title: Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
authors.forename: Raffaele
authors.identifier: 0000-0002-6208-5260
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.|Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, UK.
authors.forename: Jana
authors.initials: J
authors.lastname: Vandrovcova
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.|Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Guelfi
authors.affiliation: NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Aree
authors.initials: A
authors.lastname: Witeolar
authors.affiliation: Department of Psychiatry, Washington University, St. Louis, Missouri, USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Cognitive Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: Department of Cognitive Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Chun C
authors.initials: CC
authors.lastname: Fan
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla, California, USA.|Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Brewer
authors.affiliation: Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Momeni
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Dillon
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Leo P
authors.initials: LP
authors.lastname: Sugrue
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hess
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Bonham
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Cognitive Sciences, University of California, San Diego, La Jolla, California, USA.|Department of Radiology, University of California, San Diego, La Jolla, California, USA.|Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide