Journal article
Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes
Biological psychiatry (1969), Vol.89(8), pp.825-835
04/15/2021
DOI: 10.1016/j.biopsych.2020.12.023
PMCID: PMC8415425
PMID: 33637304
Abstract
The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.
FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.
We identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.
We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
Details
- Title: Subtitle
- Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes
- Creators
- Lianne M Reus - Amsterdam NeuroscienceBogdan Pasaniuc - University of California, Los AngelesDanielle Posthuma - Vrije Universiteit AmsterdamToni Boltz - University of California, Los AngelesYolande A L Pijnenburg - Vrije Universiteit AmsterdamRoel A Ophoff - University of California, Los AngelesInternational FTD-Genomics ConsortiumTimothy D Griffiths (Contributor) - Psychological and Brain Sciences
- Resource Type
- Journal article
- Publication Details
- Biological psychiatry (1969), Vol.89(8), pp.825-835
- DOI
- 10.1016/j.biopsych.2020.12.023
- PMID
- 33637304
- PMCID
- PMC8415425
- ISSN
- 0006-3223
- eISSN
- 1873-2402
- Grant note
- T32 HG002536 / NHGRI NIH HHS R01 AG062268 / NIA NIH HHS G0301152 / Medical Research Council R01 MH120794 / NIMH NIH HHS P01 AG019724 / NIA NIH HHS MC_UU_00024/9 / Medical Research Council MC_UU_00024/1 / Medical Research Council
- Language
- English
- Date published
- 04/15/2021
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627252102771
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