Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40

Background: Alzheimer's disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ₄₂ ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ₄₂) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers. Methods: We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer's Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ₄₂ ratio, Aβ₄₂, tau, and phosphorylated tau (ptau₁₈₁). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ₄₂ ratio, Aβ₄₂, tau, and ptau₁₈₁. Results: We found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau₁₈₁ (r=0.521) and the strength of the correlation significantly increased with the addition of genetic information (r=0.573, p=0.006). Conclusions: CSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau₁₈₁ levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.