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Genome‐wide association studies for identifying novel genetic variants providing cognitive resilience against AD pathology
Author(s) -
Hohman Timothy J.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.039432
Subject(s) - genome wide association study , genetic architecture , neuropathology , heritability , genetic association , biology , missing heritability problem , population , genetics , phenotype , single nucleotide polymorphism , disease , medicine , gene , pathology , genotype , environmental health
Background Alzheimer’s disease neuropathology is common among non‐demented older adults, and 30% meet neuropathological criteria for autopsy‐confirmed AD despite showing no clinical symptoms of disease. Yet, the genetic factors that allow these resilient individuals to remain cognitively normal in the face of substantial neuropathology remains poorly understood. We have performed large‐scale multi‐modal data harmonization to enable deep explorations into the genetic architecture of resilience. We will present comprehensive estimates of heritability of AD resilience phenotypes, describe common genetic variants that contribute to resilience, and provide an overview of gene networks and critical genetic pathways that appear to provide putative protection against the downstream consequences of AD neuropathology. Method We harmonized neuroimaging (MRI and PET), neuropsychological, fluid biomarker, and genomic data from 8 longitudinal cohort studies as part of the AD sequencing project phenotype harmonization workgroup. Resilience phenotypes were quantified using an established latent variable model based on better‐than‐predicted cognitive performance and brain volume for an individual’s AD neuropathological burden. We quantified estimates of heritability using the Genome‐wide Complex Trait Analysis (GCTA) software package. Next, we performed genome‐wide association study (GWAS) analyses covarying for age, sex, and population principal components. Summary statistics from GWAS were leveraged to characterize genetic pathways enriched for association with resilience phenotypes. Finally, we quantified gene network associations with resilience phenotypes leveraging RNA sequencing data from brain tissue and replicated leveraging predicted gene expression analyses quantified using GWAS data. Results Resilience phenotypes showed heritability estimates that are on par with complex genetic traits ( 0.19< h 2 < 0.67, p < 0.005), suggesting that genetic variation explains variance in resilience phenotypes. We observed a number of genome‐wide significant variants associated with resilience that replicate across in vivo biomarker datasets and autopsy datasets implicating acetylcholinesterase genes, bile acid homeostasis, and DNA damage repair. Finally, gene network analyses implicated gene modules involved in RNA binding and transcriptional regulation. Conclusion We highlight a number of novel genetic variants and genetic pathways that may protect the brain from the downstream consequences of AD neuropathology, highlighting the potential of resilience endophenotypes in the identification of novel therapeutic targets.