scholarly journals Rare variants in the endocytic pathway are associated with Alzheimer’s disease, its related phenotypes, and functional consequences

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009772
Author(s):  
Lingyu Zhan ◽  
Jiajin Li ◽  
Brandon Jew ◽  
Jae Hoon Sul
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Research ◽  
Brain Damage ◽  
Rare Variant ◽  
Rare Variants ◽  
Endocytic Pathway ◽  
European Ancestry ◽  
Careful Examination ◽  
Genome Wide Association Studies

Late-onset Alzheimer’s disease (LOAD) is the most common type of dementia causing irreversible brain damage to the elderly and presents a major public health challenge. Clinical research and genome-wide association studies have suggested a potential contribution of the endocytic pathway to AD, with an emphasis on common loci. However, the contribution of rare variants in this pathway to AD has not been thoroughly investigated. In this study, we focused on the effect of rare variants on AD by first applying a rare-variant gene-set burden analysis using genes in the endocytic pathway on over 3,000 individuals with European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations of rare-variant burden within the endocytic pathway with AD, which were successfully replicated in independent datasets. We further demonstrated that this endocytic rare-variant enrichment is associated with neurofibrillary tangles (NFTs) and age-related phenotypes, increasing the risk of obtaining severer brain damage, earlier age-at-onset, and earlier age-of-death. Next, by aggregating rare variants within each gene, we sought to identify single endocytic genes associated with AD and NFTs. Careful examination using NFTs revealed one significantly associated gene, ANKRD13D. To identify functional associations, we integrated bulk RNA-Seq data from over 600 brain tissues and found two endocytic expression genes (eGenes), HLA-A and SLC26A7, that displayed significant influences on their gene expressions. Differential expressions between AD patients and controls of these three identified genes were further examined by incorporating scRNA-Seq data from 48 post-mortem brain samples and demonstrated distinct expression patterns across cell types. Taken together, our results demonstrated strong rare-variant effect in the endocytic pathway on AD risk and progression and functional effect of gene expression alteration in both bulk and single-cell resolution, which may bring more insight and serve as valuable resources for future AD genetic studies, clinical research, and therapeutic targeting.

scholarly journals Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng-Fei Wu ◽  
Xing-Hao Zhang ◽  
Ping Zhou ◽  
Rui Yin ◽  
Xiao-Ting Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Reverse Direction ◽  
Genome Wide Association Studies ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

scholarly journals Genome-Wide Meta-Analysis of Late-Onset Alzheimer's Disease Using Rare Variant Imputation in 324,809 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer's Project (IGAP)

2021 ◽  
Author(s):  
Adam C. Naj ◽  
Ganna Leonenko ◽  
Xueqiu Jian ◽  
Benjamin Grenier-Boley ◽  
Maria Carolina Dalmasso ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variant ◽  
Late Onset ◽  
Sequence Data ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Uk

Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer's Project (IGAP). Existing genotype data were imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P<10-5 were meta-analyzed with the European Alzheimer's Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10-12), SHARPIN (P=1.56×10-9), and ATF5/SIGLEC11 (P=1.03[mult]10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10-8), APH1B (P=2.10×10-13), and CLNK (P=2.24×10-10). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.

scholarly journals Whole-genome sequencing reveals new Alzheimer’s disease-associated rare variants in loci related to synaptic function and neuronal development

2020 ◽  
Author(s):  
Dmitry Prokopenko ◽  
Sarah L. Morgan ◽  
Kristina Mullin ◽  
Oliver Hofmann ◽  
Brad Chapman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Variants ◽  
Spatial Clustering ◽  
Synaptic Function ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genome Wide

AbstractINTRODUCTIONGenome-wide association studies have led to numerous genetic loci associated with Alzheimer’s disease (AD). Whole-genome sequencing (WGS) now permit genome-wide analyses to identify rare variants contributing to AD risk.METHODSWe performed single-variant and spatial clustering-based testing on rare variants (minor allele frequency ≤1%) in a family-based WGS-based association study of 2,247 subjects from 605 multiplex AD families, followed by replication in 1,669 unrelated individuals.RESULTSWe identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, CLSTN2.DISCUSSIONDownstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity. These loci have not been previously associated with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of coding regions.

scholarly journals Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

2018 ◽  
Author(s):  
BW Kunkle ◽  
B Grenier-Boley ◽  
R Sims ◽  
JC Bis ◽  
AC Naj ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variants ◽  
Late Onset ◽  
Association Studies ◽  
Meta Analysis ◽  
The Elderly ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Load Risk

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

scholarly journals Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jong-Ho Park ◽  
Inho Park ◽  
Emilia Moonkyung Youm ◽  
Sejoon Lee ◽  
June-Hee Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Disease Risk ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Ε4 Allele

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E−07) and rs12594991 (P = 2.03E−07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.

scholarly journals Quantitative phenotype scan statistic (QPSS) reveals rare variant associations with Alzheimer’s disease endophenotypes

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuriko Katsumata ◽  
David W. Fardo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variant ◽  
Rare Variants ◽  
Region Of Interest ◽  
Csf Biomarkers ◽  
Sequencing Data ◽  
Scan Statistic ◽  
Genetic Sequencing ◽  
Quantitative Phenotype

Abstract Background Current sequencing technologies have provided for a more comprehensive genome-wide assessment and have increased genotyping accuracy of rare variants. Scan statistic approaches have previously been adapted to genetic sequencing data. Unlike currently-employed association tests, scan-statistic-based approaches can both localize clusters of disease-related variants and, subsequently, examine the phenotype association within the resulting cluster. In this study, we present a novel Quantitative Phenotype Scan Statistic (QPSS) that extends an approach for dichotomous phenotypes to continuous outcomes in order to identify genomic regions where rare quantitative-phenotype-associated variants cluster. Results We demonstrate the performance and practicality of QPSS with extensive simulations and an application to a whole-genome sequencing (WGS) study of cerebrospinal fluid (CSF) biomarkers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Using QPSS, we identify regions of rare variant enrichment associated with levels of AD-related proteins, CSF Aβ1–42 and p-tau181P. Conclusions QPSS is implemented under the assumption that causal variants within a window have the same direction of effect. Typical self-contained tests employ a null hypothesis of no association between the target variant set and the phenotype. Therefore, an advantage of the proposed competitive test is that it is possible to refine a known region of interest to localize disease-associated clusters. The definition of clusters can be easily adapted based on variant function or annotation.

scholarly journals Causal effects of circulating cytokine concentrations on risk of Alzheimer’s disease: A bidirectional two-sample Mendelian randomization study

2020 ◽  
Author(s):  
Panagiota Pagoni ◽  
Laura D Howe ◽  
George Davey Smith ◽  
Yoav Ben-Shlomo ◽  
Evie Stergiakouli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Causal Effect ◽  
Causal Effects ◽  
Causal Role ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Weak Evidence ◽  
Increased Risk

ABSTRACTBackgroundThere is considerable interest in the role of neuroinflammation in the pathogenesis of Alzheimer’s disease. Evidence from observational studies suggests an association between cytokine concentrations and Alzheimer’s disease. However, establishing a causal role of cytokine concentrations on risk of Alzheimer’s disease is challenging due to bias from reverse causation and residual confounding.MethodsWe used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer’s disease and vice versa, employing genetic variants associated with cytokine concentrations (N=8,293) and Alzheimer’s disease (71,880 cases / 383,378 controls) from the largest non-overlapping genome-wide association studies (GWAS) of European ancestry.ResultsThere was weak evidence to suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR= 1.09 95%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimer’s disease. There was also weak evidence of a causal effect of 1 SD increase in levels of MIP-1b (CCL4) (OR=1.04 95%CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95%CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95%CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95%CI: 0.97 to 1.41, p=0.10), IL-8 (Wald Ratio: OR=1.21 95%CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95%CI: 0.94 to 1.56, p=0.14) on greater risk of Alzheimer’s disease. There was little evidence of a causal effect of genetic liability to Alzheimer’s disease on circulating cytokine concentrations.ConclusionsOur study provides some evidence supporting a causal role of cytokines in the pathogenesis of Alzheimer’s disease. However, more studies are needed to elucidate the specific mechanistic pathways via which cytokines alter the risk of Alzheimer’s disease.

scholarly journals A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yanfa Sun ◽  
Jingjing Zhu ◽  
Dan Zhou ◽  
Saranya Canchi ◽  
Chong Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Target Genes ◽  
Prediction Models ◽  
Association Studies ◽  
Strong Support ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. Methods We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry. Results We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10−6). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal. Conclusions Our study provides new insights into the etiology and underlying genetic architecture of AD.

scholarly journals Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer's disease-associated genes: DTNB and DLG2

2021 ◽  
Author(s):  
Dmitry Prokopenko ◽  
Sanghun Lee ◽  
Julian Hecker ◽  
Kristina Mullin ◽  
Sarah Morgan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Variants ◽  
Case Control ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Burden Test ◽  
Control Samples

Alzheimer's disease (AD) is a genetically complex disease for which roughly 30 genes have been identified via genome-wide association studies. We attempted to identify rare variants (minor allele frequency <0.01) associated with AD in a region-based, whole genome sequencing (WGS) association study (GSAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved p-values < 10-6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden test and replicated in case/control samples from the ADSP study (pmeta= 4.74*10-8). SKAT analysis revealed region-based association around the discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta=1*10-6). Here, in a region-based GSAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.

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