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Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

Published on Sep 23, 2019in bioRxiv
· DOI :10.1101/774554
Shengjun Hong1
Estimated H-index: 1
(University of Lübeck),
Dmitry Prokopenko11
Estimated H-index: 11
(Harvard University)
+ 43 AuthorsLars Bertram54
Estimated H-index: 54
(University of Lübeck)
Sources
Abstract
Alzheimer9s 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 Alzheimer9s 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 of 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.
  • References (32)
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References32
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#1Isabelle Bos (UM: Maastricht University)H-Index: 4
#2Stephanie J.B. Vos (UM: Maastricht University)H-Index: 13
Last. Pieter Jelle Visser (UM: Maastricht University)H-Index: 49
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Abstract Introduction We investigated relations between amyloid-β (Aβ) status, apolipoprotein E ( APOE ) e4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). Methods We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ− vs. ...
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#1Iris E. Jansen (VU: VU University Amsterdam)H-Index: 14
#2Jeanne E. Savage (VU: VU University Amsterdam)H-Index: 12
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Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, ...
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#1Shunian Xiang (IUPUI: Indiana University – Purdue University Indianapolis)H-Index: 1
#2Zhi Huang (Purdue University)H-Index: 3
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Background Gene co-expression network (GCN) mining is a systematic approach to efficiently identify novel disease pathways, predict novel gene functions and search for potential disease biomarkers. However, few studies have systematically identified GCNs in multiple brain transcriptomic data of Alzheimer’s disease (AD) patients and looked for their specific functions.
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The e4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor of Alzheimer’s disease (AD) but does not account for the entirety of genetic risk. Genetic risk scores (GRSs) incorporating additional genetic variants have been developed to determine the genetic risk for AD, yet there is no systematic review assessing the contribution of GRSs for AD beyond the effect of APOE e4. The purpose of this systematic PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-ana...
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#1Isabelle Bos (UM: Maastricht University)H-Index: 4
#2Stephanie J.B. Vos (UM: Maastricht University)H-Index: 13
Last. Pieter Jelle Visser (UM: Maastricht University)H-Index: 49
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Background There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer’s disease (AD) in the predementia stages and to predict the rate of decline. Therefore, we set up the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study. In this report we describe the design of the study, the methods used and the characteristics of the participants.
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#1Alzheimer’s Disease Neuroimaging Initiative (WashU: Washington University in St. Louis)H-Index: 14
Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 fe...
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#1Liana G. Apostolova (IUPUI: Indiana University – Purdue University Indianapolis)H-Index: 38
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Importance Late-onset Alzheimer disease (AD) is highly heritable. Genome-wide association studies have identified more than 20 AD risk genes. The precise mechanism through which many of these genes are associated with AD remains unknown. Objective To investigate the association of the top 20 AD risk variants with brain amyloidosis. Design, Setting, and Participants This study analyzed the genetic and florbetapir F 18 data from 322 cognitively normal control individuals, 496 individuals with mild...
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A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation...
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The Alzheimer's Association's Research Roundtable met in May 2014 to explore recent progress in developing biomarkers to improve understanding of disease pathogenesis and expedite drug development. Although existing biomarkers have proved extremely useful for enrichment of subjects in clinical trials, there is a clear need to develop novel biomarkers that are minimally invasive and that more broadly characterize underlying pathogenic mechanisms, including neurodegeneration, neuroinflammation, an...
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