TY - JOUR T1 - Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases JF - Journal of Neurology, Neurosurgery & Psychiatry JO - J Neurol Neurosurg Psychiatry SP - 152 LP - 164 DO - 10.1136/jnnp-2016-314411 VL - 88 IS - 2 AU - Raffaele Ferrari AU - Yunpeng Wang AU - Jana Vandrovcova AU - Sebastian Guelfi AU - Aree Witeolar AU - Celeste M Karch AU - Andrew J Schork AU - Chun C Fan AU - James B Brewer AU - International FTD-Genomics Consortium (IFGC), AU - International Parkinson's Disease Genomics Consortium (IPDGC), AU - International Genomics of Alzheimer's Project (IGAP), AU - Parastoo Momeni AU - Gerard D Schellenberg AU - William P Dillon AU - Leo P Sugrue AU - Christopher P Hess AU - Jennifer S Yokoyama AU - Luke W Bonham AU - Gil D Rabinovici AU - Bruce L Miller AU - Ole A Andreassen AU - Anders M Dale AU - John Hardy AU - Rahul S Desikan Y1 - 2017/02/01 UR - http://jnnp.bmj.com/content/88/2/152.abstract N2 - Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD.Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci.Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10–12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10−7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes.Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk. ER -