Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease

PLoS Genetics
Maria Victoria FernándezCarlos Cruchaga

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.

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Citations

Mar 29, 2019·International Journal of Molecular Sciences·Vo Van GiauSangYun Kim
Jul 10, 2019·Journal of Alzheimer's Disease : JAD·Sara López-GarcíaPascual Sánchez-Juan
Sep 18, 2020·Annals of Clinical and Translational Neurology·Weiwei ZhangLu Shen
Jul 28, 2020·Genes·Ryan HoganGilbert Bernier
Apr 26, 2018·Frontiers in Neuroscience·Laura IbanezBruno A Benitez
Jun 12, 2019·Scientific Reports·Vo Van GiauSang Yun Kim
Jun 23, 2020·Journal of Alzheimer's Disease : JAD·Laura LuukkainenJohanna Krüger
May 10, 2019·Molecular Neurodegeneration·Jorge L Del-AguilaCarlos Cruchaga
Jan 31, 2020·Acta Neuropathologica Communications·Tatiana OrmeJose Bras
May 10, 2018·Frontiers in Medicine·Yun Freudenberg-HuaPeter Davies
Feb 26, 2021·Translational Psychiatry·Sonia Moreno-GrauUNKNOWN Alzheimer’s Disease Neuroimaging Initiative
Jan 4, 2022·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Dolly Reyes-DumeyerRichard Mayeux

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Methods Mentioned

BETA
PCR
PCAs

Software Mentioned

Plink1
dbGAP
GeneMapper
SnpEff
R package
fastq
rvtest

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