Directionality of Effects from Thyroid to Kidney Function Is Supported by a Mendelian Randomization Study

Abstract Observational studies showed an inverse association between birth weight and chronic kidney disease (CKD) in adulthood existed. However, whether such an association is causal remains fully elusive. Moreover, none of prior studies distinguished the direct fetal effect from the indirect maternal effect. Herein, we aimed to investigate the causal relationship between birth weight and CKD and to understand the relative fetal and maternal contributions. Meta-analysis (n = ~22 million) showed that low birth weight led to ~83% (95% confidence interval [CI] 37–146%) higher risk of CKD in late life. With summary statistics from large scale GWASs (n = ~300 000 for birth weight and ~481 000 for CKD), linkage disequilibrium score regression demonstrated birth weight had a negative maternal, but not fetal, genetic correlation with CKD and several other kidney-function related phenotypes. Furthermore, with multiple instruments of birth weight, Mendelian randomization showed there existed a negative fetal casual association (OR = 1.10, 95% CI 1.01–1.16) between birth weight and CKD; a negative but non-significant maternal casual association (OR = 1.09, 95% CI 0.98–1.21) was also identified. Those associations were robust against various sensitivity analyses. However, no maternal/fetal casual effects of birth weight were significant for other kidney-function related phenotypes. Overall, our study confirmed the inverse association between birth weight and CKD observed in prior studies, and further revealed the shared maternal genetic foundation between low birth weight and CKD, and the direct fetal and indirect maternal causal effects of birth weight may commonly drive this negative relationship.

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Genetic overlap and causal inferences between kidney function and cerebrovascular disease

Neurology ◽

10.1212/wnl.0000000000009642 ◽

2020 ◽

Vol 94 (24) ◽

pp. e2581-e2591 ◽

Cited By ~ 1

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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Coffee Consumption and Kidney Function: A Mendelian Randomization Study

American Journal of Kidney Diseases ◽

10.1053/j.ajkd.2019.08.025 ◽

2020 ◽

Vol 75 (5) ◽

pp. 753-761 ◽

Cited By ~ 6

Author(s):

Oliver J. Kennedy ◽

Nicola Pirastu ◽

Robin Poole ◽

Jonathan A. Fallowfield ◽

Peter C. Hayes ◽

...

Keyword(s):

Kidney Function ◽

Mendelian Randomization ◽

Coffee Consumption

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Assessing the relationship between high-sensitivity C-reactive protein and kidney function employing mendelian randomization in a Japanese community based J-MICC Study

Journal of Epidemiology ◽

10.2188/jea.je20200540 ◽

2021 ◽

Author(s):

Ryosuke Fujii ◽

Asahi Hishida ◽

Takeshi Nishiyama ◽

Masahiro Nakatochi ◽

Keitaro Matsuo ◽

...

Keyword(s):

Kidney Function ◽

Mendelian Randomization ◽

High Sensitivity ◽

C Reactive Protein ◽

Community Based ◽

Reactive Protein ◽

The Relationship

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Arterial Stiffness and Kidney Function: A Mendelian Randomization Study

SSRN Electronic Journal ◽

10.2139/ssrn.3463276 ◽

2019 ◽

Author(s):

Ting-Ting Geng ◽

Marianne Ravn Knop ◽

Tao Huang

Keyword(s):

Arterial Stiffness ◽

Kidney Function ◽

Mendelian Randomization

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Abstract 028: Biomarkers Of Kidney Function And Cognitive Ability: A Mendelian Randomization Study

Circulation ◽

10.1161/circ.143.suppl_1.028 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Erin Richard ◽

Linda McEvoy ◽

Steven Cao ◽

Andrea Z Lacroix ◽

Rany Salem

Keyword(s):

Uric Acid ◽

Glomerular Filtration Rate ◽

Reaction Time ◽

Cognitive Function ◽

Cognitive Performance ◽

Kidney Function ◽

Filtration Rate ◽

Estimated Glomerular Filtration Rate ◽

Mendelian Randomization ◽

Numeric Reasoning

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 357,590 participants from the UK Biobank. Polygenic scores for serum uric acid (SUA), urine albumin to creatinine ratio (ACR), estimated glomerular filtration rate based on serum creatinine (eGFRcre) and serum cystatin-c (eGFRcys) were used as instruments, and cognitive function outcomes included a test of verbal-numeric reasoning and reaction time. Sensitivity analyses were carried out to address potential pleiotropy using MR-Egger and weighted median regression. Results: We found no evidence of a causal effect of genetically determined SUA, eGFRcre or eGFRcys on either cognitive function outcomes. There was no association between a polygenic score for ACR and verbal-numeric reasoning. However, there was suggestive evidence of a relationship between genetically increased ACR and slower reaction time (β (95% confidence interval [CI])) for 1 standard deviation log ACR = 4.93 (1.60 to 8.26), p=0.004). 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 lower processing speed, but results need confirmation in independent samples.

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

Journal of the American Society of Nephrology ◽

10.1681/asn.2020071086 ◽

2021 ◽

pp. ASN.2020071086 ◽

Cited By ~ 1

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.

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

Nutrients ◽

10.3390/nu13030906 ◽

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.

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