5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer’s Disease

Background: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer’s disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. Objective: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date. Methods: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control. Results: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects. Conclusion: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.

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5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer’s Disease

10.21203/rs.3.rs-774460/v1 ◽

2021 ◽

Author(s):

Lei Chen ◽

Shunliang Xu ◽

Qianqian Shen ◽

Hongzhuan Yu ◽

Shengjie Pei ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Cell Free Dna ◽

Cognitively Normal ◽

Free Dna ◽

Genome Wide ◽

Significant Difference ◽

Normal Controls ◽

Circulating Cell Free Dna

Abstract Background: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in nervous system. It has been reported that 5hmC is significant associated with Alzheimer’s disease (AD). Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. However, there is no research about genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD to date. Methods: We carried out a case-control study and used a highly sensitive and selective high-throughput sequencing of chemical labels to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in AD patients and the control. Results: We detected a significant difference of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls. AD patients can be well distinguished from cognitively normal controls by differentially hydroxymethylated regions (DhMRs) in cfDNA. Specially, we found 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) had prediction diagnostic potential based on their significant correlations with MMSE and MoCA scores. Conclusions: The present results suggest that 5hmC markers derived from plasma cfDNA can be served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD. Trial registration: Chinese Clinical Trial Registry, ChiCTR2100042537, registered 13 January 2021-retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=120582.

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A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

BMC Medical Genomics ◽

10.1186/1755-8794-1-44 ◽

2008 ◽

Vol 1 (1) ◽

Cited By ~ 111

Author(s):

Richard Abraham ◽

Valentina Moskvina ◽

Rebecca Sims ◽

Paul Hollingworth ◽

Angharad Morgan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Late Onset ◽

Genome Wide Association ◽

Dna Pooling ◽

Genome Wide ◽

A Genome

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A genome-wide association study of late-onset Alzheimer’s disease in a Japanese population

Psychiatric Genetics ◽

10.1097/ypg.0000000000000090 ◽

2015 ◽

Vol 25 (4) ◽

pp. 139-146 ◽

Cited By ~ 11

Author(s):

Atsushi Hirano ◽

Tomoyuki Ohara ◽

Atsushi Takahashi ◽

Masayuki Aoki ◽

Yuta Fuyuno ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Japanese Population ◽

Genome Wide Association Study ◽

Late Onset ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer’s disease in Caribbean Hispanics

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00866-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Andréa R. V. R. Horimoto ◽

Diane Xue ◽

Timothy A. Thornton ◽

Elizabeth E. Blue

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Native American ◽

Late Onset ◽

European Ancestry ◽

Admixture Mapping ◽

Native American Ancestry ◽

Genome Wide ◽

A Genome ◽

The Brain

Abstract Background Genetic studies have primarily been conducted in European ancestry populations, identifying dozens of loci associated with late-onset Alzheimer’s disease (AD). However, much of AD’s heritability remains unexplained; as the prevalence of AD varies across populations, the genetic architecture of the disease may also vary by population with the presence of novel variants or loci. Methods We conducted genome-wide analyses of AD in a sample of 2565 Caribbean Hispanics to better understand the genetic contribution to AD in this population. Statistical analysis included both admixture mapping and association testing. Evidence for differential gene expression within regions of interest was collected from independent transcriptomic studies comparing AD cases and controls in samples with primarily European ancestry. Results Our genome-wide association study of AD identified no loci reaching genome-wide significance. However, a genome-wide admixture mapping analysis that tests for association between a haplotype’s ancestral origin and AD status detected a genome-wide significant association with chromosome 3q13.11 (103.7–107.7Mb, P = 8.76E−07), driven by a protective effect conferred by the Native American ancestry (OR = 0.58, 95%CI = 0.47−0.73). Within this region, two variants were significantly associated with AD after accounting for the number of independent tests (rs12494162, P = 2.33E−06; rs1731642, P = 6.36E−05). The significant admixture mapping signal is composed of 15 haplotype blocks spanning 5 protein-coding genes (ALCAM, BBX, CBLB, CCDC54, CD47) and four brain-derived topologically associated domains, and includes markers significantly associated with the expression of ALCAM, BBX, CBLB, and CD47 in the brain. ALCAM and BBX were also significantly differentially expressed in the brain between AD cases and controls with European ancestry. Conclusion These results provide multiethnic evidence for a relationship between AD and multiple genes at 3q13.11 and illustrate the utility of leveraging genetic ancestry diversity via admixture mapping for new insights into AD.

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P3-196: A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

Alzheimer s & Dementia ◽

10.1016/j.jalz.2008.05.1762 ◽

2008 ◽

Vol 4 ◽

pp. T578-T578 ◽

Cited By ~ 1

Author(s):

Richard Abraham ◽

Lyudmila Georgieva ◽

Rebecca Sims ◽

Angharad Morgan ◽

Paul Hollingworth ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Late Onset ◽

Genome Wide Association ◽

Dna Pooling ◽

Genome Wide ◽

A Genome

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P3-216: Identification of CIS variants associating with expression levels of 12 late-onset Alzheimer's disease (LOAD) candidate genes in a Genome-Wide Association Study (GWAS)

Alzheimer s & Dementia ◽

10.1016/j.jalz.2008.05.1783 ◽

2008 ◽

Vol 4 ◽

pp. T584-T584

Author(s):

Nilufer Ertekin-Taner ◽

Fanggeng Zou ◽

Minerva Carrasquillo ◽

Samuel Younkin ◽

Li Ma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Candidate Genes ◽

Genome Wide Association Study ◽

Late Onset ◽

Genome Wide Association ◽

Expression Levels ◽

Genome Wide ◽

A Genome

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Integrated Genomic Analysis Revealed Associated Genes for Alzheimer’s Disease in APOE4 Non-Carriers

Current Alzheimer Research ◽

10.2174/1567205016666190823124724 ◽

2019 ◽

Vol 16 (8) ◽

pp. 753-763 ◽

Cited By ~ 4

Author(s):

Shan Jiang ◽

Chun-Yun Zhang ◽

Ling Tang ◽

Lan-Xue Zhao ◽

Hong-Zhuan Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genome Wide Association Study ◽

Late Onset ◽

Glycogen Synthase ◽

Critical Role ◽

Genomic Analysis ◽

Gene Clusters ◽

Tau Phosphorylation ◽

Genome Wide

Background: APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). LOAD patients carrying or not carrying APOE4 manifest distinct clinico-pathological characteristics. APOE4 has been shown to play a critical role in the pathogenesis of AD by affecting various aspects of pathological processes. However, the pathogenesis involved in LOAD not-carrying APOE4 remains elusive. Objective: We aimed to identify the associated genes involved in LOAD not-carrying APOE4. Methods: An integrated genomic analysis of datasets of genome-wide association study, genome-wide expression profiling and genome-wide linkage scan and protein–protein interaction network construction were applied to identify associated gene clusters in APOE4 non-carriers. The role of one of hub gene of an APOE4 non-carrier-associated gene cluster in tau phosphorylation was studied by knockdown and western blot. Results: We identified 12 gene clusters associated with AD APOE4 non-carriers. The hub genes associated with AD in these clusters were MAPK8, POU2F1, XRCC1, PRKCG, EXOC6, VAMP4, SIRT1, MME, NOS1, ABCA1 and LDLR. The associated genes for APOE4 non-carriers were enriched in hereditary disorder, neurological disease and psychological disorders. Moreover, knockdown of PRKCG to reduce the expression of protein kinase Cγ isoform enhanced tau phosphorylation at Thr181 and Thr231 and the expression of glycogen synthase kinase 3β and cyclin-dependent kinase 5 in the presence of APOE3 but not APOE4. Conclusion: The study provides new insight into the mechanism of distinct pathogenesis of LOAD not carrying APOE4 and prompts the functional exploration of identified genes based on APOE genotypes.

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Potential Novel Genes for Late-Onset Alzheimer’s Disease in East-Asian Descent Identified by APOE-Stratified Genome-Wide Association Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210145 ◽

2021 ◽

pp. 1-10

Author(s):

Sarang Kang ◽

Jungsoo Gim ◽

Jiwoon Lee ◽

Tamil Iniyan Gunasekaran ◽

Kyu Yeong Choi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Late Onset ◽

East Asian ◽

Genome Wide Association ◽

Japanese Cohort ◽

Genome Wide ◽

A Genome

The present study reports two novel genome-wide significant loci for late-onset Alzheimer’s disease (LOAD) identified from APOE ε4 non-carrier subjects of East Asian origin. A genome-wide association study of Alzheimer’s disease was performed in 2,291 Korean seniors in the discovery phase, from the Gwangju Alzheimer’ and Related Dementias (GARD) cohort study. The study was replicated in a Japanese cohort of 1,956 subjects that suggested two novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants is feasible in non-European ethnic groups using samples comprising fewer subjects from the more homogeneous genetic background.

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