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

Abstract

Background Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

A roadmap to human hippocampal neurogenesis in adulthood, aging and AD.

“…Notably, in contrast to DEGs, the number of DE peaks was substantially different between immature and inhibitory neurons. While in the former we observed a large number of differential peaks (41,341 in AD/NCI, 94 up and 41,247 down; 67,532 total in AD/YA, 67 of them were up and 67,465 down), in GABA neurons the effect was smaller. There were 1659 DE peaks in AD/YC (39 up, 1620 down) and only 87 in AD/HA (8 up, 79 down) (Figure 6I,J).…”

“…Similarly, several cell types, including neuroblasts and inhibitory neurons secrete NRXN1,3 which binds NLGN2 receptors in immature and CA neurons (Figure 7E,F). These pathways play critical roles in synaptic plasticity and are implicated in cognitive de cits and AD dementia [41][42][43][44] . These analyses further inferred ligand-receptor pathways that may play a role in a decline in cell-cell interaction as a function of pathology in immature neurons, as well as ligands and receptors that may be exclusively expressed in immature neurons (Supplemental Figure 8, Supplemental Tables 16,17).…”

Top 100 most-cited articles on tau protein: a bibliometric analysis and evidence mapping

“…Furthermore, GWAS have gained significant attention as they allow researchers to identify genetic variations associated with increased susceptibility or protection against certain diseases. Recently, GWAS have revealed the unique genetic structure of proteins associated with AD ( Neumann et al, 2023 ; Oatman et al, 2023 ; Ta et al, 2023 ).…”

Recently Updated Role of Chitinase 3-like 1 on Various Cell Types as a Major Influencer of Chronic Inflammation

“…Recent studies confirmed that DNA variants in CHI3L1 could be associated with increased neuronal injury and inflammation, and CSF levels of CHI3L1 could lead to an increased risk of AD. Also, the CHI3L1 expression in both blood and CSF is positively associated with variants in CHI3L1 [36,87]. The suppression of CHI3L1 DNA variants may contribute to lower levels of blood and CSF CHI3L1, which reduces the risk of AD development.…”