Shared Genetic Architecture Between Kidney Function and Alzheimer Disease Across Ancestries

Area of Science:

• Genetics
• Neuroscience
• Nephrology
• Complex Disease Genetics

Background:

• Epidemiological studies consistently link chronic kidney disease (CKD) to increased Alzheimer disease (AD) risk.
• The genetic basis for this association is largely unexplored beyond genome-wide correlation analyses.
• Understanding shared genetic architecture is crucial for deciphering disease mechanisms and developing targeted therapies.

Purpose of the Study:

• To conduct the first comprehensive, multi-ancestry genetic investigation into shared components between kidney function and AD.
• To identify specific genetic loci and pleiotropic mechanisms connecting estimated glomerular filtration rate (eGFR) and late-onset AD (LOAD).
• To explore both horizontal and vertical pleiotropy and their implications across different ancestries.

Main Methods:

• Leveraged large-scale genome-wide association study (GWAS) summary statistics for eGFR (N≈1.5M European, N≈145K African) and LOAD (N>460K European, N≈9K African).
• Employed a novel framework integrating linkage disequilibrium score regression, polygenic risk score analysis, local association analysis, conjunctional false discovery rate, Bayesian colocalization, fine-mapping, and bidirectional cis-Mendelian randomization.
• Analyzed multi-ancestry cohorts to identify shared and ancestry-specific genetic loci.

Main Results:

• No significant genome-wide genetic correlation (r_g ≈ 0) between eGFR and LOAD was observed.
• Identified 16 pleiotropic loci in European ancestry, including APOE, PICALM, SPI1, and EFTUD1, with significant local genetic correlations at 15 loci.
• Fine-mapping indicated horizontal pleiotropy at most loci, with distinct causal variants for each trait, except for an APOE ε4 allele (rs429358) showing shared causality. Vertical pleiotropy was detected at PICALM and EFTUD1 via cis-Mendelian randomization. APOE was the sole shared locus across European and African ancestries.

Conclusions:

• Alzheimer disease and kidney function share genetic components at specific loci, not genome-wide, characterized by mixed directional effects and predominantly horizontal pleiotropy.
• Evidence supports a complex kidney-brain genetic axis, with genetic variants influencing kidney function potentially impacting AD risk at specific loci.
• The significant ancestry-specific genetic architecture, particularly highlighted by APOE as the only shared locus, has critical implications for AD risk prediction and therapeutic strategies.