title: A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy.
abstract: OBJECTIVE
  Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level.
  
  
  OBJECTIVE
  To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP.
  
  
  METHODS
  We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed.
  
  
  METHODS
  Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP.
  
  
  RESULTS
  Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD.
  
  
  CONCLUSIONS
  Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Chen
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis-Turak
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Memory and Aging Center, University of California, San Francisco.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Karydas
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Sandy C
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Sears
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Doxa
authors.initials: D
authors.lastname: Chatzopoulou
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Alden Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wojta
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Eric
authors.initials: E
authors.lastname: Klein
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
authors.forename: Jason
authors.initials: J
authors.lastname: Lee
authors.affiliation: National Alzheimer's Coordinating Center, University of Washington, Seattle.
authors.forename: Duane L
authors.initials: DL
authors.lastname: Beekly
authors.affiliation: Memory and Aging Center, University of California, San Francisco.
authors.forename: Adam
authors.initials: A
authors.lastname: Boxer
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Faber
authors.affiliation: Department of Psychology, School of Education and Social Policy, Northwestern University, Evanston, Illinois.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Haase
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey.
authors.forename: Josh
authors.initials: J
authors.lastname: Miller
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: Department of Neurology, Emory University, Atlanta, Georgia.
authors.forename: Ami
authors.initials: A
authors.lastname: Rosen
authors.affiliation: Memory and Aging Center, University of California, San Francisco.
authors.forename: Howard
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Department of Psychology, University of California, Berkeley.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapozhnikova
authors.affiliation: Department of Neurology, University of California, Los Angeles.
authors.forename: Jill
authors.initials: J
authors.lastname: Shapira
authors.affiliation: Department of Neurology, University of Southern California, Los Angeles.
authors.forename: Arousiak
authors.initials: A
authors.lastname: Varpetian
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Department of Psychology, University of California, Berkeley.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Levenson
authors.affiliation: Department of Neurology, Emory University, Atlanta, Georgia.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: National Alzheimer's Coordinating Center, University of Washington, Seattle.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
authors.affiliation: Department of Neurology, University of California, Los Angeles.
authors.forename: Mario F
authors.initials: MF
authors.lastname: Mendez
authors.affiliation: Department of Neurology, University of California, Los Angeles12Mary S. Easton Center for Alzheimer's Disease Research at UCLA, University of California, Los Angeles.
authors.forename: John
authors.initials: J
authors.lastname: Ringman
authors.affiliation: Department of Neurology, University of Southern California, Los Angeles.
authors.forename: Helena
authors.initials: H
authors.lastname: Chui
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine.
authors.forename: Carl
authors.initials: C
authors.lastname: Cotman
authors.affiliation: Department of Neurology, University of California, Davis.
authors.forename: Charles
authors.initials: C
authors.lastname: DeCarli
authors.affiliation: Memory and Aging Center, University of California, San Francisco.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles10Department of Neurology, University of California, Los Angeles.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles10Department of Neurology, University of California, Los Angeles.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D012306:Risk; D013494:Supranuclear Palsy, Progressive / Q000235:genetics*