Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.

TitleAnalysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsFernández MVictoria, Kim JHun, Budde JP, Black K, Medvedeva A, Saef B, Deming Y, Del-Aguila J, Ibañez L, Dube U, Harari O, Norton J, Chasse R, Morris JC, Goate A, Cruchaga C
Corporate AuthorsNIA-LOAD family study group, NCRAD
JournalPLoS Genet
Volume13
Issue11
Paginatione1007045
Date Published2017 Nov
ISSN1553-7404
KeywordsAdult, Aged, Aged, 80 and over, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Case-Control Studies, Female, Frontotemporal Lobar Degeneration, Genetic Predisposition to Disease, Genotype, Humans, Longitudinal Studies, Male, Middle Aged, Mutation, Parkinson Disease, Pedigree, Presenilin-1, Protein Kinases
Abstract

Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations.

DOI10.1371/journal.pgen.1007045
Alternate JournalPLoS Genet.
PubMed ID29091718
PubMed Central IDPMC5683650
Grant ListR01 AG044546 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
RF1 AG053303 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
S10 OD018522 / OD / NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R25 DA027995 / DA / NIDA NIH HHS / United States