Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.

Maria Victoria Fernández,Ben Saef,Kathleen Black,John P Budde,Jong Hun Kim,Alison Goate,Joanne Norton,Umber Dube,Jorge Del-Aguila,Ncrad ,Alexandra Medvedeva,John C Morris,Carlos Cruchaga,Yuetiva Deming,Rachel Chasse,Oscar Harari,Nia-Load Family Study Group ,Laura Ibañez

doi:10.1371/journal.pgen.1007045

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.

Highlights

Neurodegenerative diseases like Alzheimer Disease (AD), Frontotemporal dementia (FTD), Parkinson disease (PD) and Amyotrophic Lateral Sclerosis (ALS) share clinical and pathologic features
NIALOAD samples were collected under a cooperative agreement grant (U24 AG026395) awarded by the National Institute on Aging
The Discovery Phase analysis of sequence data is supported through UF1AG047133; U01AG049505 to Dr Seshadri; U01AG049506 to Dr Boerwinkle; U01AG049507 to Dr Wijsman; and U01AG049508 to Dr Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr Goate and U01AG052410 to Dr Pericak-Vance

Summary

Introduction

Neurodegenerative diseases like Alzheimer Disease (AD), Frontotemporal dementia (FTD), Parkinson disease (PD) and Amyotrophic Lateral Sclerosis (ALS) share clinical and pathologic features. Dementia is characteristic of AD and FTD, but may present in PD and ALS [1] In all these diseases we can observe two types of manifestations, either a rare and following Mendelian inheritance, or a more common seemingly non-familial representation [2]. All these diseases share the pathologic hallmark of presenting protein aggregates in different areas of the central nervous system. A clinical, and pathological crossover has been observed in the idiopathic forms [3] allowing for the assumption that different types of dementia may have overlapping genetic causes

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