Abstract
BackgroundA 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 (G×G) interactions or gene-by-environmental interactions, making them a powerful tool for detecting G×G.MethodsWe performed genome-wide association studies to identify rQTL between tau and Aβ42 and ptau and Aβ42 with over 3000 individuals using age, gender, series, APOE ε2, APOE ε4, 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.ResultsWe found four significant tau/Aβ42 rQTL from three unique locations and six ptau/Aβ42 rQTL from five unique locations. G×G screens with these rQTL produced four significant G×G interactions (one Aβ42, 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.ConclusionsThe two most significant rQTL (rs8027714 and rs1036819) for ptau/Aβ42 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/Aβ42 relationship but may suggest that these two loci share a pathway. In addition to a ptau/Aβ42 rQTL and association with AD case/control status, rs1036819 is a strong rQTL for case/control status/Aβ42 and for tau/Aβ42. It resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/Aβ42 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 β-secretase enzyme that initiates production of the β-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.
Highlights
A relationship quantitative trait locus exists when the correlation between multiple traits varies by genotype for that locus
Using the significant Relationship quantitative trait loci (rQTL) as a priori hypotheses, subsequent G×G screens identified loci from four different regions involved in significant two-locus interactions with four of the rQTL (Table 3, Fig. 1)
The respective threshold for G×G screens with the tau/Aβ42 rQTL was p < 1.67 × 10−8 and p < 1 × 10−8 for G×G screens with the ptau/Aβ42 rQTL
Summary
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 (G×G) interactions or gene-by-environmental interactions, making them a powerful tool for detecting G×G. Aβ42, tau, and ptau are important biomarkers for Alzheimer’s disease (AD). Aβ42 is decreased in CSF as the disease progresses, and tau levels increase. This combination of changes appears to be specific to AD [1]. A better understanding of the genes and pathways that regulate the relationships between these biomarkers may provide important insights into AD pathology, even at the earliest stages of the disease. Screening for rQTL is a way to identify important loci that would typically be “invisible” to normal GWAS because they often do not show marginal effects on either trait [7]. It is a powerful avenue to identify G×G interactions without paying the statistical penalty of performing all possible two-locus tests. rQTL provide a window into pleiotropy, pleiotropic variability, and selection on traits in complex interconnecting systems [8]
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