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Background and Aim: The causal linkage between primary sclerosing cholangitis (PSC) and kidney function is unexplored despite their potential for long‐term detrimental effects on kidney function. Methods: Two‐sample summary‐level Mendelian randomization (MR) study was conducted to identify the association between PSC and kidney function. The genetic variants were extracted from the PSC‐specific multi‐trait analyzed genome‐wide association study (GWAS) of European ancestry. Summary‐level data for kidney function traits, including estimated glomerular filtration rate (eGFR), annual eGFR decline, and chronic kidney disease (CKD), were obtained from the CKDGen consortium. Multiplicative random‐effects inverse‐variance weighted (MR‐IVW), and a series of pleiotropy‐robust analyses were performed to investigate the causal effects and ascertain their robustness. Results: Significant causal associations between genetically predicted PSC and kidney function traits were identified. Genetically predicted PSC was associated with decreased log‐transformed eGFR (MR‐IVW; beta = −0.41%; standard error [SE] = 0.02%; P < 0.001), increased rate of annual eGFR decline (MR‐IVW; beta = 2.43%; SE = 0.18%; P < 0.001), and higher risk of CKD (MR‐IVW; odds ratio = 1.07; 95% confidence interval = 1.06–1.08; P < 0.001). The main findings were supported by pleiotropy‐robust analysis, including MR‐Egger with bootstrapped error and weighted median. Conclusions: Our study demonstrates that genetically predicted PSC is causally associated with kidney function impairment. Further studies are warranted to identify the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Interleukins (ILs), key cytokine family of inflammatory response, are closely associated with kidney function. However, the causal effect of various ILs on kidney function needs further investigation. Here we show two-sample summary-level Mendelian randomization (MR) analysis that examined the causality between serum IL levels and kidney function. Genetic variants with strong association with serum IL levels were obtained from a previous genome-wide association study meta-analysis. Summary-level data for estimated glomerular filtration rate (eGFR) were obtained from CKDGen database. As a main MR analysis, multiplicative random-effects inverse-variance weighted method was performed. Pleiotropy-robust MR analysis, including MR-Egger with bootstrapped error and weighted median methods, were also implemented. We tested the causal estimates from nine ILs on eGFR traits. Among the results, higher genetically predicted serum IL-1 receptor antagonist level was significantly associated with higher eGFR values in the meta-analysis of CKDGen and the UK Biobank data. In addition, the result was consistent towards eGFR decline phenotype of the outcome database. Otherwise, nonsignificant association was identified between other genetically predicted ILs and eGFR outcome. These findings support the clinical importance of IL-1 receptor antagonist-associated pathway in relation to kidney function in the general individuals, particularly highlighting the importance of IL-1 receptor antagonist. Mendelian randomization analysis reveals that higher genetically predicted serum IL-1 receptor antagonist levels are associated with preserved kidney function (higher estimated glomerular filtration rate) in the meta-analysis of CKDGen and the UK Biobank data. [ABSTRACT FROM AUTHOR]

Background Further investigation is needed to determine the causal effects of serum bilirubin on the risk of chronic kidney disease (CKD). Methods This study is a Mendelian randomization (MR) analysis. Among the well-known single-nucleotide polymorphisms (SNPs) related to serum bilirubin levels, rs4149056 in the SLCO1B1 gene was selected as the genetic instrument for single-variant MR analysis, as it was found to be less related to possible confounders than other SNPs. The association between genetic predisposition for bilirubin levels and estimated glomerular filtration rate (eGFR) or CKD was assessed in 337 129 individuals of white British ancestry from the UK Biobank cohort. Two-sample MR based on summary-level data was also performed. SNPs related to total or direct bilirubin levels were collected from a previous genome-wide association study and confounder-associated SNPs were discarded. The independent CKDGen meta-analysis data for CKD were employed as the outcome summary statistics. Results The alleles of rs4149056 associated with higher bilirubin levels were associated with better kidney function in the UK Biobank data. In the summary-level MR, both of the genetically predicted total bilirubin {per 5 µmol/L increase; odds ratio [OR] 0.931 [95% confidence interval (CI) 0.871–0.995]} and direct bilirubin [per 1 µmol/L increase; OR 0.910 (95% CI 0.834–0.993)] levels were significantly associated with a lower risk of CKD, supported by the causal estimates from various MR sensitivity analyses. Conclusion Genetic predisposition for higher serum bilirubin levels is associated with better kidney function. This result suggests that higher serum bilirubin levels may have causal protective effects against kidney function impairment. [ABSTRACT FROM AUTHOR]

Background An investigation into the causality of the effects of physical activity and specific sedentary activities on kidney function in the general population is warranted. Methods In this observational cohort study, first, the clinical associations of the prevalence of stages 3–5 chronic kidney disease (CKD) and the estimated glomerular filtration rate (eGFR) with physical activity, determined by self-report or objective wrist-band accelerometer results, and sedentary activities (watching television, using a computer and driving) were investigated in 329 758 UK Biobank participants. To assess causality, a two-sample Mendelian randomization (MR) analysis was performed to investigate the associations of a genetic predisposition to physical activity and a sedentary lifestyle with the risk of kidney function impairment in an independent CKDGen genome-wide association study (N  = 567 460). The findings were replicated with the 321 024 UK White British Biobank participants in the allele-score-based one-sample MR. Results A higher degree of self-reported or accelerometer-determined moderate-to-vigorous physical activity was associated with a higher eGFR, while a longer time spent watching television was significantly associated with a lower eGFR and a higher prevalence of CKD. The two-sample MR demonstrated that the genetic predisposition to a higher degree of physical activity was associated with a lower risk of CKD and a higher eGFR, while the genetically predicted television watching duration was associated with a higher risk of CKD and a lower eGFR. The other sedentary behaviors yielded inconsistent results. The findings were similarly replicated in the one-sample MR. Conclusion Physical activity and television watching causally affect kidney function in the general population. [ABSTRACT FROM AUTHOR]

Background and aims: An observational association between nonalcoholic fatty liver disease (NAFLD) and kidney function impairment has been reported. We aimed to investigate the causal effects from NAFLD on estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) study. Methods: We first performed single‐variant MR with rs738409 as a genetic instrument for NAFLD. Another genetic instrument was developed from a genome‐wide association study for biopsy‐confirmed NAFLD among individuals of European ancestry (1483 cases and 17 781 controls). The eGFR outcome was assessed in individuals of white British ancestry from the UK Biobank (N = 321 405). The associations were reassessed in the negative control subgroup (body mass index < 30 kg/m2, absence of central obesity, 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). Results: In the UK Biobank, a genetic predisposition for NAFLD, determined either by the single SNP rs738409 or by the group of variants, was significantly associated with a reduced eGFR even with adjustment for metabolic disorders. Although the associations were not significant in the negative control subgroup with a low probability of developing NAFLD, they were significant in the subgroup 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. Conclusions: This MR analysis supports the causal reduction in kidney function by NAFLD. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies suggested that a reduction in estimated glomerular filtration rate (eGFR) or a supranormal eGFR value was associated with adverse cardiovascular risks. However, a previous Mendelian randomization (MR) study under the linearity assumption reported null causal effects from eGFR on myocardial infarction (MI) risks. Further investigation of the nonlinear causal effect of kidney function assessed by eGFR on the risk of MI by nonlinear MR analysis is warranted.Methods: In this MR study, genetic instruments for log-eGFR based on serum creatinine were developed from European samples included in the CKDGen genome-wide association study (GWAS) meta-analysis (N=567,460). Alternate instruments for log-eGFR based on cystatin C were developed from a GWAS of European individuals that included the CKDGen and UK Biobank data (N=460,826). Nonlinear MR analysis for the risk of MI was performed using the fractional polynomial method and the piecewise linear method on data from individuals of white British ancestry in the UK Biobank (N=321,024, with 12,205 MI cases).Results: Nonlinear MR analysis demonstrated a U-shaped (quadratic P value < 0.001) association between MI risk and genetically predicted eGFR (creatinine) values, as MI risk increased as eGFR declined in the low eGFR range and the risk increased as eGFR increased in the high eGFR range. The results were similar even after adjustment for clinical covariates, such as blood pressure, diabetes mellitus, dyslipidemia, or urine microalbumin levels, or when genetically predicted eGFR (cystatin C) was included as the exposure.Conclusion: Genetically predicted eGFR is significantly associated with the risk of MI with a parabolic shape, suggesting that kidney function impairment, either by reduced or supranormal eGFR, may be causally linked to a higher MI risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

As adult height is linked to various health outcomes, further investigation of its causal effects on kidney function later in life is warranted. This study involved a cross-sectional observational analysis and summary-level Mendelian randomization (MR) analysis. First, the observational association between height and estimated GFR determined by creatinine (eGFRcreatinine) or cystatin C (eGFRcystatinC) was investigated in 467,182 individuals aged 40–69 using UK Biobank. Second, the genetic instrument for adult height, as reported by the GIANT consortium, was implemented, and summary-level MR of eGFRcreatinine and CKDcreatinine in a CKDGen genome-wide association study was performed (N = 567,460), with multivariable MR being adjusted for the effects of genetic predisposition on body mass index. To replicate the findings, additional two-sample MR using the summary statistics of eGFRcystatinC and CKDcystatinC in UK Biobank was performed (N = 321,405). In observational analysis, adult height was inversely associated with both eGFRcreatinine (per 1 SD, adjusted beta -1.039, standard error 0.129, P < 0.001) and eGFRcystatinC (adjusted beta -1.769, standard error 0.161, P < 0.001) in a multivariable model adjusted for clinicodemographic, anthropometric, metabolic, and social factors. Moreover, multivariable summary-level MR showed that a taller genetically predicted adult height was causally linked to a lower log-eGFRcreatinine (adjusted beta -0.007, standard error 0.001, P < 0.001) and a higher risk of CKDcreatinine (adjusted beta 0.083, standard error 0.019, P < 0.001). Other pleiotropy-robust sensitivity MR analysis results supported the findings. In addition, similar results were obtained by two-sample MR of eGFRcystatinC (adjusted beta -1.303, standard error 0.140, P < 0.001) and CKDcystatinC (adjusted beta 0.153, standard error 0.025, P < 0.001) in UK Biobank. In conclusion, the results of this study suggest that a taller adult height is causally linked to worse kidney function in middle-aged to elderly individuals, independent of the effect of body mass index. [ABSTRACT FROM AUTHOR]

Background: Further exploration of the possible effects of vegetable intake on kidney function is warranted.Objective: We aimed to study the causality of the association between vegetable intake and kidney function by implementing Mendelian randomization (MR) analysis.Methods: This study comprised a cross-sectional dietary investigation using UK Biobank data and MR analysis. For the cross-sectional investigation, 432,732 participants aged 40-69 y from the UK Biobank cohort were included. Self-reported vegetable intake was the exposure, and the outcomes were the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). Next, we included 337,138 participants of white British ancestry in the UK Biobank, and a genome-wide association study (GWAS) was performed to generate a genetic instrument. For MR, we first performed polygenic score (PGS)-based 1-sample MR. In addition, 2-sample MR was performed with CKDGen GWAS for kidney function traits, and the inverse variance weighted method was the main MR method.Results: Higher vegetable intake was cross-sectionally associated with a higher eGFR (per heaped tablespoon increase; β: 0.154; 95% CI: 0.144, 0.165) and lower odds of CKD (OR: 0.975; 95% CI: 0.968, 0.982). A PGS for vegetable intake was significantly associated with a higher eGFR [per ordinal category increase (0, 1-3, 4-6, ≥7 tablespoons per day); β: 4.435; 95% CI: 2.337, 6.533], but the association with CKD remained nonsignificant (OR: 0.468; 95% CI: 0.143, 1.535). In the 2-sample MR, the causal estimates indicated that a higher genetically predicted vegetable intake was associated with a higher eGFR (percent change; β: 3.071; 95% CI: 0.602, 0.560) but nonsignificantly associated with the risk of CKD (OR: 0.560; 95% CI: 0.289, 1.083) in the European ancestry data from the CKDGen.Conclusions: This study suggests that higher vegetable intake may have a causal effect on higher eGFRs in the European population. [ABSTRACT FROM AUTHOR]

• Variability in amplitude of resting-state networks (RSNs) was assessed across 37,842 subjects. • Network amplitudes are closely linked to functional connectivity between RSNs. • Temporal synchrony between brain regions is a key factor determining RSN amplitudes. • Sex effects on temporal synchrony differ between sensory and cognitive RSNs. • Genetic variants associated with RSN amplitudes overlap with those associated with synchrony. Resting-state fMRI studies have shown that multiple functional networks, which consist of distributed brain regions that share synchronised spontaneous activity, co-exist in the brain. As these resting-state networks (RSNs) have been thought to reflect the brain's intrinsic functional organization, intersubject variability in the networks' spontaneous fluctuations may be associated with individuals' clinical, physiological, cognitive, and genetic traits. Here, we investigated resting-state fMRI data along with extensive clinical, lifestyle, and genetic data collected from 37,842 UK Biobank participants, with the object of elucidating intersubject variability in the fluctuation amplitudes of RSNs. Functional properties of the RSN amplitudes were first examined by analyzing correlations with the well-established between-network functional connectivity. It was found that a network amplitude is highly correlated with the mean strength of the functional connectivity that the network has with the other networks. Intersubject clustering analysis showed the amplitudes are most strongly correlated with age, cardiovascular factors, body composition, blood cell counts, lung function, and sex, with some differences in the correlation strengths between sensory and cognitive RSNs. Genome-wide association studies (GWASs) of RSN amplitudes identified several significant genetic variants reported in previous GWASs for their implications in sleep duration. We provide insight into key factors determining RSN amplitudes and demonstrate that intersubject variability of the amplitudes primarily originates from differences in temporal synchrony between functionally linked brain regions, rather than differences in the magnitude of raw voxelwise BOLD signal changes. This finding additionally revealed intriguing differences between sensory and cognitive RSNs with respect to sex effects on temporal synchrony and provided evidence suggesting that synchronous coactivations of functionally linked brain regions, and magnitudes of BOLD signal changes, may be related to different genetic mechanisms. These results underscore that intersubject variability of the amplitudes in health and disease need to be interpreted largely as a measure of the sum of within-network temporal synchrony and amplitudes of BOLD signals, with a dominant contribution from the former. [ABSTRACT FROM AUTHOR]