Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset

Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline

Genome-wide meta-analysis of short-tandem repeats for Parkinson’s disease risk using genotype imputation

Idiopathic Parkinson’s disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinson’s disease reported on eight suggestive short-tandem repeat-based risk loci (α = 5.3 × 10−6), of which four were novel, i.e. they had not been implicated in Parkinson’s disease risk by genome-wide association analyses of single-nucleotide polymorphisms before. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson’s disease case–control dataset (n = 4757). Furthermore, we combined the results from both studies by meta-analysis resulting in the largest Parkinson’s disease genome-wide association study of short-tandem repeats to date (n = 43 844). Lastly, we investigated whether leading short-tandem repeat risk variants exert functional effects on gene expression regulation based on methylation quantitative trait locus data in human ‘post-mortem’ brain (n = 142). None of the eight previously reported short-tandem repeats were significantly associated with Parkinson’s disease in our independent dataset after multiple testing correction (α = 6.25 × 10−3). However, we observed modest support for short-tandem repeats near CCAR2 and NCOR1 in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (α = 6.3 × 10−7) short-tandem repeat signals, we identified seven novel suggestive Parkinson’s disease short-tandem repeat risk loci (α = 5.3 × 10−6). Of these, especially a short-tandem repeat near MEIOSIN showed consistent evidence for association across datasets. CCAR2, NCOR1 and one novel suggestive locus identified here (LINC01012) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinson’s disease risk and cis DNA methylation in brain. Larger studies, ideally using short-tandem repeats called from whole-sequencing data, are needed to more fully investigate their role in Parkinson’s disease

Epigenome-wide association study in peripheral tissues highlights DNA methylation profiles associated with episodic memory performance in humans

The decline in episodic memory (EM) performance is a hallmark of cognitive aging and an early clinical sign in Alzheimer’s disease (AD). In this study, we conducted an epigenome-wide association study (EWAS) using DNA methylation (DNAm) profiles from buccal and blood samples for cross-sectional (n = 1019) and longitudinal changes in EM performance (n = 626; average follow-up time 5.4 years) collected under the auspices of the Lifebrain consortium project. The mean age of participants with cross-sectional data was 69 ± 11 years (30–90 years), with 50% being females. We identified 21 loci showing suggestive evidence of association (p < 1 × 10−5) with either or both EM phenotypes. Among these were SNCA, SEPW1 (both cross-sectional EM), ITPK1 (longitudinal EM), and APBA2 (both EM traits), which have been linked to AD or Parkinson’s disease (PD) in previous work. While the EM phenotypes were nominally significantly (p < 0.05) associated with poly-epigenetic scores (PESs) using EWASs on general cognitive function, none remained significant after correction for multiple testing. Likewise, estimating the degree of “epigenetic age acceleration” did not reveal significant associations with either of the two tested EM phenotypes. In summary, our study highlights several interesting candidate loci in which differential DNAm patterns in peripheral tissue are associated with EM performance in humans

Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset

Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets

Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease

Abstract Background Studies on DNA methylation (DNAm) in Alzheimer’s disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression. Methods Here, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined these with two previously published EC datasets by meta-analysis (total n = 337). Results We identified 12 cytosine-phosphate-guanine (CpG) sites showing epigenome-wide significant association with either case–control status or Braak’s tau-staging. Four of these CpGs, located in proximity to CNFN/LIPE, TENT5A, PALD1/PRF1, and DIRAS1, represent novel findings. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. Lastly, by calculating rates of epigenetic age acceleration using two recently proposed “epigenetic clock” estimators we found a significant association with accelerated epigenetic aging in the brains of AD patients vs. controls. Conclusion In summary, our study represents the hitherto most comprehensive EWAS in AD using EC and highlights several novel differentially methylated loci with potential effects on gene expression

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning: Summary statistics

Summary statistics for a genome-wide association study (GWAS) of Alzheimer's disease CSF biomarkers principal components (PCs). This dataset accompanies the publication "Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning". The article is currently in press at Genome Medicine. A link will be provided upon publication, but see the medRxiv preprint in the meantime: Neumann, A., Ohlei, O., Küçükali, F., Bos, I. J., Vos, S., Prokopenko, D., ... & Kristel Sleegers & Lars Bertram. (2022). Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning. medRxiv, 2022-08. https://doi.org/10.1101/2022.08.02.22278185 A GWAS was performed for five different PC biomarkers. PC1: Tau pathology/degeneration PC2: Aβ Pathology PC3: Injury/inflammation PC4: Non-AD inflammation PC5: Non-AD synaptic functioning Each GWAS was performed in either males and females ("all"), in females only ("female"), or in males only ("male"). In addition, we also ran an interaction model with sex as moderator ("interaction"). Each file includes output of the meta-analysis between the EMIF-AD study and ADNI. The files contain following columns: CHROM: Chromosome POS: Position according to Build 37 ID: Chromosome:Position A1: Effect allele A2: Other allele BETA: Effect of one copy of the effect allele on biomarker PCs in SD. In case of sex interaction, the effect specific to females. SE: Standard Error P: p-value D: Direction in ADNI and EMIF-AD respectively Het: Heterogeneity statistics (I2, and corresponding χ2, degrees of freedom and p-value

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.

Introduction Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. Methods We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). Results Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. Discussion The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets