Linking kidney impairment to amygdala volume changes and mental disorders: a Mendelian randomization study

Mental disorders are highly prevalent among patients with chronic kidney disease (CKD); however, the causal effects of kidney dysfunction on specific brain volume traits and mental disorders remain underexplored.

In this Mendelian randomization (MR) study, genetic instruments for kidney function and CKD, derived from genome-wide association studies (GWAS) in Chronic Kidney Disease Genetics and the UK Biobank (n = 1,201,909), were utilized for two-sample MR analysis in the discovery phase. Summary-level data from these GWAS provided exposure-outcome associations to calculate causal estimates using the inverse variance weighted method. Validation analysis was conducted using one-sample MR with individual-level data from the UK Biobank.

Two-sample MR identified causal associations (odds ratios [ORs] as point estimates) between estimated glomerular filtration rate (exposures) and amygdala traits (outcomes), with ORs ranging from 0.559 to 0.723 (p < 0.05). Two-sample MR between CKD (exposures) and amygdala volume traits (outcomes) reported ORs ranging from 1.042 to 1.059 (p < 0.05). These associations also linked kidney dysfunction to an increased risk of depression, using two-sample MR across 507 brain volume and 242 mental disorder GWAS datasets. Leave-one-out analyses and pleiotropy tests, including MR Egger, supported the robustness of these findings. Validation analysis confirmed reproducibility using one-sample MR.

Our results demonstrate that kidney dysfunction causally alters amygdala volume, increasing susceptibility to mental disorders such as depression. These findings highlight the kidney-brain axis and underscore the importance of integrating mental health screening and interventions into the clinical management of patients with CKD.