title: Expression of novel Alzheimer's disease risk genes in control and Alzheimer's disease brains.
abstract: Late onset Alzheimer's disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.
authors.affiliation: Department of Psychiatry and Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Jeng
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: Janet
authors.initials: J
authors.lastname: Cady
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D017668:Age of Onset; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D051152:Clusterin / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007109:Immunity / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors; D013569:Synapses / Q000235:genetics / Q000473:pathology
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; C495242:CLU protein, human; D051152:Clusterin; C574492:MS4A6A protein, human; D008565:Membrane Proteins