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

Hong, Shengjun; Prokopenko, Dmitry; Dobričić, Valerija; Kilpert, Fabian; Bos, Isabelle; Vos, Stephanie J.B.; Tijms, Betty M.; Andréasson, Ulf; Blennow, Kaj; Vandenberghe, Rik; Cleynen, Isabelle; Gabel, Silvy; Schaeverbeke, Jolien; Scheltens, Philip; Teunissen, Charlotte E.; Niemantsverdriet, Ellis; Engelborghs, Sebastiaan; Frisoni, Giovanni B.; Blin, Olivier; Richardson, Jill C.; Bordet, Régis; Molinuevo, José Luís; Rami, Lorena; Kettunen, Petronella; Wallin, Anders; Lleó, Alberto; Sala, Isabel; Popp, Julius; Peyratout, Gwendoline; Martínez-Lage, Pablo; Tainta, Mikel; Dobson, Richard; Legido‐Quigley, Cristina; Sleegers, Kristel; Broeckhoven, Christine Van; Kate, Mara ten; Barkhof, Frederik; Zetterberg, Henrik; Lovestone, Simon; Streffer, Johannes; Wittig, Michael; Franke, André; Tanzi, Rudolph E.; Visser, Pieter Jelle; Bertram, Lars

doi:10.1038/s41398-020-01074-z

Cited by 51 publications

(63 citation statements)

References 31 publications

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“…Nevertheless, we identified two other SNPs (rs4975209 and rs10009321) in the 4q28.2 locus in a prior Alzheimer disease (AD) GWAS that also used Braak as a quantitative trait, however they were not in high D’ with rs56405341, our lead SNP 52 . We also observed in a separate AD GWAS using the cerebral spinal fluid Aβ42/40 ratio (dichotomized normal and abnormal) another SNP in the region (rs13129839) in high D’ with our lead and supporting SNPs (>0.89), at a genome-wide suggestive significance level and with a positive (protective) odds ratio ( p = 9.0 × 10 −6 , OR = 0.043) 53 . Taken together, these two independent genetic studies in AD suggest the signal in our GWAS might not be spurious.…”

Section: Resultssupporting

confidence: 67%

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Genome-wide association study and functional validation implicates JADE1 in tauopathy

Farrell¹,

Kim²,

Han³

et al. 2021

Preprint

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Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

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Section: Resultssupporting

confidence: 67%

“…Our study highlighted a novel locus on chromosome 4q28.2, that previously gave a suggestive signal in an independent autopsy GWAS in AD that also used Braak NFT stage as an endophenotype and a second GWAS focusing on dichotomized CSF Aβ positivity 53,90 . This prompted us to focus on this locus for further validation and functional studies.…”

Section: Discussionmentioning

confidence: 70%

Genome-wide association study and functional validation implicates JADE1 in tauopathy

Farrell¹,

Kim²,

Han³

et al. 2021

Preprint

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“…A detailed account of the genotyping procedures in EMIF-AD MBD and subsequent bioinformatic workflows can be found in the supporting information and Hong et al 17 In brief, a total of 936 DNA samples were sent for genome-wide SNP genotyping using the Infinium Global Screening Array (GSA) with Shared Custom Content (Illumina Inc.). After extensive quality control (QC) and imputation, a total of 7,778,465 autosomal SNPs with minor allele frequency (MAF) ≥0.01 were retained in 898 individuals of European ancestry for the downstream genome-wide association analyses.…”

Section: Dna Extraction Genotype Imputation and Quality Controlmentioning

confidence: 99%

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

Hong

Dobričić

Ohlei

et al. 2021

Alzheimer's & Dementia

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Introduction:Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods:We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results:We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

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“…ADNI samples were genotyped using either the Illumina 2.5-M array (a byproduct of the ADNI whole-genome sequencing sample) or the Illumina OmniQuad array [29] APOE genotype was assessed with two SNPs (rs429358, rs7412) that define the epsilon 2, 3, and 4 alleles, using DNA extracted by Cogenics from a 3 mL aliquot of EDTA blood. In EMIF, APOE genotypes were measured using genome-wide SNP genotyping with Global Screening Array (Illumina Inc., San Diego, CA, USA) [29].…”

Section: Apoe E4 Genotypingmentioning

confidence: 99%

CSF Proteomic Alzheimer’s Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals

et al. 2021

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We recently discovered three distinct pathophysiological subtypes in Alzheimer’s disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood–brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood–brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%–71%). Longitudinal p181-tau and amyloid β 1–42 (Aβ42) CSF analysis showed that in the hyperplasticity subtype p181-tau increased (β = 2.6 pg/mL per year, p = 0.01) and Aβ42 decreased over time (β = −4.4 pg/mL per year, p = 0.03), in the innate immune activation subtype p181-tau increased (β = 3.1 pg/mL per year, p = 0.01) while in the blood–brain barrier dysfunction subtype Aβ42 decreased (β = −3.7 pg/mL per year, p = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.

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

Cited by 51 publications

References 31 publications

Genome-wide association study and functional validation implicates JADE1 in tauopathy

Genome-wide association study and functional validation implicates JADE1 in tauopathy

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

CSF Proteomic Alzheimer’s Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals

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