Sarah J. Eger, United States of America
Stanford University Neurology and Neurological SciencesAuthor Of 2 Presentations
A NOVEL AGE-INFORMED APPROACH FOR GENETIC ASSOCIATION ANALYSIS IN ALZHEIMER’S DISEASE
Abstract
Aims
Most Alzheimer’s disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery.
Methods
Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals and replicated suggestive associations in 21,631 genotype-imputed individuals (Table1).
Table1. Demographics for discovery and replication samples.
| Sample | N (% females) | Age μ(σ) |
|---|---|---|
| Discovery | ||
| Controls | 5075(59.0) | 85.2(5.4) |
| AD cases | 6052(57.8) | 76.3(8.2) |
| Replication | ||
| Controls | 10539(59.4) | 76.7(8.5) |
| AD cases | 11092(60.5) | 73.3(9.3) |
Results
Modelling variable AD risk across age results in 10-20% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss (Figure1). Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD (Figure2).
Figure1. Power of different association models evaluated for a common variant with moderate effect size. A-C) Simulation based on 1000/1000 cases/controls at a significance level of α=0.05, for age differences observed in AD cohorts.
Figure2. Manhattan plots of exome-wide-associations in the four models. No suggestive association were observed (p<1×10-5) for the age adjusted logistic regression. TREM2 known causal variant is exome-wide-significant (p<5×10-7) in the other models. Among suggestive associations, known AD associations are in red, novel associations which replicate (p<0.05) in an independent dataset are in blue.
Conclusions
Our AD-age score provides a simple means for statistical power gain.
ASSOCIATION OF APOE SPLICE QTLS WITH ALZHEIMER’S DISEASE RISK IN APOE*4/4 CARRIERS.
Abstract
Aims
Determine whether APOE splice quantitative trait locus (sQTL) variants affect APOE4-related risk for Alzheimer’s disease (AD), age-at-AD-onset, and APOE protein levels.
Methods
Participants (N=25,120) were ages 60+, non-Hispanic, of European ancestry, had APOE genotype available, and diagnosed as cases or controls. Only rs157580 and rs439401 APOE sQTLs were genotyped in >80% of the available sample and further investigated. Associations of APOE sQTLs with AD risk (mixed model case-control regression) and log-normalized age-at-AD-onset (linear mixed model) were evaluated in APOE*3/4 and APOE*4/4 carriers. Associations with APOE protein levels were evaluated in post-mortem dorsolateral prefrontal cortex (dlPFC) tissue from APOE*3/4 carriers (APOE*4/4 not considered due to sample paucity).
Results
Rs157580 and rs439401 reduced AD risk in APOE*4/4 carriers (Table1). Rs157580 also increased age-at-AD-onset in APOE*4/4 (beta=0.027, P-value=0.023) and APOE*3/4 carriers (beta=0.004, P-value=0.089). Rs157580 increased APOE protein levels in the dlPFC of APOE*3/4 carriers (Figure1).
| Stratum | SNP | CN/AD (N) | CN/AD (MAF) | OR(CI) | P-value |
|---|---|---|---|---|---|
| APOE*4/4 | rs157580 | 237/1629 | 4.2%/1.9% | 0.39 (0.20-0.74) | 4.00E-3 |
| APOE*3/4 | rs157580 | 2662/5607 | 23.2%/22.6% | 0.96 (0.87-1.05) | 0.33 |
| APOE*4/4 | rs439401 | 237/1652 | 3.6%/0.6% | 0.10 (0.04-0.24) | 2.00E-7 |
| APOE*3/4 | rs439401 | 2702/5734 | 24.8%/24.3% | 0.97 (0.88-1.06) | 0.47 |
MAF=minor allele frequency; CN=control, OR=odds ratio; CI=95% confidence interval.
Figure1. Association of rs157580 with APOE protein levels. Error bars show 95-percentile range. X-axis indicates genotypes and sample sizes.
Conclusions
Our results bring new insights into mechanisms that alter APOE expression and how this affects APOE4-related AD risk. This is crucially relevant for the development of AD drug therapies aimed at APOE4.