O2‐10‐02: Whole Exome Sequencing Analysis in Early Onset Alzheimer Reveals Novel Candidate Genes
Year: 2019
Type: article
Study design: Observational Study
Abstract: Early Onset Alzheimer Disease (EOAD) constitutes about 4% of total AD. After autosomal dominant familial forms caused by mutations in APP, PSEN1 or PSEN2, EOAD is the most aggressive form Some EOAD individuals carry mutations in these genes or in AD risk genes (ABCA7, SORL1, TREM2) but the majority of EOAD cases are not explained by mutation in these genes. Participants for this study were selected from the NIA-LOAD and Knight-ADRC cohorts. Cases (CA) had to have an age at onset ≤ 65 whereas controls (CO) had to have an age at last assessment ≥ 85. Whole exome sequencing and variant calling was performed as previously described [doi.org/10.3389/fnins.2018.00209]. We used PLINK1.9 to perform PCA and IBD analysis to select unrelated European American individuals. Carriers of known risk variants in any of the Mendelian genes (APP, PSEN1, PSEN2, GRN, MAPT) or major risk loci (TREM2) were removed from analyses. A total of 894 individuals (454 CA, 440 CO) were included in this study. Single variant and gene-based association analyses were focused on rare, non-synonymous variants (MAF < 1%). We used PLINK1.9 to perform single variant logistic regression and SKAT-O for gene-based association analysis, while correcting for PC and sex. The single variant association analysis identified nominally significant non-synonymous protective variants in ABCA7 and ZNF232. Suggestive association was found for two additional protective variants in PLXNA2 and SLC12A5, two genes highly expressed in the human brain (neurons particularly) with functions in axon guidance and neural homeostasis. The gene based analysis reported suggestive associations for TCF7L1, MAP2, and BIRC2, involved in cell cycle regulation, neurogenesis, and inflammation. We have expanded our cohort into a much larger dataset that includes 1400 CA and 2000 CO and we are currently performing variant calling. The new dataset has enough power (0.9) to detect risk variants with moderate risk (OR=2.5) and nominally significant genes (power = 0.8). We will perform association as well as pathway analysis on the new dataset. We expect the new dataset will provide stronger evidence for our preliminary data and novel loci.
Source: Alzheimer s & Dementia
Authors: Victoria Fernandez, Dalton Huey, John P. Budde, Fabiana H.G. Farias, Oscar Harari, Joanne Norton, Jen Gentsch, John C. Morris, Alison Goate, Rosa Rademakers, Neill R. Graff-Radford, Bradley F. Boeve, John Kauwe, Carlos Cruchaga, NIA-LOAD/NCRAD Family Study Group
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980794641