Dataset Information

Biomarkers of kidney function and cognitive ability: A Mendelian randomization study.

ABSTRACT:

Background

Estimated glomerular filtration rate (eGFR), albuminuria and serum uric acid (SUA) are markers of kidney function that have been associated with cognitive ability. However, whether these associations are causal is unclear.

Methods

We performed one-sample Mendelian randomization (MR) to estimate the effects of kidney function markers on cognitive performance using data from the UK Biobank. Polygenic scores for SUA, urine albumin to creatinine ratio (ACR), estimated glomerular filtration rate based on serum creatinine (eGFRcre) and serum cystatin C (eGFRcys) were used as instrumental variables, and cognitive function outcomes included tests of verbal-numeric reasoning, reaction time, visual memory, and numeric memory.

Results

We found no evidence of a causal effect of genetically determined SUA, eGFRcre or eGFRcys on cognitive function outcomes. There was no association between a polygenic score for ACR and verbal-numeric reasoning or numeric memory. However, there was suggestive evidence of a relationship between genetically increased ACR and slower reaction time and worse visual memory. ACR was no longer significantly associated with visual memory in analyses using an unweighted polygenic score and in analyses stratified by sex and age category. Pleiotropy adjusted estimates were directionally consistent with those of the principal analysis but overlapped with the null.

Conclusions

This MR study does not support causal effects of SUA, eGFRcre or eGFRcys on cognitive performance. Genetically increased ACR was associated with slower processing speed and visual memory, but results need confirmation in independent samples.

SUBMITTER: Richard EL

PROVIDER: S-EPMC8635776 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Biomarkers of kidney function and cognitive ability: A Mendelian randomization study.

Richard Erin L EL McEvoy Linda K LK Cao Steven Y SY Oren Eyal E Alcaraz John E JE LaCroix Andrea Z AZ Salem Rany M RM

Journal of the neurological sciences 20210914

<h4>Background</h4>Estimated glomerular filtration rate (eGFR), albuminuria and serum uric acid (SUA) are markers of kidney function that have been associated with cognitive ability. However, whether these associations are causal is unclear.<h4>Methods</h4>We performed one-sample Mendelian randomization (MR) to estimate the effects of kidney function markers on cognitive performance using data from the UK Biobank. Polygenic scores for SUA, urine albumin to creatinine ratio (ACR), estimated glome ...[more]

PMID: 34534883

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Project description:Background: Uncertainty in the mechanism and directionality of observational associations between thyroid function and kidney function may be addressed by genetic analysis with an instrumental variable method termed bidirectional Mendelian randomization (MR). Methods: In the Women's Genome Health Study (WGHS), observational associations between thyroid measures and kidney function were evaluated. Genetic instruments for MR were from recent genome-wide association studies (GWAS) of hypothyroidism, thyrotropin (TSH), and free thyroxine (fT4) concentrations within the reference range, thyroid peroxidase antibodies (TPOAb), estimated glomerular filtration rate from creatinine (eGFRcrea), eGFR from cystatin C (eGFRcys), and chronic kidney disease (CKD). In WGHS individual-level data, these instruments were used for bidirectional MR between thyroid (N = 3336) and kidney (N = 23,186) functions. To increase power, MR was also performed using GWAS summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) for eGFRcrea (N = 567,460), eGFRcys (N = 24,063), CKD [N(total) = 480,698, N(cases) = 41,395], and urinary albumin/creatinine ratio (UACR/N = 54,450). Results: In the WGHS, hypothyroidism was observationally associated with decreased eGFRcrea [beta (standard error, SE): -0.024 (0.009) ln(mL/min/1.73 m2), p = 0.01]. By MR, hypothyroidism was associated with decreased eGFRcrea in the WGHS [beta (SE): -0.007 (0.002) per doubled odds hypothyroidism, p = 1.7 × 10-3] and in CKDGen [beta (SE): -0.004 (0.0005), p = 2.0 × 10-22], and robust to sensitivity analysis. Hypothyroidism was also associated by MR with increased CKD in CKDGen (odds ratio, OR [confidence interval, CI]: 1.05 [1.03-1.08], p = 3.3 × 10-5), but not in the WGHS (OR [CI]: 1.02 [0.95-1.10], p = 0.57). Increased TSH within the reference range had an MR association with increased eGFRcrea in the WGHS [beta (SE): -0.018 (0.007) ln(mL/min/1.73 m2)/standard deviation, SD, p = 6.5 × 10-3] and CKDGen [beta (SE): -0.008 (0.001) ln(mL/min/1.73 m2)/SD, p = 6.8 × 10-17], and with CKD in CKDGen (OR [CI]: 1.10 [1.04-1.15], p = 3.1 × 10-4). There were no MR associations of hypothyroidism or TSH with eGFRcys or UACR, and MR associations of fT4 in the reference range with kidney function were inconsistent in both the WGHS and CKDGen. However, by MR in CKDGen, TPOAb were robustly associated with decreased eGFRcrea [beta (SE): -0.041 (0.009), p = 6.2 × 10-6] and decreased eGFRcys [beta (SE): -0.294 (0.065), p = 6.2 × 10-6]. TPOAb were less robustly associated with CKD but not associated with UACR. In reverse MR in the WGHS, kidney function was not consistently associated with thyroid function. Conclusions: Bidirectional MR supports a directional association from hypothyroidism, increased TSH, and TPOAb, but not fT4, to decreased eGFRcrea and increased CKD.

Project description:BackgroundMany observational epidemiology studies discovered that kidney cancer and impaired kidney function have a bidirectional relationship. However, it remains unclear whether these two kinds of traits are causally linked. In this study, we aimed to investigate the bidirectional causal relation between kidney cancer and kidney function biomarkers (creatinine-based estimated glomerular filtration rate (eGFRcrea), cystatin C-based estimated glomerular filtration rate (eGFRcys), blood urea nitrogen (BUN), serum urate, and urinary albumin-to-creatinine ratio (UACR)).MethodsFor both directions, single-nucleotide polymorphisms (SNPs), as genetic instruments, for the five kidney function traits were selected from up to 1,004,040 individuals, and SNPs for kidney cancer were from 408,786 participants(1338 cases). In the main analysis, we applied two state-of-the-art MR methods, namely, contamination mixture and Robust Adjusted Profile Score to downweight the effect of weak instrument bias, pleiotropy, and extreme outliers. We additionally conducted traditional MR analyses as sensitivity analyses. Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Kaiser Permanente.ResultsBased on 99 SNPs, we found that the eGFRcrea had a significant negative causal effect on the risk of kidney cancer (OR = 0.007, 95% CI:2.6 × 10-4 -0.569, p = 0.041). After adjusting for body composition or diabetes, urate had a significant negative causal effect on kidney cancer (OR <1, p < 0.05). For UACR, it showed a strong causal effect on kidney cancer, after adjusting for body composition (OR = 14.503, 95% CI: 2.546-96.001, p = 0.032). Due to lacking significant signals and effect power for the reverse MR, further investigations are warranted.ConclusionsOur study suggested a potential causal effect of damaged kidney function on kidney cancer. EGFRcrea and UACR might be causally associated with kidney cancer, especially when patients were comorbid with obesity or diabetes. We called for larger sample-size studies to further unravel the underlying causal relationship and the exact mechanism.

Project description:ObjectivesExtensive researches highlight the detrimental impact of sleep disorders such as insomnia and insufficient sleep duration on kidney function. However, establishing a clear causal relationship between insomnia, sleep duration, and kidney function remains challenging. This study aims to estimate this relationship using Mendelian randomization (MR).MethodsIndependent genetic variants strongly associated with insomnia (N = 462,341) and sleep duration (N = 460,099) were selected as instrumental variables from corresponding genome-wide association studies (GWAS). Kidney function parameters, including serum creatinine, estimated glomerular filtration rate by cystatin C (eGFRcys), acute renal failure (ARF), chronic renal failure (CRF), kidney injury molecule-1, neutrophil gelatinase associated lipocalin, microalbuminuria, cystatin C, and β2 microglobulin, were derived from GWAS databases. A two-sample MR study was conducted to assess the causal relationship between sleep disorders and kidney function, and multivariable MR was used to identify potential mediators. The inverse-variance weighted was used as the primary estimate.ResultsMR analysis found robust evidence indicating that insomnia and short sleep duration were associated with an increased risk of elevated serum creatinine, regardless of adjusting for obesity. Causal links between sleep duration and eGFRcys or cystatin C were also identified. While genetically predicted insomnia and sleep duration were found to potentially impact ARF, CRF, microalbuminuria, and β2 microglobulin, the p-values in multivariable MR analysis became nonsignificant. No pleiotropy was detected.ConclusionsThis study demonstrates a causal impact of insomnia on the risk of elevated serum creatinine and a positive effect of sleep duration on serum creatinine, eGFRcys, and cystatin C. Our findings also suggest their potential indirect effects on ARF, CRF, microalbuminuria, and β2 microglobulin mediated by obesity.

Project description:BackgroundObesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD).MethodsUsing summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses.ResultsOne standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR], P = 1 × 10-43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10-6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04-1.28], P = 0.009] and CKD [1.13 (1.07-1.19), P = 3 × 10-6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR.ConclusionsGenetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.

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Dataset Information

Biomarkers of kidney function and cognitive ability: A Mendelian randomization study.

Background

Methods

Results

Conclusions

Publications

Biomarkers of kidney function and cognitive ability: A Mendelian randomization study.

Similar Datasets

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