Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

AbstractFrontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated thatC9orf72 repeat expansions andGRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations inTBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within theDPP6 gene led by rs118113626 (p value  = 4.82e − 08, OR = 2.12), and two known loci:UNC13A, led by rs1297319 (p value  = 1.27e − 08, OR = 1.50) andHLA-DQA2 led by rs17219281 (p value  = 3.22e − 08, OR = 1.98). WhileHLA represents a locus previously implicated in clinical FTLD and related...

Source: Acta Neuropathologica - February 9, 2019 Category: Neurology Source Type: research