Network-based analysis of genetic variants associated with hippocampal volume in Alzheimer's disease: a study of ADNI cohorts.

Journal Article (Journal Article)

Background

Alzheimer's disease (AD) is a neurodegenerative disease that causes dementia. While molecular basis of AD is not fully understood, genetic factors are expected to participate in the development and progression of the disease. Our goal was to uncover novel genetic underpinnings of Alzheimer's disease with a bioinformatics approach that accounts for tissue specificity.

Findings

We performed genome-wide association studies (GWAS) for hippocampal volume in two Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. We used these GWAS in a subsequent tissue-specific network-wide association study (NetWAS), which applied nominally significant associations in the initial GWAS to identify disease relevant patterns in a functional network for the hippocampus. We compared prioritized gene lists from NetWAS and GWAS with literature curated AD-associated genes from the Online Mendelian Inheritance in Man (OMIM) database. In the ADNI-1 GWAS, where we also observed an enrichment of low p-values, NetWAS prioritized disease-gene associations in accordance with OMIM annotations. This was not observed in the ADNI-2 dataset. We provide source code to replicate these analyses as well as complete results under permissive licenses.

Conclusions

We performed the first analysis of hippocampal volume using NetWAS, which uses machine learning algorithms applied to tissue-specific functional interaction network to prioritize GWAS results. Our findings support the idea that tissue-specific networks may provide helpful context for understanding the etiology of common human diseases and reveal challenges that network-based approaches encounter in some datasets. Our source code and intermediate results files can facilitate the development of methods to address these challenges.

Full Text

Duke Authors

Cited Authors

  • Song, A; Yan, J; Kim, S; Risacher, SL; Wong, AK; Saykin, AJ; Shen, L; Greene, CS; Alzheimer’s Disease Neuroimaging Initiative,

Published Date

  • January 19, 2016

Published In

Volume / Issue

  • 9 /

Start / End Page

  • 3 -

PubMed ID

  • 26788126

Pubmed Central ID

  • PMC4717572

Electronic International Standard Serial Number (EISSN)

  • 1756-0381

International Standard Serial Number (ISSN)

  • 1756-0381

Digital Object Identifier (DOI)

  • 10.1186/s13040-016-0082-8

Language

  • eng