Large Genome-wide Association Studies Research Articles

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

The causality of physical activity status and intelligence: A bidirectional Mendelian randomization study.

Observational studies suggest physical activity (PA) enhances intelligence, while sedentary behavior (SB) poses a risk. However, causality remains unclear. We extracted genetic instruments from large genome-wide association studies summary data and employed an inverse-variance weighted (IVW) approach within a random-effects model as the primary method of Mendelian randomization (MR) analysis to estimate the overall effect of various physical activity statuses on intelligence. To assess IVW stability and MR sensitivity, we also utilized supplementary methods including weighted median, MR-Egger, and MR-PRESSO. Furthermore, multivariable MR analysis was conducted to examine the independent effects of each physical activity trait on intelligence. The MR primary results indicated that LST was negatively associated with intelligence (β = -0.133, 95%CI: -0.177 to -0.090, p = 1.34×10-9), while SBW (β = 0.261, 95% CI: 0.059 to 0.463, p = 0.011) may have a positive effect on intelligence; however, MVPA and SC did not show significant effects on intelligence. Inverse causality analyses demonstrated intelligence significantly influenced all physical activity states. Our study highlights a bidirectional causal relationship between physical activity states and intelligence.

No evidence of genetic causal association between sex hormone-related traits and systemic lupus erythematosus: A two-sample Mendelian randomization study.

Previous studies have demonstrated an association between sex hormone-related traits and systemic lupus erythematosus (SLE). However, because of the difficulties in determining sequential temporality, the causal association remains elusive. In this study, we used two-sample Mendelian randomization (MR) to explore the genetic causal associations between sex hormone-related traits and SLE. We used a two-sample MR to explore the causal association between sex hormone-related traits and SLE. The summarized data for sex hormone-related traits (including testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), and bioavailable testosterone (BT)) originated from large genome-wide association studies (GWASs) of European descent. Aggregated data for SLE were derived from the FinnGen consortium (835 cases and 300,162 controls). Random-effects inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods were used for the MR analysis. Random-effects IVW was the primary method used to analyze the genetic causal association between sex hormone-related traits and SLE. Heterogeneity of the MR results was detected using the IVW Cochran's Q estimates. The pleiotropy of MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, leave-one-out analysis was performed to determine whether MR results were affected by a single single-nucleotide polymorphism (SNP). Random-effects IVW as the primary method showed that testosterone (odds ratio (OR), 0.87; 95% confidence interval (CI), 0.41-1.82; P = 0.705), E2 (OR, 0.95; 95% CI, 0.73-1.23; P = 0.693), SHBG (OR, 1.25; 95% CI, 0.74-2.13; P = 0.400), and BT (OR, 0.99; 95% CI, 0.67-1.47; P = 0.959) had no potential causal association with SLE. The MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods all indicated consistent results. The results of the MR-Egger regression showed that there was no pleiotropy in our MR analysis (P > 0.05). The IVW Cochran's Q estimates showed that the MR analysis results of E2, SHBG, and BT on SLE had no heterogeneity (P > 0.05), but testosterone and SLE had heterogeneity (P < 0.05). The leave-one-out analysis confirmed that a single SNP did not affect the MR results. Our MR analysis demonstrated that genetically predicted testosterone, E2, SHBG, and BT levels were not associated with SLE risk, but the roles of other non-genetic pathways cannot be ruled out. Key Points • This is the first MR study to explore the causal association of sex hormone-related traits with SLE. • No evidence to support causal associations between sex hormone-related traits and SLE. • Our MR analysis may provide novel insights into the causal association between sex hormone-related traits and SLE risk.

The long-term mediation role of cytokines on the causal pathway from maternal gestational age to offspring eye diseases: Lifecourse-Network Mendelian randomization

BackgroundGestational duration has a significant impact on eye diseases. A large number of evidences suggest that cytokines are associated with gestational duration and eye diseases. However, the causal relationships among cytokines, maternal gestational impairment and offspring eye diseases remain unclear. MethodsWe performed lifecourse-network Mendelian randomization (MR) to explore the causal relationships between maternal gestational duration (from the Early Growth Genetics (EGG) Consortium and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study, N = 84,689), neonatal/adult cytokines (from the NHGRI-EBI Catalog, N = 764/4,618), and adult eye diseases (from FinnGen consotium, N = 309,154) using summary-level data from large genome-wide association studies. Multiplicative random effects inverse variance weighted (IVW) and multivariable-IVW methods were the main analysis methods, and the other 15 pleiotropy-robust methods, weak IV-robust methods, and outliers-robust methods were used as auxiliary methods. ResultsMaternal gestational age (early preterm birth, preterm birth, gestational duration, and post-term birth) had a causal relationship with 42 eye diseases. Four neonatal cytokines, Tumor Necrosis Factor-α(TNF-α), IL10, GROA, and CTACK, as well as four adult cytokines, CTACK, IL10, IL12p70 and IL6 are mediators in the causal relationships between early preterm birth and preterm birth in eight eye diseases. However, after adjusting for these mediators, a null direct causal effect of early preterm birth and preterm birth on eight eye diseases was found. In addition, there was no mediator in the causal relationship between gestational duration and post-term birth to eye diseases. ConclusionThe effects of maternal gestational duration on offspring eye diseases through cytokines are long-term and life-course effects.

Causal effect of vitamin D on myasthenia gravis: a two-sample Mendelian randomization study.

Observational studies suggest that vitamin D supplementation may be effective in preventing myasthenia gravis (MG). However, the causal relationship between circulating vitamin D levels and MG remains unclear. This study aimed to examine the genetic causality of circulating vitamin D and MG using data from large population-based genome-wide association studies (GWAS). SNPs (single nucleotide polymorphisms) strongly associated with exposure were selected. Two-sample Mendelian Randomization (MR) was performed with inverse variance weighting (IVW), MR-Egger (Mendelian randomization-Egger), weight median and MR-PRESSO (Mendelian randomization pleiotropy residual sum and outlier) methods. Heterogeneity was tested via IVW and MR-Egger. Pleiotropy was tested using MR-Egger intercept test and MR-PRESSO method. MR-PRESSO was also used to detect outliers. Leave-one-out analysis was used to identify SNPs with potential effect. Reverse MR analysis was also performed. In IVW, circulating vitamin D levels had no causal effect on MG [OR = 0.91 (0.67-1.22), p = 0.532] and MG had no causal effect on circulating vitamin D [OR = 1.01 (099-1.02), p = 0.663]. No heterogeneity or pleiotropy was observed (p > 0.05). Other MR methods also agreed with IVW results. This study provides the causal relationship between genetically predicted circulating vitamin D levels and MG and provides new insights into the genetics of MG.

Causal effect of hypertension and blood pressure on aortic diseases: evidence from Mendelian randomization.

Hypertension or elevated blood pressure was documented to be an important risk factor for aortic diseases in observational studies, yet the causality remains to be determined. By applying a two-sample Mendelian randomization (MR) approach, we aim to determine whether hypertension or elevated blood pressure (systolic blood pressure [SBP] or diastolic blood pressure [DBP]) is linked causally to aortic aneurysm or aortic dissection. Genetic instruments and summary statistics for hypertension and aortic diseases were obtained from large genome-wide association studies. The traditional inverse variance weighted (IVW) method was used to obtain the causal estimates. Sensitivity analyses including MR-Egger, weighted median and multivariable MR were also performed. Our results suggested that genetic liability to hypertension was associated with aortic dissection (odds ratio [OR]: 1.81; 95% confidence interval [CI]: 1.27-2.58; P = 1.13 × 10-3) and aortic aneurysm (OR: 1.43; 95% CI: 1.22-1.66; P = 7.79 × 10-6). Per standard deviation increase in genetically-determined DBP was significantly associated with increased aortic dissection (OR: 1.14; 95% CI: 1.09-1.19; P = 1.58 × 10-9) and aortic aneurysm (OR: 1.07; 95% CI: 1.05-1.09; P = 8.37 × 10-14). There was a null association between SBP and aortic dissection (OR: 1.01; 95% CI: 0.99-1.94; P = 0.38) or aortic aneurysm (OR: 1.00; 95% CI: 0.99-1.01; P = 0.92). Sensitivity analyses documented similar results. Therefore, hypertension and elevated DBP are causally associated with higher risks of aortic aneurysm and aortic dissection. Preventive interventions for aortic diseases may consider individuals with hypertension, especially those with higher DBP. Meanwhile, further research is required to determine the mechanisms underlying the significantly greater correlation between DBP and aortic diseases than SBP.

Differential genome-wide associated variants and enriched pathways of ECG parameters among people with versus without HIV.

People with HIV (PWH) are more likely to develop ECG abnormalities. Substantial evidence exists for genetic contribution to ECG parameters among general population. However, whether and how would host genome associate with ECG parameters among PWH is unclear. Our research aims to analyze and compare genetic variants, mapped genes, and enriched pathways of ECG parameters among PWH and HIV-negative controls. A cross-sectional study. We performed a large original genome-wide association study (GWAS) of ECG parameters among PWH ( n = 1730) and HIV-negative controls ( n = 3746). Genome-wide interaction analyses were also conducted. A total of 18 novel variants were detected among PWH, six for PR interval including rs76345397 at ATL2 , 11 for QRS duration including rs10483994 at KCNK10 and rs2478830 at JCAD , and one for QTc interval (rs9815364). Among HIV-negative controls, we identified variants located at previously reported ECG-related genes ( SCN5A , CNOT1 ). Genetic variants had a significant interaction with HIV infection ( P < 5 × 10 -8 ), implying that HIV infection and host genome might jointly influence ECG parameters. Mapped genes for PR interval and QRS duration among PWH were enriched in the biological process of viral genome replication and host response to virus, respectively, whereas enriched pathways for PR interval among HIV-negative controls were in the cellular component of voltage-gated sodium channel complex. The present GWAS indicated a distinctive impact of host genome on quantitative ECG parameters among PWH. Different from HIV-negative controls, host genome might influence the cardiac electrical activity by interfering with HIV viral infection, production, and latency among PWH.

The causal relationship between metabolic factors, drinking, smoking and intrahepatic cholangiocarcinoma: a Mendelian randomization study.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. While multiple risk factors for iCCA have been established, metabolic diseases (obesity, diabetes, NAFLD, dyslipidemia, and hypertension) and other risk factors, including smoking and drinking, are still controversial due to their potential confounders. Here, Mendelian randomization (MR) analysis was performed to identify the causal relationship between them. In this study, we obtained GWAS data related to exposures from corresponding large genome-wide association studies. Summary-level statistical data for iCCA were obtained from the UK Biobank (UKB). We performed a univariable MR analysis to identify whether genetic evidence of exposure was significantly associated with iCCA risk. A multivariable MR analysis was conducted to estimate the independent effects of exposures on iCCA. Univariable and multivariable MR analysis based on the large GWAS data indicated that there is little evidence to support the genetic role of metabolic factors, smoking, drinking, and NAFLD in iCCA development (P >0.05). In contrast to most current studies, their impact on iCCA development, if any, might be smaller than we thought. The previous positive results might be due to the comorbidities between diseases and potentially unavoidable confounding factors. In this MR study, we found no strong evidence to support causal associations between metabolic factors, NAFLD, smoking, drinking, and iCCA risk.

Large-scale rare variant burden testing in Parkinson's disease.

Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.

153-OR: Genetically Supported Therapeutic Targets for Coronary Artery Disease in Diabetes—Evidence from Proteome-Wide Mendelian Randomization

Coronary artery disease (CAD) remains a major burden in people with diabetes. Genome-wide association studies (GWASs) have identified multiple genetic loci, yet most have yet to translate to clinical applications. The aim of this study was to leverage on genetic data to identify novel drug targets for CAD in diabetes. We applied Mendelian randomization (MR) to investigate the causal association of 1677 plasma proteins from 6 large GWASs, and a recently published GWAS of 15,666 individuals with diabetes (including 3968 CAD cases and 11698 controls). 5 of the 6 proteomic studies were selected as discovery MR analysis, and the remaining one as replication MR to validate the top findings. We employed sensitivity analyses, Bayesian colocalization and transcriptome-wide association study (TWAS) to test the validity of MR assumptions and meanwhile prioritized candidates of drug targets using multi-omics layers. We further integrated phenome-wide MR using the summary data from UK Biobank (N≤408 961) studies and clinical evidence based on DrugBank database to detect potential side effects associated with hypothetical therapeutic agents for CAD in diabetes and prioritize them. Our primary discovery MR analysis identified 4 prioritized proteins (F5, LPA, NPPB and TNFRSF11B) with both MR and colocalization evidence. NPPB and TNFRSF11B could be verified by replication MR analysis. Multi-tissue TWAS analysis revealed all 4 targets whose imputed expression was associated with the outcome. No adverse side effects were found for LPA via phenome-wide MR. By combining the putative causal MR signals with clinical evidence, we suggested these 4 drug repurposing opportunities for the treatment of CAD with diabetes that warranted further investigation. In summary, we prioritized 4 potential drug targets for CAD in diabetes. In particular, LPA might represent a promising target for the treatment of CAD in diabetes, with no predicted adverse side effects. Disclosure C.Huang: None. M.Shi: None. G.Yu: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. R.C.Ma: Advisory Panel; AstraZeneca, Merck &amp; Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. Funding Research Grants Council of the Hong Kong Special Administrative Region (CU R4012-18); Croucher Foundation

Management of keratoconus: an updated review.

Keratoconus is the most common corneal ectatic disorder. It is characterized by progressive corneal thinning with resultant irregular astigmatism and myopia. Its prevalence has been estimated at 1:375 to 1:2,000 people globally, with a considerably higher rate in the younger populations. Over the past two decades, there was a paradigm shift in the management of keratoconus. The treatment has expanded significantly from conservative management (e.g., spectacles and contact lenses wear) and penetrating keratoplasty to many other therapeutic and refractive modalities, including corneal cross-linking (with various protocols/techniques), combined CXL-keratorefractive surgeries, intracorneal ring segments, anterior lamellar keratoplasty, and more recently, Bowman's layer transplantation, stromal keratophakia, and stromal regeneration. Several recent large genome-wide association studies (GWAS) have identified important genetic mutations relevant to keratoconus, facilitating the development of potential gene therapy targeting keratoconus and halting the disease progression. In addition, attempts have been made to leverage the power of artificial intelligence-assisted algorithms in enabling earlier detection and progression prediction in keratoconus. In this review, we provide a comprehensive overview of the current and emerging treatment of keratoconus and propose a treatment algorithm for systematically guiding the management of this common clinical entity.

Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis.

To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short- and long-term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. No individual SNP reached genome-wide significance (P < 5 × 10-8), either for persistence at 1 year or at 3 years. The RA PRS was not significantly associated with MTX treatment persistence at 1 year [relative risk (RR) = 0.98 (0.96-1.01)] or at 3 years [RR = 0.96 (0.93-1.00)]. The heritability of MTX treatment persistence was estimated to be 0.45 (0.15-0.75) at 1 year and 0.14 (0-0.40) at 3 years. The results in seropositive RA were comparable with those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, MTX monotherapy persistence was lower in patients with a greater genetic disposition, per the PRS, towards RA.

Genetically predicted coffee and tea consumption and risk of intracranial aneurysm.

Observational studies have shown associations between coffee and tea consumption and risk of intracranial aneurysm (IA). However, the results are not consistent. We conducted a Mendelian randomization study to clarify whether genetically predicted coffee and tea consumption has a causal effect on IA and its subtypes. Genetic variants associated with coffee and tea consumption (cups/day) were obtained from large genome-wide association studies (GWASs), up to 349,376 subjects. Summary-level data for IA were adopted from a GWAS in 79,429 subjects (23 cohorts, 7495 cases, and 71,934 controls). Genetically predicted coffee consumption was associated with a higher risk of any IA and aneurysmal subarachnoid hemorrhage (SAH), but not with unruptured IA. The ORs per 1 cup/day increase in genetically predicted coffee consumption were 1.42 (95% CI: 1.09-1.86; P = 0.010) for IA, 1.51 (95% CI: 1.13-2.03; P = 0.005) for aneurysmal SAH, and 1.20 (95% CI: 0.74-1.96; P = 0.460) for unruptured IA. Genetically predicted tea consumption was not associated with risk of any IA and its subtypes (P > 0.05). The associations remained consistent in sensitivity analyses, and no evidence of pleiotropy was detected. Our study provides evidence to support that coffee consumption may increase the risk of IA and associated hemorrhage. Coffee should be limited for those at high risk of IA and associated hemorrhage.

Improved genetic prediction of the risk of knee osteoarthritis using the risk factor-based polygenic score

BackgroundPolygenic risk score (PRS) analysis is used to predict disease risk. Although PRS has been shown to have great potential in improving clinical care, PRS accuracy assessment has been mainly focused on European ancestry. This study aimed to develop an accurate genetic risk score for knee osteoarthritis (OA) using a multi-population PRS and leveraging a multi-trait PRS in the Japanese population.MethodsWe calculated PRS using PRS-CS-auto, derived from genome-wide association study (GWAS) summary statistics for knee OA in the Japanese population (same ancestry) and multi-population. We further identified risk factor traits for which PRS could predict knee OA and subsequently developed an integrated PRS based on multi-trait analysis of GWAS (MTAG), including genetically correlated risk traits. PRS performance was evaluated in participants of the Nagahama cohort study who underwent radiographic evaluation of the knees (n = 3,279). PRSs were incorporated into knee OA integrated risk models along with clinical risk factors.ResultsA total of 2,852 genotyped individuals were included in the PRS analysis. The PRS based on Japanese knee OA GWAS was not associated with knee OA (p = 0.228). In contrast, PRS based on multi-population knee OA GWAS showed a significant association with knee OA (p = 6.7 × 10−5, odds ratio (OR) per standard deviation = 1.19), whereas PRS based on MTAG of multi-population knee OA, along with risk factor traits such as body mass index GWAS, displayed an even stronger association with knee OA (p = 5.4 × 10−7, OR = 1.24). Incorporating this PRS into traditional risk factors improved the predictive ability of knee OA (area under the curve, 74.4% to 74.7%; p = 0.029).ConclusionsThis study showed that multi-trait PRS based on MTAG, combined with traditional risk factors, and using large sample size multi-population GWAS, significantly improved predictive accuracy for knee OA in the Japanese population, even when the sample size of GWAS of the same ancestry was small. To the best of our knowledge, this is the first study to show a statistically significant association between the PRS and knee OA in a non-European population.Trial registrationNo. C278.

Correlation between obstructive sleep apnea and cerebral small vessel disease: a mendelian randomization study.

Whether obstructive sleep apnea (OSA) is causally associated with an increased risk of cerebral small vessel disease (CSVD) remains controversial. We conducted a two-sample Mendelian randomization (MR) study to clarify the causal relationship between OSA and CSVD risk. Single-nucleotide polymorphisms associated with OSA at the genome-wide significance level (P < 5 × 10- 8) in the FinnGen consortium were selected as instrumental variables. Summary-level data for white matter hyperintensities (WMHs), lacunar infarctions (LIs), cerebral microbleeds (CMBs), fractional anisotropy (FA), and mean diffusivity (MD) were obtained from three meta-analyses of genome-wide association studies (GWASs). The random-effects inverse-variance weighted (IVW) method was selected for the major analysis. Weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses. Genetically predicted OSA was not associated with LIs (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.86-1.40), WMHs (OR = 0.94, 95% CI = 0.83-1.07), FA (OR = 1.33, 95% CI = 0.75-2.33), MD (OR = 0.93, 95% CI = 0.58-1.47), CMBs (OR = 1.29, 95% CI = 0.86-1.94), mixed CMBs (OR = 1.17, 95% CI = 0.63-2.17), and lobar CMBs (OR = 1.15, 95% CI = 0.75-1.76) in IVW method. The results of the sensitivity analyses were generally consistent with the major analyses. This MR study does not support causal associations between OSA and the risk of CSVD in individuals of European ancestry. These findings need to be further validated in randomized controlled trials, larger cohort studies, and MR studies based on larger GWASs.

Association of leisure sedentary behavior and physical activity with the risk of nonalcoholic fatty liver disease: a two-sample Mendelian randomization study.

Previous observational studies have demonstrated the relationship between leisure sedentary behavior, physical activity, and nonalcoholic liver disease (NAFLD). However, whether these associations are causal or confounding factors remains unclear. Pooled genetic data from the UK Biobank and other large genome-wide association studies (GWAS) were used to extract instrumental variables representing sedentary television watching, computer use, driving, vigorous physical activity (VPA), and moderate-to-vigorous physical activity (MVPA). The two-sample Mendelian randomization (MR) method was used to explain the causal relationship between them and NAFLD. The inverse variance of the weighted method was used as the main analysis method, and MR-Egger, weighted median, MR-PRESSO, and other supplementary methods were also used. A sensitivity analysis was also performed. Simultaneously, the common risk factors for NAFLD were further analyzed for potential mediating associations. We observed that sedentary television viewing (odds ratio (OR): 1.84; 95% confidence interval (CI): 1.09-3.10; p = 0.021) and genetically predicted VPA duration (OR: 0.0033; 95% CI: 0.000015-0.70; p = 0.036) were suggestively associated with the risk of NAFLD. Using a computer (OR: 1.51; 95% CI: 0.47-4.81; p = 0.484), driving (OR: 0.78; 95% CI: 0.05-11.94; p = 0.858), and MVPA time (OR: 0.168; 95% CI: 0.01-2.81; p = 0.214) were not significantly associated with NAFLD. The role of heterogeneity versus pleiotropy was limited in all the analyses. This study supports the association between sedentary television watching and an increased risk of NAFLD, along with vigorous physical activity as a possible protective factor for NAFLD.

Association Between Educational Attainment and Thyroid Function: Results From Mendelian Randomization and the NHANES Study.

Many observational studies have reported on the association between educational attainment (EA) and thyroid function, but the causal relationship remains unclear. We aimed to obtain causal effects of EA on thyroid function and to quantify the mediating effects of modifiable risk factors. Two-sample mendelian randomization (MR) was performed by using summary statistics from large genome-wide association studies (GWAS) to assess the effect of EA on thyroid function, including hypothyroidism, hyperthyroidism, thyrotropin (TSH), and free thyroxine (FT4). A multivariable analysis was conducted to assess the mediating role of smoking and help to explain the association between EA and thyroid function. Similar analysis was further performed using data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2002. In MR analysis, EA was causally associated with TSH (β = .046; 95% CI, 0.015-0.077; P = 4.00 × 10-3), rather than hypothyroidism, hyperthyroidism, and FT4. Importantly, smoking could serve as a mediator in the association between EA and TSH, in which the mediating proportion was estimated to be 10.38%. After adjusting for smoking in the multivariable MR analysis, the β value of EA on TSH was attenuated to 0.030 (95% CI, 0.016-0.045; P = 9.32 × 10-3). Multivariable logistic regression model in NHANES suggested a dose-response relationship between TSH (quartile [Q]4 vs Q1: odds ratio = 1.33; 95% CI, 1.05-1.68; P for trend = .023) and EA. Smoking, systolic blood pressure, and body mass index partially mediated the association between EA and TSH, with the proportion of the mediation effects being 43.82%, 12.28%, and 6.81%, respectively. There is a potentially causal association between EA and TSH, which could be mediated by several risk factors, such as smoking.

The relationship between the serum lipid profile and hepatocellular carcinoma in east Asian population: A mendelian randomization study

BackgroundAlthough several studies have found that the serum lipid profile may be correlated with hepatocellular carcinoma (HCC), the causal relationships between the serum lipid profile and HCC have not been determined due to potential confounder. Here, Mendelian randomization (MR) analysis was performed to identify the relationship between the serum lipid profile and HCC in the East Asian population. MethodOur study made a MR analysis with the validation of two data sets. We obtained genome-wide association study (GWAS) data related to the serum lipid profile from Asian Genetic Epidemiology Network (AGEN). Then, the data from a recent large GWAS of the East Asian ancestry in Japan (BioBank Japan, BBJ) were extracted. Summary-level statistical data for HCC were obtained from a large GWAS of the East Asian ancestry in Japan. Univariable MR analysis were performed to identify whether the genetic evidence of serum lipid profile was significantly associated with HCC risk. Multivariable MR analysis was conducted to estimate the independent effects of exposures on HCC. ResultsUnivariable and multivariable MR analyses indicated that the serum lipid profile was not a risk factor for HCC incidence in either data set based on the East Asian population. Multivariable MR analysis revealed that the hazard ratios of the probability of HCC in AGEN were 1.134 (95% confidence interval (CI), 0.903–1.424) for TG, 1.010 (95% CI: 0.824–1.237) for HDL-C, 0.974 (95% CI: 0.746–1.271) for TC, 0.918 (95% CI: 0.734–1.147) for LDL-C, while the results in BBJ were also non-significant: 1.111 (95% CI: 0.869–1.419) for TG, 0.957 (95% CI: 0.790–1.158) for HDL-C, 0.917 (95% CI: 0.643–1.308) for TC, 0.932 (95% CI: 0.699–1.243) for LDL-C. ConclusionOur MR study with the validation of two data sets found no strong evidence to support causal associations between the serum lipid profile and HCC risk.

Tumour necrosis factor receptor 1 inhibition and cardiovascular disease: a cis-Mendelian randomization study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute for Health and Care research (NIHR). Background Tumour necrosis factor receptor 1 (TNFR1) is a newly proposed drug target that has emerged from a growing understanding of the inflammatory basis of cardiovascular disease[1]. A range of pre-clinical models and observational data in humans support the potential efficacy of TNFR1 inhibition. However, pre-clinical models are poor predictors of therapeutic efficacy in humans and observational data is inherently vulnerable to confounding and reverse causation[2,3]. Mendelian randomization (MR) is a genetic epidemiological approach that overcome these limitations and are capable of robust causal inference[3], rendering them better able to investigate the potential efficacy of novel drug targets[2]. Purpose To leverage MR to investigate the causal effect of TNFR1 inhibition on the risk of developing coronary artery disease (CAD), ischaemic stroke (IS), atrial fibrillation (AF), and heart failure (HF) (see Figure 1). Methods cis-Mendelian randomization was performed to estimate the causal effect of TNFR1 inhibition (weighted by serum C-reactive protein (CRP) levels) on liability to coronary artery disease (CAD), ischaemic stroke (IS), atrial fibrillation (AF), and heart failure (HF). Anti-TNF therapies are a cornerstone treatment modality for Crohn’s disease and so Crohn’s was included as a positive control to validate the genetic instrument for TNFR1 inhibition. Furthermore, Bayesian colocalization (coloc) was performed to assess the likelihood that a shared causal variant underlies both TNFR1 signalling and each of these four cardiovascular diseases, thus allowing for interrogation of the risk of confounding by linkage disequilibrium in MR estimates[4]. Genetic association estimates were leveraged from the largest genome-wide association studies (GWAS) for which full publicly available summary data were available. Results As expected, a significant cis-MR effect for genetically proxied TNFR1 inhibition was observed for Crohn’s disease (odds ratio (OR) per 1 standard deviation (SD) reduction in CRP = 0.05, 95% CI = 0.01 to 0.28, P = 5.32 x 10-4). However, no evidence of a causal association was observed between genetically proxied TNFR1 inhibition and the odds of developing CAD (OR per SD reduction in CRP = 0.99, 95% CI = 0.55 to 1.76), IS (OR per SD reduction in CRP = 1.55, 95% CI = 0.30 to 8.03), AF (OR per SD reduction in CRP = 1.11, 95% CI = 0.54 to 2.29), or HF (OR per SD reduction in CRP = 1.02, 95% CI = 0.46 to 2.29) (see Figure 2). No evidence of colocalization was observed between TNFR1 signalling and any of these four cardiovascular diseases. Conclusions These findings do not support TNFR1 signalling inhibition as likely to be an efficacious therapeutic target for coronary artery disease, ischaemic stroke, atrial fibrillation, or heart failure.

Causal relationships between autoimmune diseases and celiac disease: A Mendelian randomization analysis

ABSTRACT The aim of this study was to investigate the causal relationship between autoimmune disorders and celiac disease (CeD) through Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) significantly associated with 13 autoimmune diseases were extracted from the summary statistics of European genome-wide association studies (GWAS), and their effects were examined by Inverse variance-weighted (IVW) in a large European GWAS on CeD. Finally, reverse MR was performed to investigate the causal effects of CeD on autoimmune traits. Following the application of Bonferroni correction for multiple testing, genetically determined seven autoimmune diseases are causally associated with CeD: Crohn’s disease (CD) (OR [95%CI] = 1.156 [1.106 ± 1.208], P = 1.27E–10), primary biliary cholangitis (PBC) (1.229 [1.143 ± 1.321], P = 2.53E–08), primary sclerosing cholangitis (PSC) (1.688 [1.466 ± 1.944], P = 3.56E–13), rheumatoid arthritis (RA) (1.231 [1.154 ± 1.313], P = 2.74E–10), systemic lupus erythematosus (SLE) (1.127 [1.081 ± 1.176], P = 2.59E–08), type 1 diabetes (T1D) (1.41 [1.238 ± 1.606], P = 2.24E–07), and asthma (1.414 [1.137 ± 1.758], P = 1.86E–03). The IVW analysis indicated that CeD increased the risk for seven diseases: CD (1.078 [1.044 ± 1.113], P = 3.71E–06), Graves’ disease (GD) (1.251 [1.127 ± 1.387], P = 2.34E–05), PSC (1.304 [1.227 ± 1.386], P = 8.56E–18), psoriasis (PsO) (1.12 [1.062 ± 1.182], P = 3.38E–05), SLE (1.301[1.22 ± 1.388], P = 1.25E–15), T1D (1.3[1.228 ± 1.376], P = 1.57E–19), and asthma (1.045 [1.024 ± 1.067], P = 1.82E–05). The sensitivity analyses deemed the results reliable without pleiotropy. There are positive genetic correlations between various autoimmune diseases and CeD, and the latter also affects the predisposition to multiple autoimmune disorders in the European population.