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A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy.
Chen, Jason A; Wang, Qing; Davis-Turak, Jeremy; Li, Yun; Karydas, Anna M; Hsu, Sandy C; Sears, Renee L; Chatzopoulou, Doxa; Huang, Alden Y; Wojta, Kevin J; Klein, Eric; Lee, Jason; Beekly, Duane L; Boxer, Adam; Faber, Kelley M; Haase, Claudia M; Miller, Josh; Poon, Wayne W; Rosen, Ami; Rosen, Howard; Sapozhnikova, Anna; Shapira, Jill; Varpetian, Arousiak; Foroud, Tatiana M; Levenson, Robert W; Levey, Allan I; Kukull, Walter A; Mendez, Mario F; Ringman, John; Chui, Helena; Cotman, Carl; DeCarli, Charles; Miller, Bruce L; Geschwind, Daniel H; Coppola, Giovanni.
Afiliação
  • Chen JA; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Wang Q; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Davis-Turak J; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Li Y; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Karydas AM; Memory and Aging Center, University of California, San Francisco.
  • Hsu SC; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Sears RL; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Chatzopoulou D; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Huang AY; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Wojta KJ; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Klein E; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Lee J; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • Beekly DL; National Alzheimer's Coordinating Center, University of Washington, Seattle.
  • Boxer A; Memory and Aging Center, University of California, San Francisco.
  • Faber KM; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
  • Haase CM; Department of Psychology, School of Education and Social Policy, Northwestern University, Evanston, Illinois.
  • Miller J; Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey.
  • Poon WW; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine.
  • Rosen A; Department of Neurology, Emory University, Atlanta, Georgia.
  • Rosen H; Memory and Aging Center, University of California, San Francisco.
  • Sapozhnikova A; Department of Psychology, University of California, Berkeley.
  • Shapira J; Department of Neurology, University of California, Los Angeles.
  • Varpetian A; Department of Neurology, University of Southern California, Los Angeles.
  • Foroud TM; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
  • Levenson RW; Department of Psychology, University of California, Berkeley.
  • Levey AI; Department of Neurology, Emory University, Atlanta, Georgia.
  • Kukull WA; National Alzheimer's Coordinating Center, University of Washington, Seattle.
  • Mendez MF; Department of Neurology, University of California, Los Angeles.
  • Ringman J; Department of Neurology, University of California, Los Angeles12Mary S. Easton Center for Alzheimer's Disease Research at UCLA, University of California, Los Angeles.
  • Chui H; Department of Neurology, University of Southern California, Los Angeles.
  • Cotman C; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine.
  • DeCarli C; Department of Neurology, University of California, Davis.
  • Miller BL; Memory and Aging Center, University of California, San Francisco.
  • Geschwind DH; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles10Department of Neurology, University of California, Los Angeles.
  • Coppola G; Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles10Department of Neurology, University of California, Los Angeles.
JAMA Neurol ; 72(4): 414-22, 2015 Apr.
Article em En | MEDLINE | ID: mdl-25706306
ABSTRACT
IMPORTANCE 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. DESIGN, SETTING, AND

PARTICIPANTS:

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. MAIN OUTCOMES AND

MEASURES:

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 AND RELEVANCE 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paralisia Supranuclear Progressiva / Predisposição Genética para Doença / Demência Frontotemporal / Doença de Alzheimer / Exoma Tipo de estudo: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: JAMA Neurol Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paralisia Supranuclear Progressiva / Predisposição Genética para Doença / Demência Frontotemporal / Doença de Alzheimer / Exoma Tipo de estudo: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: JAMA Neurol Ano de publicação: 2015 Tipo de documento: Article