Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case–control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case–control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
Highlights
Alzheimer’s disease (AD) is a progressive and devastating neurodegenerative disorder, which leads to cognitive decline, loss of autonomy, dementia, and eventually death
And in contrast to most other previous AD genome-wide association study (GWAS) (e.g., Jansen et al.[7] and Lambert et al.8), the best-associated single-nucleotide polymorphism (SNP) in this region is the variant defining the “ε4” allele in the commonly used “ε/2/3/4” haplotype
The phenotypes analyzed here related either to clinical diagnosis (i.e., AD or MCI) or to levels of cerebrospinal fluid (CSF) biomarkers revolving around various biochemical species of amyloid or tau proteins
Summary
Alzheimer’s disease (AD) is a progressive and devastating neurodegenerative disorder, which leads to cognitive decline, loss of autonomy, dementia, and eventually death. Using genetic linkage analysis followed by positional cloning led to the discovery of rare mutations in three genes encoding the amyloid-beta precursor protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) that cause fully penetrant monogenic forms of AD3. The most strongly and most consistently associated AD risk gene (even prior to GWAS5) is APOE, which encodes apolipoprotein E, a cholesterol transport protein that has been implicated in numerous amyloid-specific pathways, including amyloid trafficking, as well as plaque clearance[2,6]. In addition to APOE, nearly three dozen independent loci have been reported to be associated with disease risk by GWAS7–9. The risk genes identified to date appear to predominantly act through modulations of the immune system response, endocytotic mechanisms, cholesterol homeostasis, and APP catabolic processes[7,8]
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