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

TitleA multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy.
Publication TypeJournal Article
Year of Publication2015
AuthorsChen JA, Wang Q, Davis-Turak J, Li Y, Karydas AM, Hsu SC, Sears RL, Chatzopoulou D, Huang AY, Wojta KJ, Klein E, Lee J, Beekly DL, Boxer A, Faber KM, Haase CM, Miller J, Poon WW, Rosen A, Rosen H, Sapozhnikova A, Shapira J, Varpetian A, Foroud TM, Levenson RW, Levey AI, Kukull WA, Mendez MF, Ringman J, Chui H, Cotman C, DeCarli C, Miller BL, Geschwind DH, Coppola G
JournalJAMA Neurol
Volume72
Issue4
Pagination414-22
Date Published2015 Apr
ISSN2168-6157
KeywordsAdult, Aged, Aged, 80 and over, Alzheimer Disease, Exome, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Microarray Analysis, Middle Aged, Risk, Supranuclear Palsy, Progressive
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.

DOI10.1001/jamaneurol.2014.4040
Alternate JournalJAMA Neurol
PubMed ID25706306
PubMed Central IDPMC4397175
Grant ListRC1 AG035610 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
R01 AG041762 / AG / NIA NIH HHS / United States
P50 AG16570 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG05142 / AG / NIA NIH HHS / United States
R01 AG042292 / AG / NIA NIH HHS / United States
R01 AG038791 / AG / NIA NIH HHS / United States
P01 AG000538 / AG / NIA NIH HHS / United States
U01 AG016979 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P30 NS062691 / NS / NINDS NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
P0I AG000538 / AG / NIA NIH HHS / United States
R01 AG032306 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
R01 AG26938 / AG / NIA NIH HHS / United States
F31 NS084556 / NS / NINDS NIH HHS / United States
UL1 TR001414 / TR / NCATS NIH HHS / United States
R01 MH097268 / MH / NIMH NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
U54 NS092089 / NS / NINDS NIH HHS / United States
U24 AG21886 / AG / NIA NIH HHS / United States
R01 AG026938 / AG / NIA NIH HHS / United States