Recent advances in the genetics of frontotemporal dementia

Abstract

Purpose of review: In this review we highlight recent advances in the human genetics of frontotemporal dementia (FTD). In addition to providing a broad survey of genes implicated in FTD in the last several years, we also discuss variation in genes implicated in both hereditary leukodystrophies and risk for FTD (e.g., TREM2, TMEM106B, CSF1R, AARS2, NOTCH3).

Recent findings: Over the past five years, genetic variation in approximately 50 genes has been confirmed or suggested to cause or influence risk for FTD and FTD-spectrum disorders. We first give background and discuss recent findings related to C9ORF72, GRN and MAPT, the genes most commonly implicated in FTD. We then provide a broad overview of other FTD-associated genes and go on to discuss new findings in FTD genetics in East Asian populations, including pathogenic variation in CHCHD10, which may represent a frequent cause of disease in Chinese populations. Finally, we consider recent insights gleaned from genome-wide association and genetic pleiotropy studies.

Summary: Recent genetic discoveries highlight cellular pathways involving autophagy, the endolysosomal system and neuroinflammation, and reveal an intriguing overlap between genes that confer risk for leukodystrophy and FTD.

Keywords: autophagy; frontotemporal lobar degeneration; genetics; inflammation; leukodystrophy; lysosomes.

Figure 1.. Leukodystrophy genes are dysregulated in pathologically proven FTLD.

Forest plots depict results from differential expression analyses in pathologically proven frontotemporal lobar degeneration (FTLD) due to progranulin mutations (GRN+; n=7) and sporadic FTLD (GRN−; n=10) compared to controls (n=11). (A) In GRN+ cases, all tested leukodystrophy genes (6/6) demonstrated dysregulated expression for at least one microarray probe (p_raw<0.05). (B) In contrast, the only dysregulated gene in GRN− cases was PSAP (p_raw<0.05). (C) In a combined analysis, all genes but TMEM106B demonstrated significant dysregulation for at least one microarray probe (p_raw<0.05). All analyses utilized linear regression. The main effect of diagnosis on relative expression for each gene is plotted with 95% confidence intervals. For details on the samples and gene expression measurement, see Chen-Plotkin et al., 2008 [55] and data available through GEO (GSE13162). Gene expression was estimated using an Affymetrix Human Genome U133A microarray. The forest plots depict all available microarray probes mapping to the query genes (AARS2 was not available for analysis). Probe identifiers are provided alongside each gene’s name in parentheses.

Figure 2.. Gene interaction network for leukodystrophy genes (PSAP, TYROBP, TMEM106B, NOTCH3, TREM2, AARS2 and CSF1R).

The network is remarkable for extensive interactions with progranulin (GRN, center of network), genes implicated in immunological function (CD81, HLA-A, HLA-B and HLA-E), lysosomal genes (CTSB, CTSD, GAA, LAPTM5, LRP1, NPC2 and TPP1), genes implicated in neurodegenerative lysosomal storage disorders (CTSD, GRN, NPC2 and TPP1), and a gene implicated in familial dementia (ITM2B). The network diagram was generated using HumanBase, a publicly available online database and analytical pipeline hosted by the Flatiron Institute (http://www.simonsfoundation.org/flatiron/). We limited our search to high-quality, brain-specific relationships connected to the query genes through co-expression, protein interaction, or shared transcription factor binding. Query genes are located on the periphery of the network to facilitate visualization of their connections with interacting network genes. The thickness of a connection represents edge weight, or strength of ties. Connection color represents ‘evidence’ for an edge, defined as the posterior probability of a functional relationship given the brain-tissue specific connectivity dataset, minus the prior probability. Detailed descriptions of the techniques used are provided in Greene et al., 2015 [56] and at https://humanbase.readthedocs.io/en/latest/functional-networks.html.