Identification of Novel Genetic Risk Factors for Cerebral Amyloid Angiopathy
Merve Atik1, Joseph S. Reddy1, Thuy Nguyen1, Katie D. Sotelo1, Frederick Q Tutor-New1, Minerva Carrasquillo2, Jonathan Graff-Radford1, Neill Graff-Radford3, Kejal Kantarci1, Michael DeTure1, Dennis Dickson1, Mariet Allen1, Nilufer Taner1
1Mayo Clinic, 2Mayo Clinic Florida, 3Mayo Clinic Jacksonville
Objective:
To investigate the genetic risk factors of Cerebral Amyloid Angiopathy (CAA)
Background:
CAA is characterized by the accumulation of amyloid-beta in the cerebrovasculature, affects blood vessel integrity leading to brain hemorrhages and an accelerated cognitive decline in Alzheimer’s Disease (AD) patients. Our previous genome-wide association study (GWAS) identified a LINC-PINT splice variant associated with lower CAA levels in individuals without APOEe4 and higher levels of LINC-PINT expression in the brain of AD cases. In this study, we expand our GWAS to include additional AD and non-AD donors.
Design/Methods:
We analyzed 1350 AD and 502 non-AD donors from the Mayo Clinic Brain Bank, scored for CAA. We performed QC and imputation. We conducted GWAS in all donors (N=1,852) by testing imputed variant dosages for association with square root transformed CAA using linear regression, adjusting for relevant covariates.To assess associations with major CAA risk factors, we performed interaction analysis with APOEe4 presence and sex; and pursued stratified analyses.
Results:
Variants at the APOE locus were identified as the most significant in our study. In addition, several other variants approached genome-wide significance after adjusting for AD neuropathology. The LINC-PINT splice variant remained associated with lower CAA scores in AD donors without the APOEe4 risk allele. To enhance the robustness of our findings, we are pursuing further expansion of our study cohort to include other available datasets. To explore putative functional consequences of key variants, we collected peripheral gene expression measures in participants from Mayo Clinic with neuroimaging measures including microhemorrhages.
Conclusions:
We expect this study will provide further insights into the genetic architecture underlying risk for CAA, both in the context of significant AD pathology, and without. Characterization of genetic variants and functional outcomes in the context of neuropathology may lead to new avenues of research aimed at identifying biomarkers and therapies to treat CAA, and AD.
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