Abstract
Objective The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.
Methods We used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.
Results We found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.
Conclusions Our findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.
Glossary
- AD=
- Alzheimer disease;
- BP=
- biological process;
- CSEA=
- cell-type SEA;
- EGFR=
- epidermal growth factor;
- FDR=
- false-discovery rate;
- bvFTD=
- behavioral variant frontotemporal dementia;
- FTLD=
- frontotemporal lobar degeneration;
- GO=
- gene ontology;
- GWAS=
- genome-wide association study;
- IFGC=
- International FTD-Genomics Consortium;
- MAPK=
- mitogen-activated protein kinase;
- PD=
- Parkinson disease;
- PDGF=
- platelet-derived growth factor;
- PINBPA=
- protein interaction network-based pathway analysis;
- SEA=
- specific enrichment analysis;
- VEN=
- Von Economo neuron;
- W-PPI-NA=
- weighted protein-protein interaction network analysis
Footnotes
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing Charge was funded by the authors.
- Received January 29, 2018.
- Accepted in final form July 31, 2018.
- Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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