Common Variants in PLXNA4 and Correlation to CSF-related Phenotypes in Alzheimer's Disease

Abstract

The Plexin-A 4 (<i>PLXNA4</i>) gene, has recently been identified in genome wide association studies (GWAS), as a novel genetic player associated with Alzheimer's disease (AD). Additionally, <i>PLXNA4</i> genetic variations were also found to increase AD risk by tau pathology <i>in vitro</i>. However, the potential roles of <i>PLXNA4</i> variants in the amyloid-β (Aβ) pathology, were not evaluated. Five targeted loci capturing the top common variations in <i>PLXNA4</i>, were extracted using tagger methods. Multiple linear regression models were used to explore whether these variations can affect the cerebrospinal fluid (CSF) (Aβ_1-42, T-tau, and P-tau) phenotypes in the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset. We detected that two loci (rs6467431, rs67468325) were significantly associated with CSF Aβ_1-42 levels in the hybrid population (rs6467431: <i>P</i> = 0.01376, rs67468325: <i>P</i> = 0.006536) and the significance remained after false discovery rate (FDR) correction (rs6467431: <i>P</i>c = 0.03441, rs67468325: <i>P</i>c = 0.03268). In the subgroup analysis, we further confirmed the association of rs6467431 in the cognitively normal (CN) subgroup (<i>P</i> = 0.01904, <i>P</i>c = 0.04761). Furthermore, rs6467431-A carriers and rs67468325-G carriers showed higher CSF Aβ_1-42 levels than non-carriers. Nevertheless, we did not detect any significant relationships between the levels of T-tau, P-tau and these <i>PLXNA4</i> loci. Our findings provided preliminary evidence that <i>PLXNA4</i> variants can confer AD risk through modulating the Aβ deposition.