Jennifer Deger1, Shabab Hannan1, Mingxue Gu1, Collen Strohlein1, Oguz Kanca1, Lindsey Goodman1, Liwen Ma1, Megan Cooper1, Catherine Burns1, Mohammed Hamdan1, Ismael Al-Ramahi1, Hugo Bellen1, Joshua Shulman2
1Baylor College of Medicine, 2Duncan Neurological Research Institute
Objective:
To pinpoint causal genes in Alzheimer’s risk loci and define their requirements in the aging brain.
Background:
Hundreds of candidate Alzheimer’s disease (AD) susceptibility genes have been nominated based on genome-wide association studies (GWAS). However, most of these genes have poorly understood roles in the nervous system. GWAS is also limited because it typically does not narrow down which genes mediate association with AD risk. Further studies are needed to resolve which genes are causal.
Design/Methods:
We considered over 500 candidate AD risk genes. We prioritized 53 according to human functional genomic evidence, 24 according to in vivo evidence for interactions with tau/Aβ-induced neurotoxicity, 14 because of AD-associated rare variants, and 15 based on published evidence for modifying AD-related pathology. In total we prioritized 106 AD risk genes. We created loss-of-function Drosophila mutants and characterized the consequences of gene loss using brain histology to reveal structural changes, electroretinograms to quantify neurophysiological function, and recovery from traumatic or thermal stressors to measure resilience. We also characterized cell type-specific expression patterns of these genes in the brain.
Results:
Loss of approximately half of the genes tested produces a defect in at least one assay. Our results suggest that multiple genes within a locus are important for neuronal health. We unexpectedly found that loss of 7 genes involved in lipid biology (e.g. APOE, ABCA7, DOC2A) enhances neuronal function as measured by electroretinograms. In addition, hierarchical clustering by phenotypes identifies 5 groups that may represent distinct pathways of biological disruption, e.g. endocytic defects and immune dysfunction, that contribute to AD risk.
Conclusions:
Our cross-species functional genomic approach pinpoints genes at AD risk loci with requirements for brain structure and function in aging. Beyond advancing our understanding of genetic mechanisms in neurodegeneration, our results reveal novel requirements for dozens of genes in neuronal homeostasis.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.