Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes
Por:
Reus, LM, Pasaniuc, B, Posthuma, D, Boltz, T, Pijnenburg, YAL, Ophoff, RA, Lleó A., Blesa, R., Ophoff, Roel A.
Publicada:
15 abr 2021
Ahead of Print:
1 mar 2021
Resumen:
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Filiaciones:
Reus, LM:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands
Pasaniuc, B:
Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
Univ Calif Los Angeles, David Geffen Sch Med, Dept Computat Med, Los Angeles, CA 90095 USA
Posthuma, D:
Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands
Boltz, T:
Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
Pijnenburg, YAL:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, Amsterdam, Netherlands
Ophoff, RA:
Erasmus MC, Dept Psychiat, Rotterdam, Netherlands
Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA
Lleó A.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Blesa, R.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Ophoff, Roel A.:
University of California, Los Angeles, Los Angeles, United States
Green Published, hybrid, Green Accepted, All Open Access, Hybrid Gold, Green
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