Genome-wide study highlights novel genes associated with Alzheimer’s-Hypertension comorbidity showing utility over CSF biomarkers

Date

2019-03-05

Authors

Phillips, Nicole R.
Pathak, Gita A.

ORCID

0000-0003-3943-0895 (Pathak, Gita A.)

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Abstract

Purpose: The aging population (65 and older) is heavily burdened with comorbidities. As the incidence of Alzheimer’s continues to rise in the aging demographic, understanding underlying causes of prevalent comorbid patterns in Alzheimer’s (AD) is crucial for early diagnosis and treatment. According to the 2011 Alzheimer’s association report, hypertension is the most prevalent comorbid condition affecting 60% of the Alzheimer’s population. However, there are no known biomarkers or risk scores associated with the AD-hypertension comorbidity; additionally, the genetic underpinnings of hypertension as a comorbidity to AD remains understudied. Hypothesis: We hypothesize that genetic variants underlie comorbidity patterns of Alzheimer’s disease and hypertension, which are distinct from genetic risk factors of Alzheimer’s disease alone. Methods: Leveraging the data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we conducted comorbidity analyses comparing healthy cohort (controls) vs Alz+/Hyp- vs Alz+/Hyp+. We compared CSF biomarkers – amyloid β, tau and p-tau in three cohorts using one-way ANOVA. We, then evaluated genome wide profiles in three groups using 535,762 SNP markers in 677 individuals (after QC). SNPs were clumped into genes based on position ± 50kb and p-value, followed by mining their role in gene-expression pathways. Results: The CSF biomarkers were not significantly different in the disease groups, indicating that these biomarkers are not able to discriminate between comorbid AD-hypertension pathology. When comparing the control with Alzheimer’s individuals, genome-wide study identifies known - TOMM40 and novel genes -PML and KMO which are known to have role in multiple CNS disorders. Interestingly, when comparing controls vs Alz+Hyp+, we observe several genes in the chromosome 16 region, including SLC9A3R2 - a known hypertension gene. This gene-cluster was also found to be co-expressed via other intermediate genes, underscoring their involvement in mitochondrial pathways. Conclusion: While the CSF biomarkers- amyloid β, tau and p-tau are known for their diagnostic contribution in vascular dementia, their profile is unaltered in Alzheimer’s-hypertension comorbidity, requiring investigation of other possible pathogenic causes. This study replicates genes known for Alzheimer’s, along with identifying possible risk loci to the developing Alzheimer’s and hypertension, thus showing potential utility over CSF profiles.

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