Analysis of rate of change in quantitative traits for identifying biomarker-mediated genetic effects on MCI and AD.

Abstract

The relationship between genetic variations such as single nucleotide polymorphisms (SNPs) and quantitative traits (QTs) is integral in the understanding of Alzheimer's Disease (AD). Given AD as a progressive disorder, QT-based rate of change (RoC) measures are important phenotypes to study in AD genetics. Further mediation analysis provides a promising method to help reveal causal relationship from genetic determinants to longitudinal changes in QTs and to clinical diagnosis. We analyzed the QT data from the Quantitative Templates for the Progression of Alzheimer's disease (QT-PAD, see http://www.pi4cs.org/qt-pad-challenge). QT-PAD is a single and shared data freeze from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 16 imaging, cognitive and fluid AD QTs. RoC between baseline and month-12 visits was calculated for each QT. Genotyping data were obtained from the ADNI database and went through a standard QC procedure. Genome wide association study (GWAS) was performed using PLINK to examine genetic associations between 565,373 SNPs and the RoC for each QT. For each SNP-RoC association with p<1e-6, a subsequent mediation analysis was performed using the "Mediation" R package to examine the mediation relationship from SNP to RoC to five different diagnostic comparisons (see Table 1). Figure 1 shows the GWAS findings on the RoC measures for the studied QTs. The results included 19 SNPs and 14 QTs, where each SNP or each QT had at least one association with p<10-6 . Table 1 shows the mediation analysis results. RoC in FAQ mediates the effects of rs429358-APOE and rs4420638-APOC1 on all five diagnostic comparisons, and mediates the effect of rs769449-APOE on four comparisons. RoC in Ventricle mediates the effects of both TOMM40 SNPs on four comparisons. RoC in CDRSB mediates the effects of rs5011804-KRAS on three comparisons. Mediation analysis of longitudinal AD biomarkers revealed several candidate causal relationships from genetic determinants (i.e., SNPs from the APOE/TOMM40/APOC1 region and KRAS) to RoC measures in QTs (FAQ, Ventricle, CDRSB), and to various diagnostic comparisons in MCI and AD. The identified patterns warrant further investigation in independent cohorts for deconvoluting mechanistic complexity of AD.