Inferring genetic relatedness in a large, multisite frontotemporal dementia series: Data from the ALLFTD consortium

Background The ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) research consortium is actively enrolling participants across 23 North American centers to characterize sporadic and familial frontotemporal dementia (FTD) prepare for disease-modifying clinical trials. ability identify, otherwise unknown, relatives among these critical rigorously build family structures downstream genetic studies. Methods Genome-wide SNP genotyping data from ALLFTD was used perform lineage analyses using PLINK. Briefly, QC performed remove individuals with low call rate filter autosomal SNPs missingness, allele frequency, deviation Hardy-Weinberg equilibrium, before pruning linkage disequilibrium. Identity-by-descent (IBD) estimates were then calculated determining relatedness, followed by family-network identification pedigree reconstruction PRIMUS. Results About 46% of that genotyped passed (n = 1,453) had reported a history, while 50% 721) did not considered sporadic. We identified total 460 at least one relative who second degree or closer (PI_HAT>0.1875) based on IBD sharing, resulting in 150 networks. This included 9 self-identified as sporadic, demonstrating the utility direct characterization determine familiality FTD. Most predicted families associated disease causing variants 3 major FTD-causing genes: 66 known C9orf72 repeat expansion carriers, 35 MAPT (including 11 variant historically p.P301L) 30 GRN pathogenic well 2 carriers both variant. also 5 other genes (2 TARDBP, VCP 1 PSEN1), 12 yet unknown etiology. Conclusions dataset sets up crucial resource increase statistical accuracy power association studies clinical, neuropsychological, neuroimaging biomarker currently being generated consortium. It will facilitate aimed novel gene discovery, haplotypes modifiers FTD causal genes.