysis in the GTEx database, and target validation in human induced pluripotent stem cell - derived cardiomyocytes (hiPS-CM) from CHD patients. We discovered that the MYL4-KPNB1 locus (rs11570508, beta = 0.24, P = 1.2×10−11) was associated with the general CHD group. An additional four variants were significantly associated with the different CHD subgroups. Two of these, rs1342740627 associated with left ventricular outflow tract obstruction defects and rs1293973611 associated with septal defects, were Finnish population enriched. The variant rs11570508 associated with the expression of MYL4 (normalized expression score (NES) = 0.1, P = 0.0017, in the atrial appendage of the heart) and KPNB1 (NES = -0.037, P = 0.039, in the left ventricle of the heart). Furthermore, lower expression levels of both genes were observed in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) from CHD patients compared to healthy controls. Together, the results demonstrate KPNB1 and MYL4 as in a potential genetic risk loci associated with the development of CHD.


2021 ◽  
Vol 8 ◽  
Author(s):  
Yaozhong Liu ◽  
Biao Li ◽  
Yingxu Ma ◽  
Yunying Huang ◽  
Feifan Ouyang ◽  
...  

Background: Atrial fibrillation (AF) is the most common arrhythmia. Genome-wide association studies (GWAS) have identified more than 100 loci associated with AF, but the underlying biological interpretation remains largely unknown. The goal of this study is to identify gene expression and DNA methylation (DNAm) that are pleiotropically or potentially causally associated with AF, and to integrate results from transcriptome and methylome.Methods: We used the summary data-based Mendelian randomization (SMR) to integrate GWAS with expression quantitative trait loci (eQTL) studies and methylation quantitative trait loci (mQTL) studies. The HEIDI (heterogeneity in dependent instruments) test was introduced to test against the null hypothesis that there is a single causal variant underlying the association.Results: We prioritized 22 genes by eQTL analysis and 50 genes by mQTL analysis that passed the SMR & HEIDI test. Among them, 6 genes were overlapped. By incorporating consistent SMR associations between DNAm and AF, between gene expression and AF, and between DNAm and gene expression, we identified several mediation models at which a genetic variant exerted an effect on AF by altering the DNAm level, which regulated the expression level of a functional gene. One example was the genetic variant-cg18693985-CPEB4-AF axis.Conclusion: In conclusion, our integrative analysis identified multiple genes and DNAm sites that had potentially causal effects on AF. We also pinpointed plausible mechanisms in which the effect of a genetic variant on AF was mediated by genetic regulation of transcription through DNAm. Further experimental validation is necessary to translate the identified genes and possible mechanisms into clinical practice.


2021 ◽  
Vol 12 ◽  
Author(s):  
Ruimei Liu ◽  
Wei Tang ◽  
Weiping Wang ◽  
Feikang Xu ◽  
Weixing Fan ◽  
...  

It has been proposed that immune abnormalities may be implicated with pathophysiology of schizophrenia. The nod-like receptor pyrin domain-contraining protein 3 (NLRP3) can trigger immune-inflammatory cascade reactions. In this study, we intended to identify the role of gene encoding NLRP3 (NLRP3) in susceptibility to schizophrenia and its clinical features. For the NLRP3 mRNA expression analysis, 53 drug-naïve patients with first-episode schizophrenia and 56 healthy controls were enrolled. For the genetic study, a total of 823 schizophrenia patients and 859 controls were recruited. Among them, 239 drug-naïve patients with first-episode schizophrenia were enrolled for clinical evaluation. There is no significant difference in NLRP3 mRNA levels between patients with schizophrenia and healthy controls (p = 0.07). We did not observe any significant differences in allele and genotype frequencies of rs10754558 polymorphism between the schizophrenia and control groups. We noticed significant differences in the scores of RBANS attention and total scores between the patients with different genotypes of rs10754558 polymorphism (p = 0.001 and p < 0.01, respectively). Further eQTL analysis presented a significant association between the rs10754558 polymorphism and NLRP3 in frontal cortex (p = 0.0028, p = 0.028 after Bonferroni correction). Although our findings did not support NLRP3 confer susceptibility to schizophrenia, NLRP3 may be a risk factor for cognitive impairment, especially attention deficit in this disorder.


2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Yogita Ghodke-Puranik ◽  
Zhongbo Jin ◽  
Kip D. Zimmerman ◽  
Hannah C. Ainsworth ◽  
Wei Fan ◽  
...  

Abstract Background We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. Methods Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16− CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. Results The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. Conclusions We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.


2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Young Ho Park ◽  
Jung-Min Pyun ◽  
Angela Hodges ◽  
Jae-Won Jang ◽  
Paula J. Bice ◽  
...  

Abstract Background The interaction between the brain and periphery might play a crucial role in the development of Alzheimer’s disease (AD). Methods Using blood transcriptomic profile data from two independent AD cohorts, we performed expression quantitative trait locus (cis-eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-wide association study to investigate the effects of the AD genetic variants on gene expression levels and identify their potential target genes. We then performed differential gene expression analysis of identified AD target genes and linear regression analysis to evaluate the association of differentially expressed genes with neuroimaging biomarkers. Results A cis-eQTL analysis identified and replicated significant associations in seven genes (APH1B, BIN1, FCER1G, GATS, MS4A6A, RABEP1, TRIM4). APH1B expression levels in the blood increased in AD and were associated with entorhinal cortical thickness and global cortical amyloid-β deposition. Conclusion An integrative analysis of genetics, blood-based transcriptomic profiles, and imaging biomarkers suggests that APH1B expression levels in the blood might play a role in the pathogenesis of AD.


2021 ◽  
Author(s):  
Zheng Cheng ◽  
Yonghong Zhang ◽  
Yang Zhuo ◽  
Jie Fan ◽  
Ying Xu ◽  
...  

Abstract Background/Aim: Long noncoding RNA TARID (lncRNA TARID) can activate the tumor suppressor TCF21 in tumorigenesis by inducing promoter demethylation. However, the impact on lncRNA TARID and its variants of coronary artery disease (CAD) are poorly understood. Methods We performed a case-control study enrolling 949 case patients and 892 controls to assess genotype. Five variants were genotyped by TaqMan assay. 20 case patients and 20 controls were used to evaluate the expression of lncRNA TARID. The qRT-PCR and cell cycle analysis were applied to examined cell proliferation and cell distribution. Results This study indicated that rs2327433 GG genotype was associated with CAD risk adjusting for traditional risk factors (OR=2.74, 95%CI: 1.10-6.83, P=0.03). Our results analyses revealed that the genotype of rs2327433 was related to the proportion of CAD patients with left anterior descending artery disease and left circumflex artery disease (P=0.025 and P=0.025, respectively). The results showed that the minor allele frequency of rs2327433 was significantly correlated with the severity of the disease (P=0.029). The eQTL analysis showed that rs2327433 may affect the transcription factors TCF21 regulated by lncRNA TARID. We found that TARID silencing regulated the cell proliferation and altered cell cycle progression by induced upregulation of CDK1 and PCNA. Conclusions SNP rs2327433 in lncRNA TARID was associated with CAD risk and the severity of CAD in Chinese Han population. Furthermore, SNP rs2327433 may affect the expression of atherosclerosis-related transcription factor TCF21 regulated by lncRNA TARID. Finally, our study provided a new lncRNA-dictated regulatory mechanism participating in cell proliferation.


2021 ◽  
Author(s):  
Julien Bryois ◽  
Daniela Calini ◽  
Will Macnair ◽  
Lynette Foo ◽  
Eduard Urich ◽  
...  

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous brain tissues as opposed to specific cell types. To investigate the genetics of gene expression in adult human cell types from the central nervous system (CNS), we performed an eQTL analysis using single nuclei RNA-seq from 196 individuals in eight CNS cell types. We identified 6108 eGenes, a substantial fraction (43%, 2620 out of 6108) of which show cell-type specific effects, with strongest effects in microglia. Integration of CNS cell-type eQTLs with GWAS revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene colocalized in a single cell type providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among CNS cell types and reveal genetic mechanisms by which disease risk genes influence neurological disorders.


2021 ◽  
Author(s):  
Benjamin Patel ◽  
Sam O. Kleeman ◽  
Drew Neavin ◽  
Joseph Powell ◽  
Georgios Baskozos ◽  
...  

AbstractTrigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.


2021 ◽  
Vol 11 ◽  
Author(s):  
Sheng-Kai Liang ◽  
Li-Hsin Chien ◽  
Gee-Chen Chang ◽  
Ying-Huang Tsai ◽  
Wu-Chou Su ◽  
...  

ObjectivesLung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1) and its ligands, programmed death ligand 1 (CD274) and 2 (PDCD1LG2), associated with lung cancer risk in never-smoking women.Materials and MethodsDuring September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs.ResultsA total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 (p < 0.001), rs12237624 (p = 0.019), and rs78096119 (p = 0.019) were associated with the expression levels of programed death ligand 2.ConclusionsNovel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening.


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