Causal Effects of Positive Affect, Life Satisfaction, Depressive Symptoms, and Neuroticism on Kidney Function: A Mendelian Randomization Study

2021 ◽  
pp. ASN.2020071086 ◽  
Author(s):  
Sehoon Park ◽  
Soojin Lee ◽  
Yaerim Kim ◽  
Yeonhee Lee ◽  
Min Woo Kang ◽  
...  
Keyword(s):  
Life Satisfaction ◽  
Depressive Symptoms ◽  
Confidence Interval ◽  
Positive Affect ◽  
Kidney Function ◽  
Mendelian Randomization ◽  
Causal Effects ◽  
European Ancestry ◽  
Uk Biobank ◽  
Lower Egfr

BackgroundFurther investigation of the causal effects of psychologic wellbeing on kidney function is warranted.MethodsIn this Mendelian randomization (MR) study, genetic instruments for positive affect, life satisfaction, depressive symptoms, and neuroticism were introduced from a previous genome-wide association study meta-analysis of European individuals. Summary-level MR was performed using the CKDGen data of European ancestry (n=567,460), and additional allele score–based MR was performed in the individual-level data of White British UK Biobank participants (n=321,024).ResultsIn summary-level MR with the CKDGen data, depressive symptoms were a significant causative factor for kidney function impairment (CKD OR, 1.45; 95% confidence interval, 1.07 to 1.96; eGFR change [%] beta −2.18; 95% confidence interval, −3.61 to −0.72) and pleiotropy-robust sensitivity analysis results supported the causal estimates. A genetic predisposition for positive affect was significantly associated with better kidney function (CKD OR, 0.69; 95% confidence interval, 0.52 to 0.91), eGFR change [%] beta 1.50; 95% confidence interval, 0.09 to 2.93) and sensitivity MR analysis results supported the finding for CKD outcome, but was nonsignificant for eGFR. Life satisfaction and neuroticism exposures showed nonsignificant causal estimates. In the UK Biobank with covariate-adjusted allele score MR analysis, allele scores for positive affect and life satisfaction were causally associated with reduced risk of CKD and higher eGFR. In contrast, neuroticism allele score was associated with increased risk of CKD and lower eGFR, and depressive symptoms allele score was associated with lower eGFR, but showed nonsignificant association with CKD.ConclusionsHealth care providers in the nephrology field should be aware of the causal linkage between psychologic wellbeing and kidney function.

scholarly journals Causal effects from non-alcoholic fatty liver disease on kidney function: A Mendelian randomization study

2021 ◽  
Author(s):  
Sehoon Park ◽  
Soojin Lee ◽  
Yaerim Kim ◽  
Semin Cho ◽  
Kwangsoo Kim ◽  
...  
Keyword(s):  
Liver Disease ◽  
Kidney Function ◽  
Fatty Liver Disease ◽  
Mendelian Randomization ◽  
Negative Control ◽  
Causal Effects ◽  
European Ancestry ◽  
Uk Biobank ◽  
Low Probability ◽  
The Uk

AbstractBackground & aimsAn observational association between nonalcoholic fatty liver disease (NAFLD) and kidney function impairment has been reported. A genetic variant linked to an increased risk of NAFLD, the G allele of rs738409, has been reported to be associated with a reduction in estimated glomerular filtration rate (eGFR).Approach & ResultsIn this Mendelian randomization (MR) study, we first performed single-variant MR with rs738409 as a genetic instrument to predict NAFLD. Another genetic instrument was developed from a previous genome-wide association study for the NAFLD phenotype in the Million Veteran Program cohort among individuals of European ancestry (68,725 cases and 95,472 controls). The eGFR outcome was assessed in individuals of white British ancestry included in the UK Biobank (N = 321,405). Further, the associations were reassessed in two negative control subgroups (body mass index < 25 kg/m2 and serum alanine aminotransferase level < 20 IU/mL) with a low probability of developing NAFLD. As a replication analysis, a summary-level MR was performed with the European ancestry CKDGen dataset (N = 567,460). In the UK Biobank dataset, a genetic predisposition for NAFLD, either by rs738409 or a group of variants, was significantly associated with a reduced eGFR even with adjustment for major metabolic disorders. Although the associations were not significant in the negative control subgroups with a low probability of developing NAFLD, they were significant in the subgroups with a remaining risk of NAFLD, suggesting the absence of a horizontal pleiotropic pathway. The summary-level MR from the CKDGen dataset supported the causal effects of NAFLD on reduced eGFR.ConclusionsThis MR analysis supports the causal reduction in kidney function by NAFLD.

scholarly journals Causal Effects of Homocysteine, Folate, and Cobalamin on Kidney Function: A Mendelian Randomization Study

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 906
Author(s):  
Sehoon Park ◽  
Soojin Lee ◽  
Yaerim Kim ◽  
Semin Cho ◽  
Kwangsoo Kim ◽  
...  
Keyword(s):  
Kidney Function ◽  
Estimated Glomerular Filtration Rate ◽  
Mendelian Randomization ◽  
Homocysteine Level ◽  
Meta Analysis ◽  
Causal Effects ◽  
European Ancestry ◽  
Genome Wide ◽  
Function Impairment ◽  
Genetic Instruments

Blood homocysteine level and related vitamin levels are associated with various health outcomes. We aimed to assess causal effects of blood homocysteine, folate, and cobalamin on kidney function in the general population by performing Mendelian randomization (MR) analysis. Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association (GWAS) meta-analysis of European individuals. Summary-level MR analysis was performed for the estimated glomerular filtration rate (eGFR) from the CKDGen consortium GWAS that included 567,460 European ancestry individuals. For replication, allele-score-based MR was performed with an independent U.K. Biobank cohort of 337,138 individuals of white British ancestry. In summary-level MR for the CKDGen data, high genetically predicted homocysteine levels were significantly associated with low eGFR (per 1 standard deviation, beta for eGFR change −0.95 (−1.21, −0.69) %), supported by pleiotropy-robust MR sensitivity analysis. Genetically predicted high folate levels were significantly associated with high eGFR change (0.86 (0.30, 1.42) %); however, causal estimates from cobalamin were nonsignificant (−0.11 (−0.33, 0.11) %). In the U.K. Biobank data, the results were consistently identified. Therefore, a high blood homocysteine level causally decreases eGFR. Future trials with appropriate homocysteine-lowering interventions may be helpful for the primary prevention of kidney function impairment.

scholarly journals The association between lymphocyte mitochondrial DNA abundance and Stroke: a combination of multivariable-adjusted survival and mendelian randomization analyses

2021 ◽  
Author(s):  
Leon G Martens ◽  
JIAO LUO ◽  
Marieke J H Wermer ◽  
Ko Willems van Wijk ◽  
Sara Hagg ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Confidence Interval ◽  
Hemorrhagic Stroke ◽  
Mendelian Randomization ◽  
Hazard Ratio ◽  
European Ancestry ◽  
Proportional Hazard ◽  
Uk Biobank ◽  
Cox Proportional Hazard ◽  
Risk Of Disease

Background and Purpose: Mitochondrial dysfunction is associated with increased Reactive Oxygen Species that are thought to drive risk of disease, including stroke. We investigated the association between mtDNA abundance, as a proxy for mitochondrial function, and incident stroke using multivariable-adjusted survival and Mendelian Randomization (MR) analyses. Methods: Cox-proportional hazard model analyses were conducted to assess the association between lymphocyte mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-years follow-up in unrelated European-ancestry participants from UK Biobank. MR was conducted using independent (R2<0.001) lead variants for lymphocyte mtDNA abundance (p < 5x10-8) as instrumental variables. Single-Nucleotide Polymorphism (SNP)-ischemic stroke associations were derived from three published open source European-ancestry results databases (cases/controls): MEGASTROKE (60,341/454,450), UK Biobank (2,404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed. Results: A total of 288,572 unrelated participants (46% men) with mean (SD) age of 57 (8) years were included in the cox-proportional hazard analyses. After correction for considered confounders (BMI, hypertension, cholesterol, T2D), no association was found between mtDNA abundance and ischemic or hemorrhagic stroke (lowest 20% versus highest 20%: ischemic stroke, hazard ratio, 1.06 [95% confidence interval 0.95, 1.18]; hemorrhagic stroke, hazard ratio 0.97 [95% confidence interval, 0.82, 1.15]). In line, in the MR analyses, we found no evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.04; confidence interval, 0.95, 1.15).

scholarly journals Atrial fibrillation and kidney function: A bidirectional Mendelian randomization study

2020 ◽  
Author(s):  
Sehoon Park ◽  
Soojin Lee ◽  
Yaerim Kim ◽  
Yeonhee Lee ◽  
Min Woo Kang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Kidney Function ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Individual Level ◽  
Level Data ◽  
Lower Egfr

Aims: To investigate the causal effects between atrial fibrillation (AF) and kidney function. Methods and Results: We performed a bidirectional Mendelian randomization (MR) analysis implementing the results from large-scale genome-wide association study (GWAS) for estimated glomerular filtration rate (eGFR) by the CKDGen (N = 1,046,070) and for AF (N = 588,190) to determine genetic instruments. A bidirectional two-sample MR based on summary-level data was performed. Inverse variance weighted method was the main MR method. For replication, an allele-score based MR was performed by individual-level data within the UK Biobank cohort of white British ancestry with eGFR values (N= 321,260). The genetical predisposition to AF was significantly associated with lower eGFR [beta -0.002 (standard error 0.0005), P < 0.001] and higher risk of chronic kidney disease [beta 0.051 (0.012), P < 0.001], and the significance remained in various MR sensitivity analyses. The causal estimates were consistent when we limited the analysis to individuals of European ancestry. The genetically predicted eGFR did not show significant association with risk of AF [beta -0.189 (0.184), P = 0.305]. The results were similar in allele-score based MR, as allele-score for AF was significantly associated with lower eGFR [beta -0.069 (0.021), P < 0.001] but allele-score for eGFR did not show significant association with risk of AF [beta -0.001 (0.009), P = 0.907]. Conclusions: Our study supports that genetical predisposition to AF is a causal risk factor for kidney function impairment. However, effect from kidney function on AF was not identified in this study.

scholarly journals Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1940
Author(s):  
Karl Michaëlsson ◽  
Susanna C. Larsson
Keyword(s):  
Bone Mineral Density ◽  
Confidence Interval ◽  
Bone Mineral ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Alpha Tocopherol ◽  
European Ancestry ◽  
Mineral Density ◽  
Standard Deviation Increase ◽  
A Genome

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10−8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

scholarly journals MR-pheWAS with stratification and interaction: Searching for the causal effects of smoking heaviness identified an effect on facial aging

2018 ◽  
Author(s):  
Louise A C Millard ◽  
Marcus R Munafò ◽  
Kate Tilling ◽  
Robyn E Wootton ◽  
George Davey Smith
Keyword(s):  
Lung Function ◽  
Detrimental Effect ◽  
Genetic Variant ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Effects ◽  
Uk Biobank ◽  
Facial Aging ◽  
Heavy Smoking ◽  
Never Smokers

AbstractMendelian randomization (MR) is an established approach for estimating the causal effect of an environmental exposure on a downstream outcome. The gene x environment (GxE) study design can be used within an MR framework to determine whether MR estimates may be biased if the genetic instrument affects the outcome through pathways other than via the exposure of interest (known as horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and a recently published tool (PHESANT) means that it is now possible to do this comprehensively, across thousands of traits in UK Biobank. In this study, we introduce the GxE MR-pheWAS approach, and search for the causal effects of smoking heaviness – stratifying on smoking status (ever versus never) – as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. If this effect is entirely mediated by tobacco intake, we would expect to see an effect in ever smokers but not never smokers. We used PHESANT to search for the causal effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by: 1) strength of effect of rs16969968 among ever smokers, and 2) strength of interaction between ever and never smokers. We replicated previously established causal effects of smoking heaviness, including a detrimental effect on lung function and pulse rate. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify causal effects of an exposure, while simultaneously assessing the extent that results may be biased by horizontal pleiotropy.Author summaryMendelian randomization uses genetic variants associated with an exposure to investigate causality. For instance, a genetic variant that relates to how heavily a person smokes has been used to test whether smoking causally affects health outcomes. Mendelian randomization is biased if the genetic variant also affects the outcome via other pathways. We exploit additional information – that the effect of heavy smoking only occurs in people who actually smoke – to overcome this problem. By testing associations in ever and never smokers separately we can assess whether the genetic variant affects an outcome via smoking or another pathway. If the effect is entirely via smoking heaviness, we would expect to see an effect in ever but not never smokers, and this would suggest that smoking causally influences the outcome. Previous Mendelian randomization studies of smoking heaviness focused on specific outcomes – here we searched for the causal effects of smoking heaviness across over 18,000 traits. We identified previously established effects (e.g. a detrimental effect on lung function) and novel results including a detrimental effect of heavier smoking on facial aging. Our approach can be used to search for the causal effects of other exposures, where the exposure only occurs in known subsets of the population.

Circulating adiponectin levels and systemic lupus erythematosus: a two-sample Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Yi-Lin Dan ◽  
Peng Wang ◽  
Zhongle Cheng ◽  
Qian Wu ◽  
Xue-Rong Wang ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Effects ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inverse Variance ◽  
Weighted Median

Abstract Objectives Several studies have reported increased serum/plasma adiponectin levels in SLE patients. This study was performed to estimate the causal effects of circulating adiponectin levels on SLE. Methods We selected nine independent single-nucleotide polymorphisms that were associated with circulating adiponectin levels (P &lt; 5 × 10−8) as instrumental variables from a published genome-wide association study (GWAS) meta-analysis. The corresponding effects between instrumental variables and outcome (SLE) were obtained from an SLE GWAS analysis, including 7219 cases with 15 991 controls of European ancestry. Two-sample Mendelian randomization (MR) analyses with inverse-variance weighted, MR-Egger regression, weighted median and weight mode methods were used to evaluate the causal effects. Results The results of inverse-variance weighted methods showed no significantly causal associations of genetically predicted circulating adiponectin levels and the risk for SLE, with an odds ratio (OR) of 1.38 (95% CI 0.91, 1.35; P = 0.130). MR-Egger [OR 1.62 (95% CI 0.85, 1.54), P = 0.195], weighted median [OR 1.37 (95% CI 0.82, 1.35), P = 0.235) and weighted mode methods [OR 1.39 (95% CI 0.86, 1.38), P = 0.219] also supported no significant associations of circulating adiponectin levels and the risk for SLE. Furthermore, MR analyses in using SLE-associated single-nucleotide polymorphisms as an instrumental variable showed no associations of genetically predicted risk of SLE with circulating adiponectin levels. Conclusion Our study did not find evidence for a causal relationship between circulating adiponectin levels and the risk of SLE or of a causal effect of SLE on circulating adiponectin levels.

scholarly journals Genetic overlap and causal inferences between kidney function and cerebrovascular disease

Neurology ◽  
2020 ◽  
Vol 94 (24) ◽  
pp. e2581-e2591 ◽  
Author(s):  
Sandro Marini ◽  
Marios K. Georgakis ◽  
Jaeyoon Chung ◽  
Jonathan Q.A. Henry ◽  
Martin Dichgans ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Kidney Function ◽  
Mendelian Randomization ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
Large Artery ◽  
Disease Phenotypes ◽  
Vessel Disease ◽  
Genetic Overlap ◽  
Lower Egfr

ObjectiveLeveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes.MethodsWe used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]) and cerebrovascular disease phenotypes (ischemic stroke and its subtypes, intracerebral hemorrhage [ICH], and white matter hyperintensities [WMH] on brain MRI). We (1) tested the genetic overlap between them with polygenic risk scores (PRS), (2) searched for common pleiotropic loci with pairwise GWAS analyses, and (3) explored causal associations by employing 2-sample Mendelian randomization.ResultsA PRS for lower eGFR was associated with higher large artery stroke (LAS) risk (p = 1 × 10−4). Multiple pleiotropic loci were identified between kidney function traits and cerebrovascular disease phenotypes, with 12q24 associated with eGFR and both LAS and small vessel stroke (SVS), and 2q33 associated with UACR and both SVS and WMH. Mendelian randomization revealed associations of both lower eGFR (odds ratio [OR] per 1-log decrement, 2.10; 95% confidence interval [CI], 1.38–3.21) and higher UACR (OR per 1-log increment, 2.35; 95% CI, 1.12–4.94) with a higher risk of LAS, as well as between higher UACR and higher risk of ICH.ConclusionsImpaired kidney function, as assessed by decreased eGFR and increased UACR, may be causally involved in the pathogenesis of LAS. Increased UACR, previously proposed as a marker of systemic small vessel disease, is involved in ICH risk and shares a genetic risk factor at 2q33 with manifestations of cerebral small vessel disease.

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