Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels

Background: A relationship quantitative trait locus exists when the correlation between multiple traits varies by genotype for that locus. Relationship quantitative trait loci (rQTL) are often involved in gene-by-gene (GxG) interactions or gene-by-environmental interactions, making them a powerful tool for detecting GxG. Methods: We performed genome-wide association studies to identify rQTL between tau and A beta 42 and ptau and A beta 42 with over 3000 individuals using age, gender, series, APOE epsilon 2, APOE epsilon 4, and two principal components for population structure as covariates. Each significant rQTL was separately screened for interactions with other loci for each trait in the rQTL model. Parametric bootstrapping was used to assess significance. Results: We found four significant tau/A beta 42 rQTL from three unique locations and six ptau/A beta 42 rQTL from five unique locations. GxG screens with these rQTL produced four significant GxG interactions (one A beta 42, two ptau, and one tau) with four rQTL where each second locus was from a unique location. On follow-up, rs1036819 and rs74025622 were associated with Alzheimer's disease (AD) case/control status; rs15205 and rs79099429 were associated with rate of decline. Conclusions: The two most significant rQTL (rs8027714 and rs1036819) for ptau/A beta 42 are on different chromosomes and both are strong hits for pelvic organ prolapse. While diseases of the nervous system can cause pelvic organ prolapse, it is unlikely related to the ptau/A beta 42 relationship but may suggest that these two loci share a pathway. In addition to a ptau/A beta 42 rQTL and association with AD case/control status, rs1036819 is a strong rQTL for case/control status/A beta 42 and for tau/A beta 42. It resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/A beta 42 rQTL rs74025622. It is in the CHL1 gene, which is a neural cell adhesion molecule and may be involved in signal transduction pathways. CHL1 is related to BACE1, which is a beta-secretase enzyme that initiates production of the beta-amyloid peptide involved in AD and is a primary drug target. Overall, there are numerous loci that affect the relationship between these important AD endophenotypes and some are due to interactions with other loci. Some affect the risk of AD and/or rate of progression.