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JAMA Neurol. 2015 Apr;72(4):414-22. doi: 10.1001/jamaneurol.2014.4040.

A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy.

Author information

  • 1Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
  • 2Memory and Aging Center, University of California, San Francisco.
  • 3National Alzheimer's Coordinating Center, University of Washington, Seattle.
  • 4Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
  • 5Department of Psychology, School of Education and Social Policy, Northwestern University, Evanston, Illinois.
  • 6Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey.
  • 7Institute for Memory Impairments and Neurological Disorders, University of California, Irvine.
  • 8Department of Neurology, Emory University, Atlanta, Georgia.
  • 9Department of Psychology, University of California, Berkeley.
  • 10Department of Neurology, University of California, Los Angeles.
  • 11Department of Neurology, University of Southern California, Los Angeles.
  • 12Department of Neurology, University of California, Los Angeles12Mary S. Easton Center for Alzheimer's Disease Research at UCLA, University of California, Los Angeles.
  • 13Department of Neurology, University of California, Davis.
  • 14Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles10Department of Neurology, University of California, Los Angeles.

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.

PMID:
25706306
[PubMed - indexed for MEDLINE]
PMCID:
PMC4397175
Free PMC Article

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