Independent Single Nucleotide Polymorphisms Research Articles

Disentangling the causal effects of education and participation bias on Alzheimer's disease using Mendelian Randomization.

People with university degrees have a lower incidence of Alzheimer's Disease (AD). However, the relationship between education and AD could be due to selection, collider, and ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. Here, we use two-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD. We used genome-wide association study (GWAS) summary statistics for educational attainment, three different measures of participation, AD (clinically diagnosed AD), and AD/ADRD (clinical diagnosis and family history of AD and related dementias). Independent genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Fixed-effects inverse variance weighted meta-analysis was the primary MR method; Cochran's Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and Radial-MR was used to identify outliers. Sensitivity analyses included MR Egger, Weighted Median, and Weighted mode. Bidirectional analyses were used to test if AD pathology affects participation and multivariable MR (MVMR) assessed independent exposure-outcome effects. Educational attainment reduced the risk of AD (OR IVW 95% CI= 0.70 [0.63, 0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, though the results were not robust to sensitivity analyses (OR IVW 95% CI= 1.09 [1.02, 1.15], p = 0.006). Participation in MHQ reduced the odds of AD (OR IVW 95% CI= 0.325 [0.128, 0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (OR IVW 95% CI= 0.76 [0.62, 0.92], p = 0.006). Univariate MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR indicated that participation is unlikely to explain the effect of education on AD identified in MR, and the protective effect of educational attainment may be due to other biological mechanisms, such as cognitive reserve.

Associations between genetically predicted TIMP-3 levels and risk of venous thromboembolism: A two sample Mendelian randomization study

TIMP metallopeptidase inhibitor 3 (TIMP-3) may contribute to the pathogenesis of venous thromboembolism (VTE). However, few studies have investigated the effect of TIMP-3 on VTE. Therefore, a two-sample Mendelian randomization (MR) analysis was conducted to investigate the association between TIMP-3 levels and VTE. Seven independent single-nucleotide polymorphisms (SNPs) for TIMP-3 levels were obtained from a published genome-wide association study (the KORA Consortium, including 997 Europeans). We obtained outcome datasets for VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) from the FinnGen Consortium. The primary analytical method used in the MR analysis was the inverse variance weighted (IVW) method. To enhance the robustness of the MR results, some other MR methods including weighted median, MR-Egger, and MR-PRESSO were conducted. Moreover, several sensitivity analyses were performed to identify potential horizontal pleiotropy and heterogeneity. In primary IVW MR analyses, per log increase in genetically predicted TIMP-3 levels were positively associated with the incidence of VTE (odds ratio [OR], 1.03; 95 % confidence interval (CI), 1.01, 1.06; P = 0.010), PE (OR, 1.04; 95 % CI, 1.01, 1.08; P = 0.009), and DVT (OR, 1.06; 95 % CI, 1.02, 1.10; P= 0.003). The results of the weighted median, MR-Egger, and MR-PRESSO were similar to the main findings. No unbalanced pleiotropy or heterogeneity was observed. The study suggests that genetically predicted high levels of TIMP-3 may be associated with an increased risk of VTE. These findings indicate that strategies targeting TIMP-3 may provide a basis for the prevention and treatment of VTE. Further investigation is required to clarify this potential mechanism.

Risk Factors for Pelvic Organ Prolapse: Wide-Angled Mendelian Randomization Analysis.

We hypothesized that some metabolic factors, lifestyle factors, and socioeconomic factors may have a causal effect on pelvic organ prolapse (POP). We selected instruments from corresponding genome-wide association studies (GWAS), which identified independent single nucleotide polymorphisms strongly associated with 12 potential risk factors. Summary statistics for POP were derived from two GWAS datasets, serving for discovery and replication stage. The primary analysis involved the use of the inverse-variance weighting mendelian randomization (MR) method, with additional sensitivity MR analyses conducted. The univariable mendelian randomization (UVMR) analysis in both the discovery and replication stage provided evidence for significant causal effects between higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI) levels, lower high-density lipoprotein cholesterol (HDL-C) levels, and lower educational attainment and higher POP risk, as well as a suggestive positive causal effect between triglycerides and POP. The multivariable mendelian randomization (MVMR)analysis showed that only HDL-C among the three blood lipid fractions could reduce the risk of POP. Mediation analysis indicated that HDL-C may partially mediate the effect of WHRadjBMI on POP risk, and the causal effect between educational attainment and POP may be mediated through WHRadjBMI and HDL-C. Our study's evidence supported a causal relationship between WHRadjBMI, triglycerides, HDL-C, educational attainment, and POP risk. This highlights that clinicians may guide the general female population to control obesity and blood lipid levels to reduce the risk of POP.

Causal associations between platelet count, alcohol consumption, and the risk of liver hepatocellular carcinoma based on a Mendelian randomization study.

Liver hepatocellular carcinoma (LIHC) exhibits a multifactorial etiology, insidious onset, and a significantly low 5-year survival rate. We aimed to evaluate the causal impact of exposure factors (Alzheimer's disease, platelet count, ambidextrousness, cigarettes smoked per day, alcohol consumption, and endocarditis) on the risk of LIHC using a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms (SNPs) strongly associated with Alzheimer's disease, platelet count, ambidextrousness, daily cigarette consumption, alcohol intake, and endocarditis were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). Genetic summary statistics for LIHC came from a GWAS that included 168 cases and 372,016 controls of European individuals. Multivariable MR analyses were performed to find the causal association between 6 exposure factors and LIHC risk. The inverse-variance weighted (IVW)-MR was employed as the primary analysis, and the MR-Egger regression, LASSO regression, and weighted Median approaches were performed as complementary analyses. Multivariable MR analysis showed causal association between Alzheimer's disease [Odds ratio (OR) = 0.9999, 95% confidence intervals (CI) = 0.9998-0.9999, p = 0.0010], platelet count (OR = 0.9997, 95% CI = 0.9995-0.9999, p = 0.0066), alcohol consumption (OR = 0.9994, 95% CI = 0.9990-0.9999, p = 0.0098) and the LIHC outcome. After IVW-MR, MR-Egger and LASSO tests, the results are still significant. Next, we used different MR Methods to analyze platelet count, alcohol consumption, and Alzheimer's disease separately. Moreover, both funnel plots and MR-Egger intercepts provided compelling evidence to refute the presence of directional pleiotropy in the association between platelet count, alcohol consumption, Alzheimer's disease and the risk of LIHC. The IVW-MR analysis revealed a significant causal association between an elevated platelet count and a reduced risk of LIHC (OR = 0.9996, 95% CI= 0.9995-0.9998, p = 0.0005). Similarly, the analysis of weighted median revealed a negative correlation between platelet count and the risk of LIHC (OR = 0.9995, 95% CI = 0.9993-0.9999; p = 0.0160). Conversely, we observed a positive causal effect of alcohol consumption on the incidence of LIHC (OR = 1.0004, 95% CI = 0.9999-1.0009). However, no significant causal relationship was found between alcohol assumption, Alzheimer's disease, and LIHC susceptibility. A significant causal relationship exists between platelet count, alcohol consumption, Alzheimer's disease, and an increased risk of LIHC. The study presents compelling evidence for a genetically predicted decreased susceptibility to LIHC based on platelet count. The research implies that elevated platelet count may serve as a protective mechanism against LIHC. These findings may inform clinical strategies for LIHC prevention.

Non-causal relationship of polycystic ovarian syndrome with homocysteine and B vitamins: evidence from a two-sample Mendelian randomization.

Previous observational studies have identified a correlation between elevated plasma homocysteine (Hcy) levels and polycystic ovary syndrome (PCOS). This study aimed to determine whether a causal relationship exists between Hcy and PCOS at the genetic level. A two-sample Mendelian Randomization (TSMR) study was implemented to assess the genetic impact of plasma levels of Hcy, folate, vitamin B12, and vitamin B6 on PCOS in individuals of European ancestry. Independent single nucleotide polymorphisms (SNPs) associated with Hcy (n=12), folate (n=2), vitamin B12 (n=10), and vitamin B6 (n=1) at genome-wide significance levels (P<5×10-8) were selected as instrumental variables (IVs). Data concerning PCOS were obtained from the Apollo database. The primary method of causal estimation was inverse variance weighting (IVW), complemented by sensitivity analyses to validate the results. The study found no genetic evidence to suggest a causal association between plasma levels of Hcy, folate, vitamin B12, vitamin B6, and PCOS. The effect sizes, determined through random-effect IVW, were as follows: Hcy per standard deviation increase, OR = 1.117, 95%CI: (0.842, 1.483), P = 0.442; folate per standard deviation increase, OR = 1.008, CI: (0.546, 1.860), P = 0.981; vitamin B12 per standard deviation increase, OR = 0.978, CI: (0.808, 1.185), P = 0.823; and vitamin B6 per standard deviation increase, OR = 0.967, CI: (0.925, 1.012), P = 0.145. The fixed-effect IVW results for each nutrient exposure and PCOS were consistent with the random-effect IVW findings, with additional sensitivity analyses reinforcing these outcomes. Our findings indicate no causal link between Hcy, folate, vitamin B12, vitamin B6 levels, and PCOS.

Application of two-sample Mendelian randomization method to assess the causal relationship between rheumatoid arthritis and osteoporotic fracture.

The association between rheumatoid arthritis (RA) and osteoporotic fracture has garnered considerable attention; however, the causal relationships between diseases remain uncertain. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the causal effects of RA on osteoporotic fracture. The summary data for RA and osteoporotic fracture were extracted from the genome-wide association studies (GWAS) catalog and the Finn Biobank database. The database provides information about diseased and health control subjects. We searched the database for the following conditions: RA, osteoporosis (OP), and osteoporotic fractures. Entries were published by investigating centers, which had established definitions and diagnostic criteria. We downloaded and processed the data to obtain the single-nucleotide polymorphisms (SNPs) strongly associated with RA, OP, and osteoporotic fracture. RA genetic associations were obtained from the GWAS catalog, including 1961 cases and 454,387 controls. The osteoporosis of the GWAS catalog involved 991 cases and 455,357 controls, and the data of the Finn Biobank involved 8,017 cases and 391,037 controls. Genetic associations for osteoporotic fracture were taken from the Finn Biobank of 1822 cases and 311,210 controls. Independent SNPs that are significantly associated with meeting the criteria of p < 5 × 10-8, r2 < 0.001, and kb = 10,000 were selected for MR analysis. The inverse variance-weighted (IVW) method along with other MR methods was employed for analysis, while sensitivity analyses were conducted to assess reliability and stability. The results provided strong evidence that RA was causally and positively associated with osteoporosis from the GWAS catalog (OR = 1.16590; 95% CI: 1.04067-1.30619; p = 0.00811) and the Finn Biobank database (OR = 1.07314; 95% CI: 1.03455-1.11317; p = 0.00016). Moreover, a positive causal relationship was detected between RA and osteoporotic fracture (OR = 1.10132; 95% CI: 1.00506-1.20680; p = 0.03863). The results were robust according to sensitivity tests. This study showed positive causal relationships between RA and osteoporotic fracture. These results should be considered in further studies and public health measures on osteoporosis prevention strategies.

Anorexia nervosa and bulimia nervosa: a Mendelian randomization study of gut microbiota.

Anorexia nervosa (AN) and bulimia nervosa (BN) poses a significant challenge to global public health. Despite extensive research, conclusive evidence regarding the association between gut microbes and the risk of AN and BN remains elusive. Mendelian randomization (MR) methods offer a promising avenue for elucidating potential causal relationships. Genome-wide association studies (GWAS) datasets of AN and BN were retrieved from the OpenGWAS database for analysis. Independent single nucleotide polymorphisms closely associated with 196 gut bacterial taxa from the MiBioGen consortium were identified as instrumental variables. MR analysis was conducted utilizing R software, with outlier exclusion performed using the MR-PRESSO method. Causal effect estimation was undertaken employing four methods, including Inverse variance weighted. Sensitivity analysis, heterogeneity analysis, horizontal multivariate analysis, and assessment of causal directionality were carried out to assess the robustness of the findings. A total of 196 bacterial taxa spanning six taxonomic levels were subjected to analysis. Nine taxa demonstrating potential causal relationships with AN were identified. Among these, five taxa, including Peptostreptococcaceae, were implicated as exerting a causal effect on AN risk, while four taxa, including Gammaproteobacteria, were associated with a reduced risk of AN. Similarly, nine taxa exhibiting potential causal relationships with BN were identified. Of these, six taxa, including Clostridiales, were identified as risk factors for increased BN risk, while three taxa, including Oxalobacteraceae, were deemed protective factors. Lachnospiraceae emerged as a common influence on both AN and BN, albeit with opposing effects. No evidence of heterogeneity or horizontal pleiotropy was detected for significant estimates. Through MR analysis, we revealed the potential causal role of 18 intestinal bacterial taxa in AN and BN, including Lachnospiraceae. It provides new insights into the mechanistic basis and intervention targets of gut microbiota-mediated AN and BN.

Abstract PS02-05: Trajectories and predictors of peripheral neuropathy after neoadjuvant chemotherapy in a prospective cohort of 11,014 patients with early breast cancer

Abstract Background Peripheral neuropathy (PN) is a debilitating adverse event in patients with early breast cancer (BC) receiving (neo)adjuvant chemotherapy (CT). We harnessed the CANTO cohort study to detail clinical trajectories and explore clinical and genetic predictors of PN. Methods CANTO (CANcer TOxicities - NCT01993498) prospectively enrolled invasive stage I-III BC patients (pts) of 26 French comprehensive cancer centers. Pts were assessed at diagnosis, 3-6 (M6), 12 (M12), 36 (M36), and 60 (M60) months after treatment, defined as completion of surgery, CT or radiotherapy, whichever comes last. At each time point, PN events including paresthesia, sensory and motor neuropathy were collected according to NCI-CTC v4.0 criteria. A genome-wide association study (GWAS) was conducted to identify genetic predictors of PN, using Illumina GSA BeadChips. Minimac4/1000G was used to impute additional single nucleotide polymorphisms (SNPs). After stringent quality control measures, 1,894,475 SNPs with a minor allele frequency (MAF) &amp;gt;0.05 were evaluated. Longitudinal trajectories of PN events were descriptively examined. Statistical associations between each SNP and PN events measured at different time points, and between SNPs and trajectories, were performed with logistic regression assuming a log-additive genetic model. All analyses were adjusted for key clinical parameters and the first ten axes of principal component analysis of the genetic data to control for population stratification. Results Of 12,012 included pts (data lock Aug. 2022), 11,014 (91.7%) were analyzed. Age was &amp;lt; 50 and &amp;gt;65 in 3407 and 2759 pts (31% and 25%, respectively). Overweight/obesity and diabetes were recorded in 5328 (48%) and 458 pts (4%). A neurologic history was observed in 1360 pts (13%). Stage 0-I and II-III were observed in 5356 (49%) and 5512 pts (51%), and 4011 pts had an axillary dissection (37%). CT was administered in 5790 pts (53%), including a taxane (tax) in 5542 pts (96%). Shortly, all grade and grade 2+ PN was observed in 29% and 12%; 27% and 10%; 20% and 10%; 13% and 10% of pts at M6, M12, M36 and M60, respectively. We derived 5 trajectories of overall PN, deemed “never”, “always”, “appears”, “transient” and “disappears”, in respectively 54%, 10%, 9%, 7% and 19% of the pts. Similar trajectories were built for the 3 categories of PN events. We built 9 predictive nomograms including key clinical parameters and time of analysis. E.g., grade 2+ PN at M6 was independently predicted by a medical history of carpal tunnel syndrome, past neurologic history and exposure to tax. Grade 2+ PN at M36 was predicted by past neurologic history and exposure to tax, and largely by previous PN at M6 or M12. The GWAS analysis included 7633 pts (84%). Four independent SNPs adding predictive value to the clinical nomograms were identified at a suggestive level of association (p &amp;lt; 1e-6), including one SNP in the NCAM1 gene (involved in neurogenesis) for M6 PN (OR=1.40, 95%CI 1.23-1.60, p=4.8e-7, see table) and one SNP in the CLDN11 gene (regulates oligodendrocytes) for M12 sensory PN (OR=1.32; 95%CI 1.17-1.49, p=7.5e-6). For rare ( &amp;lt; 5%) toxicities, 10 independent suggestive SNPs were identified, including one SNP in the NELL1 gene (neural cell growth regulation and differentiation) for the “always” trajectory (OR=1.61, 95%CI 1.31-1.99, p=7.6e-6) and one SNP in the KCNIP1 gene (neuronal sensor) for M36 motor PN (OR=1.5, 95%CI 1.7-3.5, p=3.1e-07). Conclusions Risk of early peripheral neuropathy is associated with previous neurological history and taxane exposure. Patients with PN at M6 or M12 are highly exposed to long-term PN. Some key SNPs may add independent predictive value for specific PN endpoints. Exploratory results of interest were produced for rarer toxicities and typical clinical trajectories. Detailed results will be presented at the meeting. All PN, M6 Multivariate analyses of the risk of peripheral neuropathy, all grades, at M6, without and with GWAS input. Citation Format: Youenn Drouet, Emilie Thomas, Florence Lerebours, Barbara Pistilli, Olivier Trédan, Christelle Jouannaud, Marion Fournier, Philippe Rouanet, Laurence Vanlemmens, CHARLES COUTANT, Asma Dhaini Merimeche, Baptiste Sauterey, Christelle Levy, Mario Campone, Carole Tarpin, Marie-Ange Mouret-Reynier, Olivier Rigal, Thierry Petit, Sophie Guillermet, Antoine Arnaud, Mahmoud Ibrahim, Sylvie Giacchetti, Florence Dalenc, Johanna Wassermann, Olivier Arsène, Ariane Darut-Jouve, Sibille Everhard, Ines Vaz Luis, Anne-Laure Martin, Fabrice André, Jean-François Deleuze, Alain Viari, Matthieu Carton, Paul Cottu. Trajectories and predictors of peripheral neuropathy after neoadjuvant chemotherapy in a prospective cohort of 11,014 patients with early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-05.

No genetic causal association between periodontitis and ankylosing spondylitis: a bidirectional two-sample mendelian randomization analysis

BackgroundObservational studies that reveal an association between periodontitis (PD) and ankylosing spondylitis (AS) exist. However, observational research is prone to reverse causality and confounding factors, which make it challenging to infer cause-and-effect relationships. We conducted a two-sample Mendelian randomization (MR) study to examine the causal relationship between the genetic prediction of PD and AS.MethodsIn our study, single-nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs). The genetic association with PD came from the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) consortium, wherein 17353 cases of European ancestry and 28210 controls of European ancestry were included in this study. The genetic association with AS from the Neale Laboratory Consortium included 337,159 individuals from the United Kingdom, with 968 cases and 336,191 controls. MR analysis was mainly performed using the inverse-variance weighted (IVW) method. In addition, the robustness of the study findings was assessed using sensitivity, pleiotropy, and heterogeneity analyses.ResultsEighteen independent SNPs with P-values significantly smaller than 1 × 10− 5 were used as IV SNPs for PD, while 39 independent SNPs with P-values significantly smaller than 1 × 10− 5 were used as IV SNPs for AS. The results of the IVW method revealed no causal association between PD and AS (odds ratio = 1.00, 95% confidence interval: 0.99953 to 1.00067, P = 0.72). The MR-Egger method did not support the causal association between PD and AS. It is unlikely that horizontal pleiotropy distorts causal estimates based on sensitivity analysis. No significant heterogeneity was observed in the Q test. The ‘’leave-one-out’’ analysis demonstrated that the robustness of our results was unaffected by eliminating any of the IVs. Likewise, no significant causative effect for AS on PD was observed in the inverse MR analysis.ConclusionsThe study results do not support shared heritability or a causal association between PD and AS.

Causal relationship between eosinophilic esophagitis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study.

Eosinophilic esophagitis (EoE) and inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are immune-mediated gastrointestinal diseases with overlapped pathogenesis and are sometimes concurrently diagnosed, but their causal relationship remains unclear. We investigated the causal relationship between EoE and IBD and its subtypes via a two-sample bidirectional Mendelian randomization (MR) approach. MR analyses were performed using summary data of a genome-wide association study (GWAS) on individuals of European ancestry. Independent single-nucleotide polymorphisms correlated with EoE (from a GWAS meta-analysis containing 1,930 cases and 13,634 controls) and IBD (from FinnGen GWASs containing 9,083 IBD, 2,033 CD, and 5,931 UC cases, and GWASs of IBD genetic consortium containing 12,882 IBD, 6,968 UC, and 5,956 CD cases) were selected as instruments. We applied the inverse variance weighted (IVW) method as the primary analysis followed by several sensitivity analyses. For the forward MR study, estimates from IVW methods were subsequently meta-analyzed using a random-effect model. Our results suggested a causal effect of EoE on IBD [pooled odds ratio (OR), 1.07; 95% confidence interval (CI), 1.02-1.13] and EoE on UC (pooled OR, 1.09, 95% CI, 1.04-1.14). No causal link between EoE and CD was observed (pooled OR, 1.05; 95% CI, 0.96-1.16). The reverse MR analyses revealed no causal effect of IBD (and its subtypes) on EoE. Sensitivity analyses confirmed the robustness of primary results. Our findings provided evidence of a suggestive causal effect of EoE on IBD (specifically on UC) in the European population. Increased awareness of concurrent or subsequent IBD in patients with EoE is called for. Still, the present evidence is not adequate enough and ought to be validated by further investigations.

No genetic causality between obesity and benign paroxysmal vertigo: A two-sample Mendelian randomization study.

We applied Mendelian randomization to explore the causal relationship between obesity and benign paroxysmal vertigo (BPV). We chose two types of obesity diseases. Obesity due to excessive calories and other or unspecified obesity from the FinnGen database. We used genomic significance (p < 5 × 10-8) to obtain independent single nucleotide polymorphisms (SNPs) as instrumental variables. Similarly, genome-wide association study data for the disease BPV were selected from the FinnGen database. R was then used to test the data for multiplicity and heterogeneity, as well as to detect the effect of individual SNPs on the results. Random effects inverse variance weighting was used as the main statistical analysis. First, by analyzing, we found an outlier in obesity due to excessive calories (rs12956821). Outliers were then removed, and the statistical results were analyzed without heterogeneity (p > 0.05) and horizontal pleiotropy (p > 0.05), as well as individual SNPs having no effect on the results. Meanwhile, random-effects IVW results showed obesity due to excessive calories (p = 0.481; OR = 0.941), and other or unspecified obesity (p = 0.640; OR = 0.964). The present study did not find a causal relationship between the above two obesity types and BPV at the genetic level.

The brain-heart axis: Integrative analysis of the shared genetic etiology between neuropsychiatric disorders and cardiovascular disease

BackgroundMultiple observational studies have reported substantial comorbidity between neuropsychiatric disorders and cardiovascular disease (CVD), but the underlying mechanisms remain largely unknown. MethodsUsing GWAS summary datasets of 8 neuropsychiatric disorders and 6 cardiovascular diseases, an integrative analysis incorporating linkage-disequilibrium-score-regression (LDSC), Mendelian randomization (MR), functional mapping and annotation (FUMA), and functional enrichment analysis, was conducted to investigate shared genetic etiology of the brain-heart axis from the whole genome level, single-nucleotide polymorphism (SNP) level, gene level, and biological pathway level. ResultsIn LDSC analysis, 18 pairwise traits between neuropsychiatric disorders and CVD were identified with significant genetic overlaps, revealing extensive genome-wide genetic correlations. In bidirectional MR analysis, 19 pairwise traits were identified with significant causal relationships. Genetic liabilities to neuropsychiatric disorders, particularly attention-deficit hyperactivity disorder and major depressive disorder, conferred extensive significant causal effects on the risk of CVD, while hypertension seemed to be a risk factor for multiple neuropsychiatric disorders, with no significant heterogeneity or pleiotropy. In FUMA analysis, 13 shared independent significant SNPs and 887 overlapping protein-coding genes were detected between neuropsychiatric disorders and CVD. With GO and KEEG functional enrichment analysis, biological pathways of the brain-heart axis were highly concentrated in neurotransmitter synaptic transmission, lipid metabolism, aldosterone synthesis and secretion, glutathione metabolism, and MAPK signaling pathway. ConclusionExtensive genetic correlations and genetic overlaps between neuropsychiatric disorders and CVD were identified in this study, which might provide some new insights into the brain-heart axis and the therapeutic targets in clinical practice.

Genetic evidence for T-wave area from 12-lead electrocardiograms to monitor cardiovascular diseases in patients taking diabetes medications.

Aims Many studies indicated use of diabetes medications can influence the electrocardiogram (ECG), which remains the simplest and fastest tool for assessing cardiac functions. However, few studies have explored the role of genetic factors in determining the relationship between the use of diabetes medications and ECG trace characteristics (ETC). Methods Genome-wide association studies (GWAS) were performed for 168 ETCs extracted from the 12-lead ECGs of 42,340 Europeans in the UK Biobank. The genetic correlations, causal relationships, and phenotypic relationships of these ETCs with medication usage, as well as the risk of cardiovascular diseases (CVDs), were estimated by linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), and regression model, respectively. Results The GWAS identified 124 independent single nucleotide polymorphisms (SNPs) that were study-wise and genome-wide significantly associated with at least one ETC. Regression model and LDSC identified significant phenotypic and genetic correlations of T-wave area in lead aVR (aVR_T-area) with usage of diabetes medications (ATC code: A10 drugs, and metformin), and the risks of ischemic heart disease (IHD) and coronary atherosclerosis (CA). MR analyses support a putative causal effect of the use of diabetes medications on decreasing aVR_T-area, and on increasing risk of IHD and CA. ConclusionPatients taking diabetes medications are prone to have decreased aVR_T-area and an increased risk of IHD and CA. The aVR_T-area is therefore a potential ECG marker for pre-clinical prediction of IHD and CA in patients taking diabetes medications.

Sex-specific and polygenic effects underlying resting heart rate and associated risk of cardiovascular disease.

Resting heart rate (RHR) is associated with cardiovascular disease (CVD) and mortality. This study aimed to identify genetic loci associated with RHR, develop a genome-wide polygenic risk score (PRS) for RHR, and assess associations between the RHR PRS and CVD outcomes, to better understand the biological mechanisms linking RHR to disease. Sex-specific analyses were conducted to potentially elucidate different pathways between the sexes. We performed a genome-wide meta-analysis of RHR (n=550,467) using two independent study populations, The Trøndelag Health Study (HUNT) and the UK Biobank (UKB), comprising 69,155 and 481,312 participants, respectively. We also developed a genome-wide PRS for RHR using UKB and tested for association between the PRS and 13 disease outcomes in HUNT. We identified 403, 253, and 167 independent single nucleotide polymorphisms (SNPs) significantly associated with RHR in the total population, women, and men, respectively. The sex-specified analyses indicated differences in the genetic contribution to RHR and revealed loci significantly associated with RHR in only one of the sexes. The SNPs were mapped to genes enriched in heart tissue and cardiac conduction pathways, as well as disease-pathways, including dilated cardiomyopathy. The PRS for RHR was associated with increased risk of hypertension and dilated cardiomyopathy, and decreased risk of atrial fibrillation. Our findings provide insight into the pleiotropic effects of the RHR variants, contributing towards an improved understanding of mechanisms linking RHR and disease. In addition, the sex-specific results might contribute to a more refined understanding of RHR as a risk factor for the different diseases.

Causal Relationship Between Branched-Chain Amino Acids and Hypertension: AMendelian Randomization Study.

This study aimed to investigate the causal relationships between branched-chain amino acids (BCAAs) and the risks of hypertension via meta-analysis and Mendelian randomization analysis. A meta-analysis of 32 845 subjects was conducted to evaluate the relationships between BCAAs and hypertension. In Mendelian randomization analysis, independent single-nucleotide polymorphisms associated with BCAAs at the genome-wide significance level were selected as the instrumental variables. Meanwhile, the summary-level data for essential hypertension and secondary hypertension end points were obtained from the FinnGen study. As suggested by the meta-analysis results, elevated BCAA levels were associated with a higher risk of hypertension (isoleucine: summary odds ratio, 1.26 [95% CI, 1.08-1.47]; leucine: summary odds ratio, 1.28 [95% CI, 1.07-1.52]; valine: summary odds ratio, 1.32 [95% CI, 1.12-1.57]). Moreover, the inverse variance-weighted method demonstrated that an elevated circulating isoleucine level might be the causal risk factor for essential hypertension but not secondary hypertension (essential hypertension: odds ratio, 1.22 [95% CI, 1.12-1.34]; secondary hypertension: odds ratio, 0.96 [95% CI, 0.54-1.68]). The increased levels of 3 BCAAs positively correlated with an increased risk of hypertension. Particularly, elevated isoleucine level is a causal risk factor for essential hypertension. Increased levels of leucine and valine also tend to increase the risk of essential hypertension, but further verification is still warranted.

Drug target Mendelian randomization supports apolipoprotein C3-lowering for lipoprotein-lipid levels reductions and cardiovascular diseases prevention

Background and aimsInhibitors of apolipoprotein C-III (apoC3) are currently approved for the reduction of triglyceride levels in patients with Familial Chylomicronemia Syndrome. We used drug target Mendelian randomization (MR) to assess the effect of genetically predicted decrease in apoC3 blood protein levels on cardiometabolic traits and diseases. MethodsWe quantified lifelong reductions in apoC3 blood levels by selecting all genome wide significant and independent (r2<0.1) single nucleotide polymorphisms (SNPs) in the APOC3 gene region ±1 Mb, from three genome-wide association studies (GWAS) of apoC3 blood protein levels (deCODE, n = 35,378, Fenland, n = 10,708 and ARIC, n = 7213). We included the largest GWASes on 18 cardiometabolic traits and 9 cardiometabolic diseases as study outcomes. ResultsA one standard deviation lowering in apoC3 blood protein levels was associated with lower triglycerides, apolipoprotein B, low-density lipoprotein cholesterol, alanine aminotransferase, and glomerular filtration rate as well as higher high-density lipoprotein cholesterol levels. ApoC3 lowering was also associated with lower risk of acute pancreatitis (odds ratio [OR] = 0.91 95% CI = 0.82 to 1.00), aortic stenosis (OR = 0.82 95% CI = 0.73 to 0.93), and coronary artery disease (OR = 0.86 95% CI = 0.80 to 0.93), and was associated with increased parental lifespan (0.06 95% CI = 0.03–0.09 years). These results were concordant across robust MR methods, the three protein datasets and upon adjustment for APOA1, APOA4 and APOA5 using a multivariable MR framework. ConclusionsThese results provide evidence that apoC3 lowering could result in widespread benefits for cardiometabolic health and encourage the launch of trials on apoC3 inhibition for coronary artery disease prevention.

Causal Association Analysis of Periodontitis and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Periodontitis has been reported to be associated with inflammatory bowel disease (IBD), including ulcerative colitis (UC), and Crohn's disease (CD). However, the causality of these 2 diseases remains unclear. We conducted bidirectional Mendelian randomization (MR) to investigate the causal relationship between periodontitis and IBD. We obtained the genome-wide association study (GWAS) summary data of European populations from FinnGen database (for IBD) and a published article (for periodontitis), from which independent single nucleotide polymorphisms were selected as instrumental variables. Inverse variance-weighted (IVW), MR-Egger, and weighted median (WM) methods were utilized for MR analysis. Heterogeneity or pleiotropy was detected through Cochran's Q test and MR-Egger intercept, respectively. Outlier was identified with MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) and leave-one-out analysis. All statistical analyses were performed with R 4.2.1 and the packages of TwoSampleMR version 0.5.6. Genetic prediction showed that periodontitis was the risk factor of UC (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.01-1.26; P = .027), rather than of CD (OR, 0.92; 95% CI, 0.74-1.15; P = .456) and IBD (OR, 0.96; 95% CI, 0.81-1.13; P = .619). To the contrary, CD, not UC or IBD, resulted in exacerbating periodontitis in terms of the results of the IVW (OR, 1.09; 95% CI, 1.01-1.17; P = .021) and WM (OR, 1.10; 95% CI, 1.01-1.20; P = .030) methods. Heterogeneity or pleiotropy was acceptable. Our results indicated that CD was the risk factor for periodontitis; conversely, periodontitis was responsible for the exacerbation of UC, enhancing the existence of mouth-gut axis. Patients with UC should pay more attention to periodontal health, while patients with periodontitis should actively pay close heed to intestinal health.

Genetic susceptibility to prostate cancer in Taiwan: A genome-wide association study.

We conducted the first genome-wide association study (GWAS) of prostate cancer (PCa) in Taiwan with 1844 cases and 80,709 controls. Thirteen independent single-nucleotide polymorphisms (SNPs) reached genome-wide significance (p < 5 × 10-8 ). Among these, three were distinct from previously identified loci: rs76072851 in CORO2B gene (15q23), odds ratio (OR) = 1.54, 95% confidence interval (CI), 1.36-1.76, p = 5.30 × 10-11 ; rs7837051, near two long noncoding RNA (lncRNA) genes, PRNCR1 and PCAT2 (8q24.21), OR = 1.41 (95% CI, 1.31-1.51), p = 8.77 × 10-21 ; and rs56339048, near an lncRNA gene, CASC8 (8q24.21), OR = 1.25 (95% CI, 1.16-1.35), p = 2.14 × 10-8 . We refined the lead SNPs for two previously identified SNPs in Taiwanese: rs13255059 (near CASC8), p = 9.02 × 10-43 , and rs1456315 (inside PRNCR1), p = 4.33 × 10-42 . We confirmed 35 out of 49 GWAS-identified East Asian PCa susceptibility SNPs. In addition, we identified twoSNPs more specific to Taiwanese than East Asians: rs34295433 in LAMC1 (1q25.3) and rs6853490 in PDLIM5 (4q22.3). A weighted genetic risk score (GRS) was developed using the 40 validated SNPs and the area under the receiver-operating characteristiccurvefor the GRS to predict PCa was 0.67 (95% CI, 0.63-0.71). These identified SNPs provide valuable insights into the molecular mechanisms of prostate carcinogenesis in Taiwan and underscore the significant role of genetic susceptibility in regional differences in PCa incidence.

Causal effects of blood pressure and the risk of frailty: a bi-directional two-sample Mendelian randomization study.

Observational studies have indicated that high blood pressure (BP) may be a risk factor to frailty. However, the causal association between BP and frailty remains not well determined. The purpose of this bi-directional two-sample Mendelian randomization (MR) study was to investigate the causal relationship between BP and frailty. Independent single nucleotide polymorphisms (SNPs) strongly (P < 5E-08) associated with systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) were selected as instrumental variables. Two different published genome-wide association studies (GWAS) on BP from the CHARGE (n = 810,865) and ICBP (n = 757,601) consortia were included. Summary-level data on frailty index (FI) were obtained from the latest GWAS based on UK Biobank and Swedish TwinGene cohorts (n = 175,226). Inverse variance weighted (IVW) approach with other sensitivity analyses were used to calculate the causal estimate. Using the CHARGE dataset, genetic predisposition to increased SBP (β = 0.135, 95% CI = 0.093 to 0.176, P = 1.73E-10), DBP (β = 0.145, 95% CI = 0.104 to 0.186, P = 3.14E-12), and PP (β = 0.114, 95% CI = 0.070 to 0.157, p = 2.87E-07) contributed to a higher FI, which was validated in the ICBP dataset. There was no significant causal effect of FI on SBP, DBP, and PP. Similar results were obtained from different MR methods, indicating good stability. There was potential heterogeneity detected by Cochran's Q test, but no horizontal pleiotropy was observed in MR-Egger intercept test (P > 0.05). These findings evinced that higher BP and PP were causally associated with an increased risk of frailty, suggesting that controlling hypertension could reduce the risk of frailty.

The causal effect of two occupational factors on osteoarthritis and rheumatoid arthritis: a Mendelian randomization study.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common types of arthritis. We conducted a two-sample Mendelian randomization (MR) study to estimate the causal effects of two common occupational factors-job involves heavy manual or physical work and job involves mainly walking or standing-on OA and RA in individuals of European ancestry. Instruments were chosen from genome-wide association studies (GWASs) that identified independent single nucleotide polymorphisms (SNPs) robustly linked to job involves heavy manual or physical work (N = 263,615) as well as job involves mainly walking or standing (N = 263,556). Summary statistics for OA and RA were taken from the Integrative Epidemiology Unit (IEU) GWAS database; both discovery and replication GWAS datasets were considered. The primary analysis utilized the inverse variance weighted (IVW) MR method supplemented by various sensitivity MR analyses. In the IVW model, we found that genetically predicted job involves heavy manual or physical work was significantly associated with OA in both the discovery [odds ratio (OR) = 1.034, 95% confidence interval (CI): 1.016-1.053, P = 2.257 × 10-4] and replication (OR = 1.857, 95% CI: 1.223-2.822, P = 0.004) analyses. The causal associations were supported in diverse sensitivity analyses. MR analyses suggested no causal effect of genetically predicted job involves heavy manual or physical work on RA. Similarly, our data provided no evidence that genetically predicted job involves mainly walking or standing was related to OA and RA. Our MR study suggests that job involves heavy manual or physical work is a risk factor for OA. It is of utmost importance to create preventive strategies aimed at reducing its impact on OA at such work sites.