Causal effects of education on chronic kidney disease: a Mendelian randomization study

Abstract Background Poor socio-economic status, including low education attainment, has been reported in chronic kidney disease (CKD) patients. We aimed to investigate the causal effects of education attainment on the risk of CKD. Methods The study was an observational cohort study including Mendelian randomization (MR) analysis. First, the clinical association between education attainment years as the exposure and prevalent CKD Stages 3–5 as the outcome was investigated by multivariable logistic regression in 308 741 individuals 40–69 years of age from the UK Biobank. MR analysis was performed with a previously reported genetic instrument from a genome-wide association meta-analysis of education attainment. Two-sample MR was performed with summary statistics for CKD in 567 460 individuals with European ancestry in the CKDGen genome-wide association meta-analysis. The findings were replicated by allele score–based MR in 321 260 individuals of white British ancestry in the UK Biobank with quality-controlled genetic data. Results Higher education attainment was significantly associated with lower adjusted odds for CKD in the clinical analysis {>17 years versus <16 years, adjusted odds ratio [OR] 0.910 [95% confidence interval (CI) 0.849–0.975]}. The causal estimates obtained by the inverse variance method in the two-sample MR indicated that higher genetically predicted education attainment causally reduced the risk of CKD [OR 0.934 (95% CI 0.873–0.999)]. Allele score–based MR also supported that higher education attainment was causally linked to a decreased risk of CKD [adjusted OR 0.944 (95% CI 0.922–0.966)]. Conclusion The study suggests that higher education attainment causally reduces the risk of CKD development in the general population.

Download Full-text

Circulating galectin-3 levels are not associated with non-alcoholic fatty liver disease: A Mendelian randomization study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab144 ◽

2021 ◽

Author(s):

Maxime Tremblay ◽

Nicolas Perrot ◽

Nooshin Ghodsian ◽

Émilie Gobeil ◽

Christian Couture ◽

...

Keyword(s):

Mendelian Randomization ◽

Meta Analysis ◽

Human Diseases ◽

Genome Wide Association ◽

Causal Association ◽

Uk Biobank ◽

Alcoholic Fatty Liver ◽

Genome Wide ◽

Galectin 3 ◽

The Uk

Abstract Context The impact of galectin-3 inhibitors on non-alcoholic fatty liver diseases (NAFLD)-related outcomes is currently under investigation in randomized clinical trials. Whether there is a causal association between plasma galectin-3 levels and NAFLD is unknown. Objective To evaluate the causal effect of circulating galectin-3 levels on NAFLD as well as >800 other human diseases. Design Inverse variance weighted Mendelian randomization (IVW-MR) and phenome-wide MR. Setting Summary statistics of genome-wide association studies. Patients Participants of the UK Biobank, eMERGE, FinnGen, PREVEND and IMPROVE cohorts. Intervention Identification of independent single-nucleotide polymorphisms (SNPs) associated with galectin-3 levels (p<5x10 -8) in the PREVEND (14 SNPs) and IMPROVE (3 SNPs) cohorts. Main outcome measures: Presence of NAFLD in a meta-analysis of genome-wide association study of the eMERGE, UK Biobank and FinnGen cohorts (3042 NAFLD cases and 504,853 controls), as well as >800 other human diseases in the UK Biobank and FinnGen. Results Using IVW-MR, we found no causal association between galectin-3 levels and NAFLD in the meta-analysis of the 3 cohorts or in each individual cohort. After correction for multiple testing, we found no causal association between galectin-3 levels and >800 human disease-related traits. Conclusions This MR study revealed no causal associations between circulating galectin-3 levels and NAFLD or any other disease traits, suggesting that plasma galectin-3 levels may not be directly implicated in the pathogenesis of NAFLD or other human diseases.

Download Full-text

Education Attainment, Intelligence and COVID-19: A Mendelian Randomization Study

Journal of Clinical Medicine ◽

10.3390/jcm10214870 ◽

2021 ◽

Vol 10 (21) ◽

pp. 4870

Author(s):

Gloria Hoi-Yee Li ◽

Stanley Kam-Ki Lam ◽

Ian Chi-Kei Wong ◽

Jody Kwok-Pui Chu ◽

Ching-Lung Cheung

Keyword(s):

Higher Education ◽

Mendelian Randomization ◽

Meta Analysis ◽

Multivariable Analysis ◽

Education Attainment ◽

Genome Wide ◽

Higher Education Attainment ◽

Lower Education ◽

Genetically Determined ◽

Reduced Risk

Background: Evidence of socioeconomic inequality in COVID-19-related outcomes is emerging, with a higher risk of infection and mortality observed among individuals with lower education attainment. We aimed to evaluate the potential interventions against COVID-19 from the socioeconomic perspective, including improvement in education and intelligence. Methods: With a two-sample Mendelian randomization approach using summary statistics from the largest genome-wide association meta-analysis, univariable analysis was adopted to evaluate the total causal effects of genetically determined education attainment and intelligence on COVID-19 outcomes. Multivariable analysis was performed to dissect the potential mechanisms. Results: Genetic predisposition to higher education attainment by 1 SD (4.2 years) was independently associated with reduced risk of COVID-19 severity (OR = 0.508 [95% CI: 0.417–0.617]; p < 0.001). Genetically higher education attainment also lowered the risk of COVID-19 hospitalization (0.685 [0.593–0.791]; p < 0.001), but the association was attenuated after adjustment for beta estimates of intelligence in multivariable analysis. Genetically higher intelligence was associated with reduced risk of COVID-19 hospitalization (0.780 [0.655–0.930]; p = 0.006), with attenuation of association after adjustment for education attainment. Null association was observed for genetically determined education attainment and intelligence with SARS-CoV-2 infection. Conclusion: Education may act independently and jointly with intelligence in improving the COVID-19 outcomes. Improving education may potentially alleviate the COVID-19-related health inequality.

Download Full-text

Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003148 ◽

2021 ◽

Author(s):

Mengyao Yu ◽

Sergiy Kyryachenko ◽

Stephanie Debette ◽

Philippe Amouyel ◽

Jean-Jacques Schott ◽

...

Keyword(s):

Mitral Valve ◽

Association Study ◽

Genome Wide Association Study ◽

Cardiac Development ◽

Meta Analysis ◽

Genome Wide Association ◽

Uk Biobank ◽

Additional Risk ◽

Genome Wide ◽

The Uk

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

Download Full-text

A genome-wide association study identifies that the GDF5 and COL27A1 genes are associated with knee pain in UK Biobank (N = 171, 516)

10.1101/525147 ◽

2019 ◽

Author(s):

Weihua Meng ◽

Mark J Adams ◽

Colin NA Palmer ◽

Jingchunzi Shi ◽

Adam Auton ◽

...

Keyword(s):

Knee Pain ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Uk Biobank ◽

Narrow Sense ◽

Narrow Sense Heritability ◽

Genome Wide ◽

A Genome ◽

The Uk

SUMMARYObjectiveKnee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo).MethodsWe performed a genome-wide association study of knee pain in the UK Biobank, where knee pain was ascertained through self-report and defined as “knee pain in the last month interfering with usual activities”. A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 × 10−8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of knee pain using Genome-wide Complex Trait Analysis (GCTA).ResultsWe identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 × 10−12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 × 10−8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 × 10−18; rs2808772: P −11 = 2.56 × 10−1’). The narrow sense heritability of knee pain was 0.08.ConclusionIn this first reported genome-wide association meta-analysis of knee pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with knee pain.

Download Full-text

Genome-wide association study of skin and soft tissue infection susceptibility

10.1101/2020.09.03.20187468 ◽

2020 ◽

Author(s):

Tormod Rogne ◽

Kristin V Liyanarachi ◽

Humaira Rasheed ◽

Laurent F Thomas ◽

Helene M Flatby ◽

...

Keyword(s):

Gene Expression ◽

Soft Tissue ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Genome Wide Association ◽

P Value ◽

Uk Biobank ◽

Genome Wide ◽

Monocytes And Macrophages ◽

The Uk

Background: Skin and soft tissue infections (SSTIs) are common worldwide, but little is known about the genetic susceptibility and the causal effect of cardiometabolic risk factors. We therefore conducted the first genome-wide association study (GWAS) of SSTIs, with downstream analyses including Mendelian randomization analyses. Methods: The GWAS was conducted using the UK Biobank as discovery cohort, with 6,107 cases and 399,239 controls, and the Trondelag Health Study (HUNT) as replication cohort with 1,657 cases and 67,522 controls. Cases and controls were those who had or had not been hospitalized with an SSTI diagnosis, respectively. Findings: One locus, lead single-nucleotide polymorphism rs3749748 in LINC01184/SLC12A2, was associated with SSTIs in the UK Biobank (odds ratio [OR] 1.19, p-value = 7.6e-16) and replicated in HUNT (OR 1.15, p-value = 6.3e-4). Meta-analysis confirmed the lead variant (OR 1.18, p-value = 4.4e-18), as well as suggested two additional loci close to genome-wide significance (rs2007361 in PSMA1, OR 0.91, p-value = 5.1e-8; and rs78625038 in GAN, OR 1.86, p-value = 5.9e-8). Gene-based association tests identified four genes linked to SSTIs: SLC12A2, PSMA1, GAN, and IL6R. The minor allele of rs3749748 reduced the gene expression of SLC12A2 primarily in monocytes and macrophages. Mendelian randomization analyses showed that increasing body mass index and lifetime smoking habits increased risk of SSTIs. Interpretation: LINC0118/SLC12A2 was robustly associated with SSTI incidence and may exert its effect through reduced gene expression in monocytes and macrophages. Reducing tobacco smoking, overweight and obesity in the population may reduce the incidence of SSTIs.

Download Full-text

Association Between Environmental Factors and Asthma Using Mendelian Randomization: Increased Effect of Body Mass Index on Adult-Onset Moderate-to-Severe Asthma Subtypes

Frontiers in Genetics ◽

10.3389/fgene.2021.639905 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tae-Woong Ha ◽

Hae-Un Jung ◽

Dong Jun Kim ◽

Eun Ju Baek ◽

Won Jun Lee ◽

...

Keyword(s):

Risk Factor ◽

Environmental Factors ◽

Severe Asthma ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effects ◽

Genome Wide Association ◽

Adult Onset ◽

Uk Biobank ◽

Genome Wide

Although asthma is one of the most common chronic diseases throughout all age groups, its etiology remains unknown, primarily due to its heterogeneous characteristics. We examined the causal effects of various environmental factors on asthma using Mendelian randomization and determined whether the susceptibility to asthma due to the causal effect of a risk factor differs between asthma subtypes, based on age of onset, severity of asthma, and sex. We performed Mendelian randomization analyses (inverse variance weighted, weighted median, and generalized summary-data-based Mendelian randomization) using UK Biobank data to estimate the causal effects of 69 environmental factors on asthma. Additional sensitivity analyses (MR-Egger regression, Cochran’s Q test, clumping, and reverse Mendelian randomization) were performed to ensure minimal or no pleiotropy. For confirmation, two-sample setting analyses were replicated using BMI SNPs that had been reported by a meta-genome-wide association study in Japanese and European (GIANT) populations and a genome-wide association study in control individuals from the UK Biobank. We found that BMI causally affects the development of asthma and that the adult-onset moderate-to-severe asthma subtype is the most susceptible to causal inference by BMI. Further, it is likely that the female subtype is more susceptible to BMI than males among adult asthma cases. Our findings provide evidence that obesity is a considerable risk factor in asthma patients, particularly in adult-onset moderate-to-severe asthma cases, and that weight loss is beneficial for reducing the burden of asthma.

Download Full-text

Summary statistics knockoff inference empowers identification of putative causal variants in genome-wide association studies

10.1101/2021.12.06.471440 ◽

2021 ◽

Author(s):

Zihuai He ◽

Linxi Liu ◽

Michael E. Belloy ◽

Yann Le Guen ◽

Aaron Sossin ◽

...

Keyword(s):

Genome Sequencing ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Superior Performance ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Causal Variants ◽

The Uk

AbstractRecent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based method, GhostKnockoff, for genome-wide association studies (GWAS) that leads to improved power and ability to prioritize putative causal variants relative to conventional GWAS approaches. The method requires only Z-scores from conventional GWAS and hence can be easily applied to enhance existing and future studies. The method can also be applied to meta-analysis of multiple GWAS allowing for arbitrary sample overlap. We demonstrate its performance using empirical simulations and two applications: (1) analysis of 1,403 binary phenotypes from the UK Biobank data in 408,961 samples of European ancestry, and (2) a meta-analysis for Alzheimer’s disease (AD) comprising nine overlapping large-scale GWAS, whole-exome and whole-genome sequencing studies. The UK Biobank analysis demonstrates superior performance of the proposed method compared to conventional GWAS in both statistical power (2.05-fold more discoveries) and localization of putative causal variants at each locus (46% less proxy variants due to linkage disequilibrium). The AD meta-analysis identified 55 risk loci (including 31 new loci) with ~70% of the proximal genes at these loci showing suggestive signal in downstream single-cell transcriptomic analyses. Our results demonstrate that GhostKnockoff can identify putatively functional variants with weaker statistical effects that are missed by conventional association tests.

Download Full-text

Serum calcium and 25-hydroxyvitamin D in relation to longevity, cardiovascular disease and cancer: a Mendelian randomization study

npj Genomic Medicine ◽

10.1038/s41525-021-00250-4 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Shuai Yuan ◽

John A. Baron ◽

Karl Michaëlsson ◽

Susanna C. Larsson

Keyword(s):

Cardiovascular Disease ◽

Serum Calcium ◽

Odds Ratio ◽

Mendelian Randomization ◽

Genome Wide Association ◽

Uk Biobank ◽

Hydroxyvitamin D ◽

Genome Wide ◽

25 Hydroxyvitamin D ◽

The Uk

AbstractAssociations of serum calcium (S-Ca) and 25-hydroxyvitamin D (S-25(OH)D) concentrations with longevity, cardiovascular disease, and cancer are not clear. We conducted a Mendelian randomization study to examine the associations of S-Ca and S-25(OH)D with longevity and risk of cardiovascular disease and cancer. The primary genetic instruments for S-Ca and S-25(OH)D were obtained from genome-wide association meta-analyses that included 61,054 individuals for S-Ca and up to 79,366 individuals for S-25(OH)D. Genetic variants associated with S-Ca and S-25(OH)D in the UK Biobank were used as confirmatory instruments. We obtained summary-level data for associations of these instruments with individual survival later than the 90th versus at most the 60th percentile of expected age at death from a genome-wide association meta-analysis including 11,262 cases and 25,483 controls, and with parental longevity (both parents in top 10% percentile) from the UK Biobank including 7,182 cases and 79,767 controls. Data for cardiovascular disease (111,108 cases and 107,684 controls) and cancer (38,036 cases and 180,756 controls) were obtained from the FinnGen consortium. A one standard deviation increase in genetically-predicted S-Ca concentration was associated with lower odds of longevity (odds ratio, 0.72; 95% CI, 0.55-0.95) and increased risk of cardiovascular disease (odds ratio, 1.11; 95% CI, 1.03-1.20). The associations were consistent in confirmatory analyses. There was no evidence supporting an association between genetically-predicted S-Ca and cancer, and no associations of genetically-predicted S-25(OH)D with the studied outcomes. Lifelong higher levels of S-Ca but not S-25(OH)D may shorten life expectancy and increase the risk of cardiovascular disease.

Download Full-text

Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02494-4 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Maria Bruzelius ◽

Susanna C. Larsson

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

Download Full-text

Reproducibility in the UK Biobank of Genome-Wide Significant Signals Discovered in Earlier Genome-wide Association Studies

10.1101/2020.06.24.20139576 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jack W. O’Sullivan ◽

John P. A. Ioannidis

Keyword(s):

Effect Size ◽

Association Studies ◽

Genome Wide Association ◽

P Value ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Single Nucleotide ◽

Genome Wide ◽

The Uk ◽

Open Question

AbstractWith the establishment of large biobanks, discovery of single nucleotide polymorphism (SNPs) that are associated with various phenotypes has been accelerated. An open question is whether SNPs identified with genome-wide significance in earlier genome-wide association studies (GWAS) are replicated also in later GWAS conducted in biobanks. To address this question, the authors examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, “discovery” GWAS and a later, replication GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNPs (of which 6,289 had reached p<5e-8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0% and it was lower for binary than for quantitative phenotypes (58.1% versus 94.8% respectively). There was a18.0% decrease in SNP effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNP effect size, phenotype trait (binary or quantitative), and discovery p-value, we built and validated a model that predicted SNP replication with area under the Receiver Operator Curve = 0.90. While non-replication may often reflect lack of power rather than genuine false-positive findings, these results provide insights about which discovered associations are likely to be seen again across subsequent GWAS.

Download Full-text