Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Area of Science:

• Neuroscience
• Genetics
• Biomarker Research

Background:

• Genome-wide association studies (GWAS) have identified some Alzheimer's disease (AD) risk loci, but many genetic factors remain unknown.
• Cerebrospinal fluid (CSF) biomarkers, including beta-amyloid, tau, NfL, YKL-40, and neurogranin, can be statistically clustered into principal components (PCs) representing distinct biological processes.
• Previous work demonstrated the utility of these CSF biomarker PCs in understanding AD pathophysiology.

Purpose of the Study:

• To identify common genetic variants associated with CSF biomarker profiles in Alzheimer's disease (AD).
• To evaluate the role of these associated genetic variants in AD pathophysiology.
• To explore potential sex-specific differences in genetic associations with AD biomarkers.

Main Methods:

• Genome-wide association studies (GWAS) were conducted for five CSF biomarker principal components (PCs) across two multi-center cohorts (EMIF-AD and ADNI).
• Analysis included 973 participants (controls, mild cognitive impairment, AD) examining 7,433,949 common SNPs and 19,511 protein-coding genes.
• Structural equation models assessed mediation of genetic risk effects on AD by biomarker PCs, with stratified and interaction models investigating sex-specific effects.

Main Results:

• Five loci demonstrated genome-wide significant association with CSF profiles: two novel (rs145791381 for inflammation, GRIN2D for synaptic functioning) and three previously known (APOE, TMEM106B, CHI3L1).
• Follow-up analyses confirmed the GRIN2D locus, containing functionally relevant genes, while the rs145791381 signal was not replicated.
• Mediation analyses revealed APOE variants influence AD via amyloid/tau pathways, whereas TMEM106B and CHI3L1 variants affect AD through neuronal injury/inflammation. Seven loci showed sex-specific associations.

Conclusions:

• Pathway and sex-specific analyses enhance the understanding of Alzheimer's disease (AD) genetics.
• The identification of novel genetic loci and pathways associated with CSF biomarkers contributes to a more nuanced view of AD pathophysiology.
• These findings may pave the way for developing precision medicine strategies in AD treatment and prevention.