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. 2018 Oct 1;4(5):e266.
doi: 10.1212/NXG.0000000000000266. eCollection 2018 Oct.

Protein Network Analysis Reveals Selectively Vulnerable Regions and Biological Processes in FTD

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Free PMC article

Protein Network Analysis Reveals Selectively Vulnerable Regions and Biological Processes in FTD

Luke W Bonham et al. Neurol Genet. .
Free PMC article

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.

Figures

Figure 1
Figure 1. bvFTD PINBPA network
The bvFTD PINBPA network is shown. Nodes are color coded according to their gene-based p-value, with warmer colors indicating lower p-values and cooler colors representing p-values closer to 0.05. Node size represents closeness centrality, a measure of a node's nearness to other nodes within a network. Edge thickness represents edge betweenness, a measure of the number of paths that go through an edge in a network.
Figure 2
Figure 2. Interactome analyses in bvFTD
(A) Protein network built through the W-PPI-NA pipeline around the 63 genes prioritized by the PINBPA protocol. The seeds are depicted in pink and their interactors in blue. (B) Inter-interactome degree distribution curve reporting the number of nodes (x-axis) able to bridge an N number of seeds (y-axis). The IIHs are the nodes marked by the rectangle. (C) List of IIHs reporting the number of seeds that they bridge and associated %. *UBC has been reported yet ignored as it is likely a false positive (as it may indicate unspecific binding of ubiquitin to proteins tagged for degradation). (D) Core of the network around the IIHs, which are depicted in pink.
Figure 3
Figure 3. Regional gene expression enrichment across the lifespan
For each of the 5 age groups used in the ABAEnrichment analyses, we counted the number of times each of the 26 available brain regions showed enrichment of the bvFTD network genes. The superior temporal cortex was the most common region of enriched expression with 5 observations (i.e., in every age grouping). Generally, the FTD cohort showed enriched expression in both frontal (DFC, VFC, M1C, PFC, OFC) and temporal (A1C, ITC, STC, MFC) regions. (A and B) The number of times each region was associated is illustrated on a model brain. Brain regions were mapped onto the illustration using information provided in Bahl et al. 2017. When regional overlap was detected (e.g., IPC is contained within PCx or DFC; VFC and OFC are contained within PFC), the more specific region(s) was chosen for presentation. (C) A graphical depiction of the data shown in (A and B). The number of times each brain region was associated from the 5 age groupings is shown. (D) Detailed results are shown in a table format with age groupings as rows and brain regions as columns. Regions shaded in black were statistically associated while unshaded regions were not. A1C = primary auditory cortex; AMY = amygdaloid complex; CN = cerebral nuclei; CB = cerebellum; CBC = cerebellar cortex; DFC = dorsolateral prefrontal cortex; HIP = hippocampus; IPC = posteroventral (inferior) parietal cortex; ITC = inferolateral temporal cortex; M1C = primary motor cortex; MFC = anterior (rostral) cingulate (medial prefrontal) cortex; OFC = orbital frontal cortex; PCx = parietal neocortex; PFC = prefrontal cortex; S1C = primary somatosensory cortex; STC = posterior (caudal) superior temporal cortex; STR = striatum; TCx = temporal neocortex; THA = thalamus; V1C = primary visual cortex; VFC = ventrolateral prefrontal cortex.

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