Genome-wide Association Studies Datasets Research Articles

The genetic correlation and causal association between key factors that influence vascular calcification and cardiovascular disease incidence.

Serum calcium (Ca), vitamin D (VD), and vitamin K (VK) levels are key determinants of vascular calcification, which itself impacts cardiovascular disease (CVD) risk. The specific relationships between the levels of these different compounds and particular forms of CVD, however, remain to be fully defined. This study was designed to explore the associations between these serum levels and CVDs with the goal of identifying natural interventions capable of controlling vascular calcification and thereby protecting against CVD pathogenesis, extending the healthy lifespan of at-risk individuals. Linkage disequilibrium score (LDSC) regression and a two-sample Mendelian randomization (MR) framework were leveraged to systematically examine the causal interplay between these serum levels and nine forms of CVD, as well as longevity through the use of large publically accessible Genome-Wide Association Studies (GWAS) datasets. The optimal concentrations of serum Ca and VD to lower CVD risk were examined through a restrictive cubic spline (RCS) approach. After Bonferroni correction, the positive genetic correlations were observed between serum Ca levels and myocardial infarction (MI) (p = 1.356E-04), as well as coronary artery disease (CAD) (p = 3.601E-04). Negative genetic correlations were detected between levels of VD and CAD (p = 0.035), while elevated VK1 concentrations were causally associated with heart failure (HF) [odds ratios (OR) per 1-standard deviation (SD) increase: 1.044], large artery stroke (LAS) (OR per 1-SD increase: 1.172), and all stroke (AS) (OR per 1-SD increase: 1.041). Higher serum Ca concentrations (OR per 1-SD increase: 0.865) and VD levels (OR per 1-SD increase: 0.777) were causally associated with reduced odds of longevity. These findings remained consistent in sensitivity analyses, and serum Ca and VD concentrations of 2.376 mmol/L and 46.8 nmol/L, respectively, were associated with a lower CVD risk (p < 0.001). Our findings support a genetic correlation between serum Ca and VD and CVD risk, and a causal relationship between VK1 levels and CVD risk. The optimal serum Ca (2.376 mmol/L) and VD levels (46.8 nmol/L) can reduce cardiovascular risk.

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations

BackgroundThe genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations.MethodsA large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle.ResultsIn the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk.ConclusionsIn summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

Genome-wide imputed differential expression enrichment analysis identifies trait-relevant tissues.

The identification of pathogenically-relevant genes and tissues for complex traits can be a difficult task. We developed an approach named genome-wide imputed differential expression enrichment (GIDEE), to prioritise trait-relevant tissues by combining genome-wide association study (GWAS) summary statistic data with tissue-specific expression quantitative trait loci (eQTL) data from 49 GTEx tissues. Our GIDEE approach analyses robustly imputed gene expression and tests for enrichment of differentially expressed genes in each tissue. Two tests (mean squared z-score and empirical Brown's method) utilise the full distribution of differential expression p-values across all genes, while two binomial tests assess the proportion of genes with tissue-wide significant differential expression. GIDEE was applied to nine training datasets with known trait-relevant tissues and ranked 49 GTEx tissues using the individual and combined enrichment tests. The best-performing enrichment test produced an average rank of 1.55 out of 49 for the known trait-relevant tissue across the nine training datasets-ranking the correct tissue first five times, second three times, and third once. Subsequent application of the GIDEE approach to 20 test datasets-whose pathogenic tissues or cell types are uncertain or unknown-provided important prioritisation of tissues relevant to the trait's regulatory architecture. GIDEE prioritisation may thus help identify both pathogenic tissues and suitable proxy tissue/cell models (e.g., using enriched tissues/cells that are more easily accessible). The application of our GIDEE approach to GWAS datasets will facilitate follow-up in silico and in vitro research to determine the functional consequence(s) of their risk loci.

The potential causal association of systemic lupus erythematosus with congestive heart failure in the East Asian population: A two-sample mendelian randomization study

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that increases the risk of cardiovascular disease, but the causal relationship has remained unknown in the East Asian population. We aim to determine the causal relationship between SLE and congestive heart failure (CHF) in the East Asian population. We conducted a two-sample Mendelian randomization MR study to examine the potential causal association of SLE with CHF, using the East Asian genome-wide association study datasets for SLE (4222 cases, 8431 controls) and CHF (9413 cases, 203,040 controls). The MR analysis showed that genetic susceptibility to SLE was associated with the increased risk of CHF (odds ratio [OR] 1.032, 95% confidence interval [CI] 1.004-1.061, p = .023). After excluding the human leukocyte antigen (HLA) regions, SLE was also associated with a higher risk of CHF (OR 1.034, 95% CI 1.007-1.062, p = .015). The multiple MR sensitivity analyses confirmed that this potential causal association was unlikely to be biased by horizontal pleiotropy. The findings of this MR study suggest that SLE potentially increases the risk of CHF in the East Asian population. Genetic predisposition to SLE may play a significant role in developing CHF in the East Asian population.

Shared genetics and causal associations between COVID-19 and multiple sclerosis.

Neuroinflammation caused by COVID-19 negatively impacts brain metabolism and function, while pre-existing brain pathology may contribute to individuals' vulnerability to the adverse consequences of COVID-19. We used summary statistics from genome-wide association studies (GWAS) to perform Mendelian randomization (MR) analyses, thus assessing potential associations between multiple sclerosis (MS) and twoCOVID-19 outcomes (severe acute respiratory syndrome coronavirus 2[SARS-CoV-2] infection and COVID-19 hospitalization). Genome-wide risk genes were compared between the GWAS datasets on hospitalized COVID-19 and MS. Literature-based analysis was conducted to construct molecular pathways connecting MS and COVID-19. We found that genetic liability to MS confers a causal effect on hospitalized COVID-19 (odd ratio [OR]: 1.09, 95% confidence interval: 1.03-1.16) but not on SARS-CoV-2 infection (1.03, 1.00-1.05). Genetic liability to hospitalized COVID-19 confers a causal effect on MS (1.15, 1.02-1.30). Hospitalized COVID-19 and MS share five risk genes within two loci, including TNFAIP8, HSD17B4, CDC37, PDE4A, and KEAP1. Pathway analysis identified a panel of immunity-related genes that may mediate the links between MS and COVID-19. Our study suggests that MS was associated with a 9% increased risk for COVID-19 hospitalization, while hospitalized COVID-19 was associated with a 15% increased risk for MS. Immunity-related pathways may underlie the link between MS on COVID-19.

Transcriptome-wide association study identifies novel genes associated with bone mineral density and lean body mass in children

ObjectiveTo identify novel candidate genes whose expression is associated with bone mineral density (BMD) and body lean mass (LM) in children.MethodsA tissue-specific transcriptome-wide association study (TWAS) was conducted utilizing a large-scale genome-wide association study (GWAS) dataset associated with BMD and LM and involving 10,414 participants. The measurement of BMD and LM phenotypes was made based on total-body dual-energy X-ray absorptiometry (TB-DXA) scans. TWAS was conducted by using FUSION software. Reference panels for muscle skeleton (MS), peripheral blood (NBL) and whole blood (YBL) were used for TWAS analysis. Functional enrichment and protein–protein interaction (PPI) analyses of the genes identified by TWAS were performed by using the online tool Metascape (http://metascape.org).ResultsFor BMD, we identified 174 genes with P < 0.05, such as IKZF1 (P = 1.46 × 10−9) and CHKB (P = 8.31 × 10−7). For LM, we identified 208 genes with P < 0.05, such as COPS5 (P = 3.03 × 10−12) and MRPS33 (P = 5.45 × 10−10). Gene ontology (GO) enrichment analysis of the BMD-associated genes revealed 200 GO terms, such as protein catabolic process (Log P = −5.09) and steroid hormone-mediated signaling pathway (Log P = −3.13). GO enrichment analysis of the LM-associated genes detected 287 GO terms, such as the apoptotic signaling pathway (Log P = −8.08) and lipid storage (Log P = −3.55).ConclusionThis study identified several candidate genes for BMD and LM in children, providing novel clues to the genetic mechanisms underlying the development of childhood BMD and LM.

Genome-wide association study of osteonecrosis of the jaw in Danish patients receiving antiresorptive therapy for osteoporosis: A case-control study

BackgroundPrior studies of the pharmacogenomics of osteonecrosis of the jaw (ONJ) have had various methodological limitations, including using candidate gene selection as their sole strategy, a small number of ONJ cases, or a study population based on an oncology setting. ObjectivesThe aim of our case-control study was to evaluate previously reported associations between genetic factors and ONJ, which were based on either genome-wide association studies (GWAS) or candidate gene approaches. Furthermore, we aimed to identify genetic risk factors for ONJ by using GWAS to determine single-nucleotide polymorphisms (SNPs) with statistically significant differences in frequency between ONJ patients and osteoporosis controls. MethodsPatients with medically confirmed ONJ and who were registered in the Scandinavian Cohort of ONJ patients were included. Controls from the general population were matched on age (±5 years), sex, and cumulative antiresorptive drug exposure. The ONJ diagnosis date for cases corresponded to the index date for matched controls. DNA isolation, genotyping, and data analyses were performed by Q2/EA Genomics using standard protocols and best practices. Blood or tissue samples for 55 ONJ cases and 125 controls were collected. Due to the low quality of the tissue samples, final analyses were based on blood samples of 40 ONJ cases and 124 controls. ResultsWe detected no significant genome-wide associations. Of the 43 SNPs with ONJ association in prior studies, none were replicated in our study. ConclusionsEven though our study sample is the largest to date, we had limited statistical power for GWAS but adequate power for replication analyses. Our study provides no evidence for any genetic predisposition to ONJ. Future studies could increase their statistical power by combining ONJ GWAS datasets and by performing a meta-analysis or pursuing a sequencing strategy in order to identify rare variants.

Mendelian randomization study reveals a causal relationship between rheumatoid arthritis and risk for pre-eclampsia.

Epidemiological observational studies have investigated the relationship between rheumatoid arthritis(RA) and pre-eclampsia, but no consistent conclusions were obtained due to various limitations. Hence, we conducted a two-sample mendelian randomization analysis to evaluate the potential causal effect of RA on pre-eclampsia. Summary-level statistics for RA were derived from a large-scale meta-analysis of datasets of genome-wide association studies(GWAS) which involved 14,361 cases and 43,923 controls. Moreover, summary statistics for pre-eclampsia or eclampsia were sourced from the Finn biobank which contained 3,903 cases and 114,735 controls. The inverse variance weighting (IVW) as well as other four effective methods including MR-Egger, weighted median, weighted mode, and simple mode were applied to deduce the potential causal relationships between RA and pre-eclampsia comprehensively. The two-sample MR analysis suggested a strong causal relationship between RA and pre-eclampsia[OR,1.05;95%CI, 1.01-1.09;p<0.05]. The OR estimates obtained from the weighted mode[OR,1.09;95%CI,1.03-1.15;p<0.01] and weighted median[OR,1.07;95%CI, 1.01-1.14;p<0.05] were similar to those from the IVW method, but there was no significant association observed in MR Egger and simple mode analysis. This MR analysis provides evidence of a positive causal association between RA and pre-eclampsia genetically. Our findings highlight the importance of more intensive prenatal care and early intervention among pregnant women with RA to prevent potential adverse obstetric outcomes. Moreover, our study provides clues for risk factor identification and early prediction of pre-eclampsia.

Mendelian randomization investigation highlights different roles of selenium status in mental disorders

Observational studies have suggested a relationship between selenium status and mental disorders (MDs). However, it remains unclear whether selenium status was causally associated with MDs. Thus, we performed a two-sample Mendelian randomization analysis using genome-wide association studies (GWAS) summary statistics to investigate the causal effects of selenium levels on seven MDs, including schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and panic disorder (PD). Strong genetic instruments of blood selenium (n = 9) and blood-toenail selenium (n = 12) were applied to the above seven MDs GWAS datasets from Psychiatric Genomics Consortium, which were further replicated in the FinnGen Biobank. The inverse-variance weighted method was employed to calculate the causal effects. The results showed that genetically predicted blood selenium levels were associated with a decreased risk of schizophrenia (odds ratio [OR] = 0.90, 95% CI: 0.87–0.95) and AN (OR = 0.87, 95% CI: 0.77–0.97). However, both blood and blood-toenail selenium levels were linked to an increased risk of MDD (blood: OR = 1.08, 95% CI: 1.05–1.12; blood-toenail: OR = 1.08, 95% CI: 1.04–1.13) and ASD (blood: OR = 1.11, 95% CI: 1.05–1.17; blood-toenail: OR = 1.13, 95% CI: 1.05–1.21), respectively. No obvious associations were found between selenium levels and BD as well as ADHD. Our findings highlighted a protective role of selenium in SZ and AN, while a risk effect in MDD and ASD. Further studies are required to verify the underlying mechanism mediating the unequal effects of Se on different MDs, which will pave a new path for the intervention of MDs.

Effects of homocysteine on nonalcoholic fatty liver related disease: A mendelian randomization study.

Background: Since the association of homocysteine and clinical results of observational studies are controversial on non-alcoholic fatty liver related disease, we compute the two-sample Mendelian Randomization (MR) study. Objective: To evaluate whether the plasma level of homocysteine has an effect on the risk of Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and Cirrhosis after its progress, we investigated the causal relationships between plasma homocysteine and the three non-alcoholic fatty liver related diseases mentioned above. Design and methods: Summary estimates were elicited from the inverse-variance weighted (IVW) method through 12 single nucleotide polymorphisms (SNPs) which related to the plasma homocysteine, the SNPs were obtained from a large genome-wide association studies (GWAS) of 44,147 European participants. And the summary statistics for the latest and largest GWAS datasets for NAFLD (307576 in total and 1,578 cases), NASH (309055 in total and 99 cases) and Cirrhosis (306145 in total and 826 cases) were collected from Ristey FinnGen website where the association of genetic variations with blood metabolite levels was conducted using comprehensive metabolite profiling. The study was performed through two-sample MR method. Results: The result indicated that the plasma homocysteine is not significantly associated with NAFLD, and its progression, NASH and Cirrhosis. Conclusion: The evidence in this study is quite deficient to support the causal association of the individual plasma homocysteine with NAFLD, NASH and Cirrhosis, the putative of associations is not exist.

Causal association of sleep disturbances and low back pain: A bidirectional two-sample Mendelian randomization study.

Previous observational studies have shown that low back pain (LBP) often coexists with sleep disturbances, however, the causal relationship remains unclear. In the present study, the causal relationship between sleep disturbances and LBP was investigated and the importance of sleep improvement in the comprehensive management of LBP was emphasized. Genetic variants were extracted as instrumental variables (IVs) from the genome-wide association study (GWAS) of insomnia, sleep duration, short sleep duration, long sleep duration, and daytime sleepiness. Information regarding genetic variants in LBP was selected from a GWAS dataset and included 13,178 cases and 164,682 controls. MR-Egger, weighted median, inverse-variance weighted (IVW), penalized weighted median, and maximum likelihood (ML) were applied to assess the causal effects. Cochran's Q test and MR-Egger intercept were performed to estimate the heterogeneity and horizontal pleiotropy, respectively. Outliers were identified and eliminated based on MR-PRESSO analysis to reduce the effect of horizontal pleiotropy on the results. Removing each genetic variant using the leave-one-out analysis can help evaluate the stability of results. Finally, the reverse causal inference involving five sleep traits was implemented. A causal relationship was observed between insomnia-LBP (OR = 1.954, 95% CI: 1.119-3.411), LBP-daytime sleepiness (OR = 1.011, 95% CI: 1.004-1.017), and LBP-insomnia (OR = 1.015, 95% CI: 1.004-1.026), however, the results of bidirectional MR analysis between other sleep traits and LBP were negative. The results of most heterogeneity tests were stable and specific evidence was not found to support the disturbance of horizontal multiplicity. Only one outlier was identified based on MR-PRESSO analysis. The main results of our research showed a potential bidirectional causal association of genetically predicted insomnia with LBP. Sleep improvement may be important in comprehensive management of LBP.

No Evidence to Support a Causal Relationship between Circulating Adiponectin Levels and Ankylosing Spondylitis: A Bidirectional Two-Sample Mendelian Randomization Study.

Based on previous observational studies, the causal association between circulating adiponectin (CA) levels and ankylosing spondylitis (AS) risk remains unclear. Therefore, this study aims to investigate whether CA levels are related to the risk of AS. We carried out a bidirectional two-sample Mendelian randomization (MR) analysis to examine the causal correlation between CA levels and AS via published genome-wide association study (GWAS) datasets. Single-nucleotide polymorphisms (SNPs) related to CA levels were derived from a large GWAS that included 39,883 individuals of European descent. SNPs related to AS were obtained from the FinnGen consortium (2252 cases and 227,338 controls). The random-effects inverse variance weighted (IVW) method was the primary method utilized in our research. We also used four complementary approaches to improve the dependability of this study (MR-Egger regression, Weighted median, Weighted mode, and Simple mode). Random-effects IVW (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.79-1.27, p = 0.984) and four complementary methods all indicated that genetically predicted CA levels were not causally related to the risk of AS. In reverse MR analysis, there is little evidence to support the genetic causality between the risk of AS and CA levels.

Genetic link between rheumatoid arthritis and autoimmune liver diseases: A two-sample Mendelian randomization study

BackgroundAn association between rheumatoid arthritis (RA) and autoimmune liver diseases (AILDs) was found in observational studies. However, neither the direction nor the cause-effect chain was clear. This study aimed to assess the causal associations between AILDs and RA. MethodsWe performed a two-sample Mendelian randomization (MR) analysis. Following a strict assessment, genome-wide association study (GWAS) datasets were used to select potential candidate single-nucleotide polymorphisms. The inverse-variance weighted (IVW) was used as the primary analysis approach, supplemented with four sensitive analysis methods applied to assess the robustness of the results. ResultsWe discovered that a genetically increased primary biliary cholangitis (PBC) risk had a positive causal effect on RA (IVW OR=1.149, 95% CI=1.063–1.241, P<0.001). According to the MR-Egger regression, horizontal pleiotropy was unlikely to impact causality (intercept = -0.028, P = 0.263). Using the leave-one-out strategy, sensitivity studies revealed that the MR analysis results were robust and reliable. Genetically determined primary sclerosing cholangitis (PSC) was not linked with the risk of RA (IVW OR=1.071, 95%CI=0.984–1.166, P = 0.111). The results of the MR analysis were further validated by sensitivity analyses utilizing the leave-one-out approach. In the other direction, there was no causal relationship between RA and PBC (OR=1.132, 95% CI=0.881–1.454, P = 0.333) or PSC (OR=1.067, 95% CI=0.891–1.279, P = 0.088). ConclusionsUsing a two-sample MR analysis, we investigated the relationship between AILDs and RA and revealed first that PBC increases the risk of RA. Large-scale cross-disease GWAS are required to further illuminate the genomic landscape of AILDs and RA.

Chickenpox and multiple sclerosis: A Mendelian randomization study.

Observational studies have suggested a suspected association between varicella-zoster virus (VZV) infection and multiple sclerosis (MS), but the connection has remained unclear. The aim of the present study is to evaluate the causal relationship between chickenpox which is caused by VZV infection and MS. We performed a two-sample Mendelian randomization analysis to investigate the association of chickenpox with MS using summary statistics from genome-wide association studies (GWAS). The GWAS summary statistics data for chickenpox was from the 23andMe cohort including 107 769 cases and 15 982 controls. A large summary of statistical data from the International Multiple Sclerosis Genetics Consortium (IMSGC) was used as the outcome GWAS data set, including 14 802 MS cases and 26 703 controls. We found evidence of a significant association between genetically predicted chickenpox and risk of MS (odds ratio [OR] = 35.27, 95% confidence interval [CI] = 22.97-54.17, p = 1.46E-59). Our findings provided evidence indicating a causal effect of chickenpox on MS. Further elucidations of this association and underlying mechanisms are needed for identifying feasible interventions to promote MS prevention.

Assessing the interaction effects of brain structure longitudinal changes and life environmental factors on depression and anxiety.

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N=15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta=-.003, p=.018 for depression; beta=-003, p=.008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta=.088, p=.002 for depression; beta=.070, p=.008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta=-.004, p=.020 for depression; beta=-.005, p=.002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety.

Transcriptome-wide association study by different approaches reveals candidate causal genes for cannabis use disorder

Cannabis is one of the most commonly used psychoactive substances, which could induce moderate-severe cannabis use disorders (CUD). Here, a tissue-specific transcriptome-wide association study (TWAS) of CUD was performed by FUSION and S-PrediXcan, utilizing a genome-wide association study (GWAS) dataset of CUD (including 43,380 cases and 141,385 controls of European ancestry) and gene expression reference data from 17 different brain-related and non-brain related tissues, with totally 26 TWAS-associated genes were identified, including CADM2 (P = 2.13 × 10-17), SRR (P = 8.09 × 10-9) and TUFM (P = 1.24 × 10-8). Fine-mapping of causal gene sets (FOCUS) was used to prioritize genes with strong evidence for causality, and SRR, CADM2-AS1, and SH2B1 were prioritized with a posterior probability of 0.973, 0.951, and 0.788, respectively. Furthermore, gene ontology (GO) and pathway enrichment analysis on CUD-associated genes were performed, including cytosol, protein binding, nucleoplasm, metabolic pathways, and herpes simplex virus 1 infection. These findings could provide new insights for understanding the mechanism of CUD.

Overlapping genetic susceptibility of seven autoimmune diseases:SPU tests based on genome-wide association summary statistics

Autoimmune diseases are a heterogeneous group of diseases with an unclear aetiology. Genome-wide association studies (GWAS) and meta-analysis are inefficient in identifying shared variants. This study aims to identify shared genetic susceptibility for seven autoimmune diseases using sum of powered score (SPU) tests. GWAS summary statistics datasets of seven autoimmune diseases were downloaded from Open Targets Genetics, Dryad and International Multiple Sclerosis Genetics Consortium (IMSGC). The MTaSPUs was applied to confirm common single-nucleotide polymorphisms (SNP), MTaSPUsSet and aSPUs were performed to identify potential shared genes, and MTaSPUsPath was conducted to explore biological functions based on Kyoto encyclopedia of genes and genomes (KEGG) biological pathways. The MTaSPUs test found 104 pleiotropic SNPs (P < 1.19 × 10-6) in our study. The 38 of these SNPs were associated with at least one trait in the original GWAS study. A total of 56 genes associated with at least one trait (P < 4.98 × 10-6) were recognized by aSPUs test. The 45 potential pleiotropic genes (P < 4.98 × 10-6) were significant in MTaSPUsSet test. By aggregating results of aSPUs test and MTaSPUsSet test, we ascertained 38 pleiotropic genes. The 10 of these 38 pleiotropic genes have been reported in previous studies, while the remaining 28 genes were newly discovered. These 38 genes were matched in 14 significant KEGG pathways. We found new variants linked with complicated illnesses derived from several GWAS datasets using the SPU testing technique. The discovery of pleiotropic genes and shared pathways may aid in the development of common treatment approaches for autoimmune disorders.

No evidence for a causal link between Helicobacter pylori infection and nonalcoholic fatty liver disease: A bidirectional Mendelian randomization study.

Although clinical studies have shown the possible relationship between Helicobacter pylori (H. pylori) infection and the development of nonalcoholic fatty liver disease (NAFLD), their causal relationship is still unknown. This bidirectional Mendelian randomization (MR) study aimed to investigate the causal link between H. pylori infection and NAFLD. Two previously reported genetic variants SNPs rs10004195 and rs368433 were used as the instrumental variables (IVs) of H. pylori infection. The genetic variants of NAFLD were extracted from the largest genome-wide association study (GWAS) summary data with 1,483 cases and 17,781 controls. The exposure and outcome data were obtained from the publicly available GWAS dataset. Then, a bidirectional MR was carried out to evaluate the causal relationship between H. pylori infection and NAFLD. In addition, the GWAS data were also collected to explore the causal relationship between H. pylori infection and relevant clinical traits of NAFLD, including triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), and body mass index (BMI). Genetically predicted H. pylori infection showed no association with NAFLD both in FinnGen GWAS (OR, 1.048; 95% CI, 0.778-1.411; value of p = 0.759) and the GWAS conducted by Anstee (OR, 0.775; 95% CI, 0.475-1.265; value of p = 0.308). An inverse MR showed no causal effect of NAFLD on H. pylori infection (OR,0.978;95% CI, 0.909-1.052; value of p = 0.543). No significant associations were observed between H. pylori infection and the levels of triglycerides, LDL-C, HDL-C, or FBG, while H. pylori infection was associated with an increase in BMI. These results indicated that there was no genetic evidence for a causal link between H. pylori and NAFLD, suggesting that the eradication or prevention of H. pylori infection might not benefit NAFLD and vice versa.

Integrated analysis of proteome-wide and transcriptome-wide association studies identified novel genes and chemicals for vertigo.

Vertigo is a leading symptom of various peripheral and central vestibular disorders. Although genome-wide association studies (GWASs) have identified multiple risk variants for vertigo, how these risk variants contribute to the risk of vertigo remains unknown. Discovery proteome-wide association study (PWAS) was first performed by integrating the protein quantitative trait loci from the dorsolateral prefrontal cortex (DLPFC) in the Banner Sun Health Research Institute dataset (n = 152) and GWAS summary of vertigo (n = 942 613), followed by replication PWAS using the protein quantitative trait loci from the DLPFC in Religious Orders Study or the Rush Memory and Aging Project dataset (n = 376). Transcriptome-wide association studies (TWASs) were then performed by integrating the same GWAS datasets of vertigo (n = 942 613) with mRNA expression reference from human fetal brain, and DLPFC. Chemical-related gene set enrichment analysis (GSEA) and Gene ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were finally conducted to further reveal the pathogenesis of vertigo. Permutation-based empirical P values were calculated in PWAS, TWAS, and GSEA. By integrating the GWAS of vertigo and two independent brain proteomes from human DLPFC, three genes were identified to genetically regulate protein abundance levels in vertigo, and were not previously implicated by GWAS, including MTERFD2 (P Banner = 0.045, P ROSMAP = 0.031), MGST1 (P Banner = 0.014, P ROSMAP = 0.018), and RAB3B (P Banner = 0.045, P ROSMAP = 0.035). Compared with TWAS results, we identified overlapping genes RAB3B (P TWAS = 0.017) and MTERFD2 (P TWAS = 0.003) that showed significant associations with vertigo at both proteome-wide and transcriptome-wide levels. Chemical-related GSEA identified multiple chemicals that might be associated with vertigo, such as nickel (P = 0.007), glycidamide (P = 0.005), and proanthocyanidins (P = 0.015). Our study provides novel clues for understanding the biological mechanism of vertigo, and highlights several possible risks and therapeutic chemicals for vertigo.

Genetic estimation of correlations and causalities between multifaceted modifiable factors and gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal dysfunction that significantly affects the quality of daily life, and health interventions are challenging to prevent the risk of GORD. In this study, we used Mendelian randomization framework to genetically determine the causal associations between multifaceted modifiable factors and the risk of GORD. Sixty-six exposures with available instrumental variables (IVs) across 6 modifiable pathways were included in the univariable MR analysis (UVMR). Summary-level genome-wide association studies (GWAS) datasets for GORD were retrieved from the Neale Lab (GORD Neale , Ncases = 29975, Ncontrols = 390556) and FinnGen (GORD Finn , Ncases = 13141, Ncontrols = 89695). Using the METAL software, meta-analysis for single nucleotide polymorphisms (SNPs) from GORD Neale and GORD Finn was conducted with an inverse variance weighted (IVW) fixed-effect model. Moreover, we leveraged partition around medoids (PAM) clustering algorithm to cluster genetic correlation subtypes, whose hub exposures were conditioned for multivariable MR (MVMR) analyses. P-values were adjusted with Bonferroni multiple comparisons. Significant causal associations were identified between 26 exposures (15 risk exposures and 11 protective exposures) and the risk of GORD. Among them, 13 risk exposures [lifetime smoking, cigarette consumption, insomnia, short sleep, leisure sedentary behavior (TV watching), body mass index (BMI), body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, hip circumference, major depressive disorder, and anxious feeling], and 10 protective exposures (leisure sedentary behavior (computer use), sitting height, hand grip strength (left and right), birth weight, life satisfaction, positive affect, income, educational attainment, and intelligence) showed novel significant causal associations with the risk of GORD. Moreover, 13 exposures still demonstrated independent associations with the risk of GORD following MVMR analyses conditioned for hub exposures (educational attainment, smoking initiation and BMI). In addition, 12 exposures showed suggestive causal associations with the risk of GORD. This study systematically elucidated the modifiable factors causally associated with the risk of GORD from multifaceted perspectives, which provided implications for prevention and treatment of GORD.