title: Genetic and neuroanatomic associations in sporadic frontotemporal lobar degeneration.
abstract: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are sensitive for tau or TDP-43 pathology in frontotemporal lobar degeneration (FTLD). Neuroimaging analyses have revealed distinct distributions of disease in FTLD patients with genetic mutations. However, genetic influences on neuroanatomic structure in sporadic FTLD have not been assessed. In this report, we use novel multivariate tools, Eigenanatomy, and sparse canonical correlation analysis to identify associations between SNPs and neuroanatomic structure in sporadic FTLD. Magnetic resonance imaging analyses revealed that rs8070723 (MAPT) was associated with gray matter variance in the temporal cortex. Diffusion tensor imaging analyses revealed that rs1768208 (MOBP), rs646776 (near SORT1), and rs5848 (PGRN) were associated with white matter variance in the midbrain and superior longitudinal fasciculus. In an independent autopsy series, we observed that rs8070723 and rs1768208 conferred significant risk of tau pathology relative to TDP-43, and rs646776 conferred increased risk of TDP-43 pathology relative to tau. Identified brain regions and SNPs may help provide an in vivo screen for underlying pathology in FTLD and contribute to our understanding of sporadic FTLD.
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: mcmillac@mail.med.upenn.edu.
authors.forename: Corey T
authors.initials: CT
authors.lastname: McMillan
authors.affiliation: Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: Department of Radiology, Penn Image Computing and Science Laboratory, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Avants
authors.affiliation: Department of Radiology, Penn Image Computing and Science Laboratory, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cook
authors.affiliation: Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Wood
authors.affiliation: Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Eunran
authors.initials: E
authors.lastname: Suh
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Powers
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Olm
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.affiliation: Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Laboratory and Pathology Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D001921:Brain / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D056324:Diffusion Tensor Imaging; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics; D059906:Neuroimaging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D016875:tau Proteins / Q000235:genetics*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D009185:Myelin Proteins; D016875:tau Proteins; D000099183:Sortilin; C054369:MAPT protein, human; C560487:MOBP protein, human
keywords: Biomarkers; Frontotemporal lobar degeneration; Genetics; Neuroimaging