School of Medicine Publications and Presentations

Genetic insights of all-cause and vascular dementia through genome-wide association studies

Document Type

Article

Publication Date

12-2022

Abstract

Background

Genome-wide association studies (GWAS) have identified more than 40 genetic loci associated with Alzheimer’s disease (AD). Although vascular dementia (VaD) is the second most common type of dementia after AD, the genetic contribution to VaD is understudied. We hypothesize that common forms of dementia will share genetic risk factors. We conducted the largest trans-ancestral GWAS of "all-cause dementia" (ACD), VaD, and examined the underlying biological mechanisms

Method

Donors from 16 population-based CHARGE cohorts, two national case-control consortia (ADGC, MEMENTO), and the UKBB contributed 46,533 and 4,078 cases of ACD and VaD, respectively. The overall sample (475,577) included European, African, Asian, and Hispanic ancestry. We conducted ancestry-specific and trans-ancestral meta-analyses using METAL and MR-MEGA, respectively. We explored the shared genetics of ACD with related disease traits and risk factors. Using a Bayesian approach, the level of polygenicity is explored across dementia and closely related traits, followed by a multi-trait GWAS including ACD with traits of identical polygenic background. Finally, genome-wide (GW) signals were functionally prioritized using a TWAS study.

Result

For ACD, we replicated ten known AD loci, including regions near APOE and BIN1. We found novel suggestive loci near SEMA4D, ANO3, AJAP1, HBEGF, and RBFFOX1. These loci were previously associated with energy transport throughout the brain (SEMA4D), neuronal excitability (ANO3), amyloid plaques (RBFOX1), and cerebral small vessel disease (-cSVD-, HBEGF). For VaD, one locus near APOE reached GW significance along with 22 suggestive, including SPRY2, FOXA2, AJAP1, and PSMA3, previously associated with hypertension, diabetes, and neuron maintenance. In addition to the genetic overlap with neurodegenerative processes, genetic risk loci for ACD exhibited overlap with vascular risk factors (T2D, blood pressure, lipid levels) and MRI markers of cSVD. Adjusting for SNP effects from traits with similar polygenic backgrounds revealed risk loci implicated in regulating cholesterol metabolism and maintaining neuronal mRNA levels

Conclusion

We leveraged data from 19 cohorts and population-based studies to assess the genetic contribution to ACD and VaD. GW suggestive signals included genes implicated in various brain activities. Bioinformatic parsing of the identified loci pointed to a genetic overlap of ACD with vascular risk factors and MRI markers of cSVD.

Comments

© 2022 the Alzheimer's Association.

University of Texas Health Science - San Antonio

Publication Title

Alzheimer's & Dementia

DOI

10.1002/alz.067165

Academic Level

faculty

Mentor/PI Department

Neuroscience

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