Journal article
Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits
Alzheimer's research & therapy, Vol.13(1), pp.34-34
01/01/2021
DOI: 10.1186/s13195-021-00773-z
PMCID: PMC7860582
PMID: 33541420
Abstract
Background Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. Methods We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. Results We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Conclusion Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.
Details
- Title: Subtitle
- Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits
- Creators
- William P. Bone - University of PennsylvaniaKatherine M. Siewert - University of PennsylvaniaAnupama Jha - University of PennsylvaniaDerek Klarin - Massachusetts General HospitalScott M. Damrauer - Philadelphia VA Medical CenterKyong-Mi Chang - Philadelphia VA Medical CenterPhilip S. Tsao - Stanford UniversityThemistocles L. Assimes - VA Palo Alto Health Care SystemMarylyn D. Ritchie - University of PennsylvaniaBenjamin F. Voight - Philadelphia VA Medical CenterVA Million Veteran Program
- Contributors
- Zuhair K Ballas (Contributor) - University of Iowa, Immunology
- Resource Type
- Journal article
- Publication Details
- Alzheimer's research & therapy, Vol.13(1), pp.34-34
- DOI
- 10.1186/s13195-021-00773-z
- PMID
- 33541420
- PMCID
- PMC7860582
- NLM abbreviation
- Alzheimers Res Ther
- ISSN
- 1758-9193
- eISSN
- 1758-9193
- Publisher
- Springer Nature
- Number of pages
- 14
- Grant note
- Linda Pechenik Montague Investigator Award DK101478; P50GM115318-01 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 20PRE35120109 / American Heart Association I01-BX003362; IK2-CX001780 / Department of Veterans Affairs Office of RD award; US Department of Veterans Affairs
- Language
- English
- Date published
- 01/01/2021
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984359702502771
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