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Bioinformatics strategy to advance the interpretation of Alzheimer's disease GWAS discoveries: The roads from association to causation.

Publication ,  Journal Article
Lutz, MW; Sprague, D; Chiba-Falek, O
Published in: Alzheimers Dement
August 2019

INTRODUCTION: Genome-wide association studies (GWAS) discovered multiple late-onset Alzheimer's disease (LOAD)-associated SNPs and inferred the genes based on proximity; however, the actual causal genes are yet to be identified. METHODS: We defined LOAD-GWAS regions by the most significantly associated SNP ±0.5 Mb and developed a bioinformatics pipeline that uses and integrates chromatin state segmentation track to map active enhancers and virtual 4C software to visualize interactions between active enhancers and gene promoters. We augmented our pipeline with biomedical and functional information. RESULTS: We applied the bioinformatics pipeline using three ∼1 Mb LOAD-GWAS loci: BIN1, PICALM, CELF1. These loci contain 10-24 genes, an average of 106 active enhancers and 80 CTCF sites. Our strategy identified all genes corresponding to the promoters that interact with the active enhancer that is closest to the LOAD-GWAS-SNP and generated a shorter list of prioritized candidate LOAD genes (5-14/loci), feasible for post-GWAS investigations of causality. DISCUSSION: Interpretation of LOAD-GWAS discoveries requires the integration of brain-specific functional genomic data sets and information related to regulatory activity.

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Published In

Alzheimers Dement

DOI

EISSN

1552-5279

Publication Date

August 2019

Volume

15

Issue

8

Start / End Page

1048 / 1058

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Geriatrics
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Computational Biology
  • Alzheimer Disease
  • 5202 Biological psychology
  • 3209 Neurosciences
  • 3202 Clinical sciences
 

Citation

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ICMJE
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Lutz, M. W., Sprague, D., & Chiba-Falek, O. (2019). Bioinformatics strategy to advance the interpretation of Alzheimer's disease GWAS discoveries: The roads from association to causation. Alzheimers Dement, 15(8), 1048–1058. https://doi.org/10.1016/j.jalz.2019.04.014
Lutz, Michael W., Daniel Sprague, and Ornit Chiba-Falek. “Bioinformatics strategy to advance the interpretation of Alzheimer's disease GWAS discoveries: The roads from association to causation.Alzheimers Dement 15, no. 8 (August 2019): 1048–58. https://doi.org/10.1016/j.jalz.2019.04.014.
Lutz, Michael W., et al. “Bioinformatics strategy to advance the interpretation of Alzheimer's disease GWAS discoveries: The roads from association to causation.Alzheimers Dement, vol. 15, no. 8, Aug. 2019, pp. 1048–58. Pubmed, doi:10.1016/j.jalz.2019.04.014.
Journal cover image

Published In

Alzheimers Dement

DOI

EISSN

1552-5279

Publication Date

August 2019

Volume

15

Issue

8

Start / End Page

1048 / 1058

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Geriatrics
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Computational Biology
  • Alzheimer Disease
  • 5202 Biological psychology
  • 3209 Neurosciences
  • 3202 Clinical sciences