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Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.

Publication ,  Journal Article
Bone, WP; Siewert, KM; Jha, A; Klarin, D; Damrauer, SM; VA Million Veteran Program; Chang, K-M; Tsao, PS; Assimes, TL; Ritchie, MD; Voight, BF
Published in: Alzheimers Res Ther
February 4, 2021

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.

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Published In

Alzheimers Res Ther

DOI

EISSN

1758-9193

Publication Date

February 4, 2021

Volume

13

Issue

1

Start / End Page

34

Location

England

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Phenotype
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Cardiovascular Diseases
  • Alzheimer Disease
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 11 Medical and Health Sciences
 

Citation

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Bone, W. P., Siewert, K. M., Jha, A., Klarin, D., Damrauer, S. M., VA Million Veteran Program, … Voight, B. F. (2021). Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits. Alzheimers Res Ther, 13(1), 34. https://doi.org/10.1186/s13195-021-00773-z
Bone, William P., Katherine M. Siewert, Anupama Jha, Derek Klarin, Scott M. Damrauer, VA Million Veteran Program, Kyong-Mi Chang, et al. “Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.Alzheimers Res Ther 13, no. 1 (February 4, 2021): 34. https://doi.org/10.1186/s13195-021-00773-z.
Bone WP, Siewert KM, Jha A, Klarin D, Damrauer SM, VA Million Veteran Program, et al. Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits. Alzheimers Res Ther. 2021 Feb 4;13(1):34.
Bone, William P., et al. “Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.Alzheimers Res Ther, vol. 13, no. 1, Feb. 2021, p. 34. Pubmed, doi:10.1186/s13195-021-00773-z.
Bone WP, Siewert KM, Jha A, Klarin D, Damrauer SM, VA Million Veteran Program, Chang K-M, Tsao PS, Assimes TL, Ritchie MD, Voight BF. Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits. Alzheimers Res Ther. 2021 Feb 4;13(1):34.
Journal cover image

Published In

Alzheimers Res Ther

DOI

EISSN

1758-9193

Publication Date

February 4, 2021

Volume

13

Issue

1

Start / End Page

34

Location

England

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Phenotype
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Cardiovascular Diseases
  • Alzheimer Disease
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 11 Medical and Health Sciences