Abstract
Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P=3.4×10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P<0.05) but did not withstand correction for multiple testing. APOE (P=0.02) and CLU (P=0.04) variants showed significant burden on AD. In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.
Highlights
Alzheimer's disease (AD) is the most common form of dementia, affecting over 850,000 people in the UK alone, a number expected to rise to 1 million by 2025 [1]
In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3,268 variants, sex, age at death and APOE ε4 and ε2 status as predictors
We report on screening of 132 Late-onset Alzheimer’s disease (LOAD) patients from the Brains for Dementia Research (BDR) resource with the aim to identify causative or predicted pathogenic coding variants in 40 selected genes
Summary
Alzheimer's disease (AD) is the most common form of dementia, affecting over 850,000 people in the UK alone, a number expected to rise to 1 million by 2025 [1]. There are two forms distinguished by the age when symptoms first appear. In the early-onset familial form (fEOAD), symptoms appear before 65 years of age, this only accounts for about 5% of cases [2]. Mutations in the familial genes APP, PSEN1 and PSEN2 are rare but highly penetrant. Individuals with these mutations are almost certain to develop fEOAD [3]. The majority of cases are sporadic in nature and classified as late-onset (LOAD), with symptoms appearing at 65 years or later. This represents the other 95% of all incidences [4]. The rare ε2 allele confers a protective effect and appears to reduce AD risk by up to 40%
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