Role of ABCA7 & TM2D3 Variants in Alzheimer's Disease

Science Center, Bent Corridor

Identification of genetic risk factors for Alzheimer's disease (AD) is an ongoing effort that will provide important diagnostic and therapeutic insight. AD has a strong genetic component that cannot all be explained by the pathogenic variants identified on APP, PSEN1 and 2, and the risk variants identified in genome wide scans. This suggests that additional unidentified genes contribute to AD risk. Next generation sequencing has allowed for the identification of new rare variants with larger effects on AD risk. While a single rare variant cannot be used to predict AD risk for the population, it may have relevance for personal risk prediction and highlight new pathways in disease pathology. Recent studies found a significant increase of ABCA7 loss-offunction variants and TM2D3 missense variants in AD cases compared to controls. We tried to replicate the association of the identified variants at the single-variant and gene level in a large European American dataset. The effect size for the associations of ABCA7 and TM2D3 variants with AD risk are lower in our study compared to the original reports. However, I replicated the direction of the associations for ABCA7 variants. The results were significant for the ABCA7 gene-based analysis (p-value=0.038; OR=1.549), but not for TM2D3 (p-value=0.7174; OR=0.4824). Our study supports the role of ABCA7 variants in AD risk and highlights the variability in minor allele frequencies (MAF) among populations. Ultimately, ABCA7 may contribute to AD pathology and aid in understanding molecular pathways involved in the disease.