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  1. Article: Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation.

    Pugalenthi, Pradeep Varathan / He, Bing / Xie, Linhui / Nho, Kwangsik / Saykin, Andrew J / Yan, Jingwen

    Research square

    2024  

    Abstract: Alzheimer's disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a significant set of SNPs associated with AD and related traits. GWAS ... ...

    Abstract Alzheimer's disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a significant set of SNPs associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. Although some GWAS lead SNPs showed dominant functional effects regardless of the neighborhood SNP alleles, several other SNPs did exhibit enhanced loss or gain of function under certain genetic contexts, suggesting potential additional information hidden in the LD blocks.
    Language English
    Publishing date 2024-02-08
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-3871665/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: miR-129-5p as a biomarker for pathology and cognitive decline in Alzheimer's disease.

    Han, Sang-Won / Pyun, Jung-Min / Bice, Paula J / Bennett, David A / Saykin, Andrew J / Kim, Sang Yun / Park, Young Ho / Nho, Kwangsik

    Alzheimer's research & therapy

    2024  Volume 16, Issue 1, Page(s) 5

    Abstract: Background: Alzheimer's dementia (AD) pathogenesis involves complex mechanisms, including microRNA (miRNA) dysregulation. Integrative network and machine learning analysis of miRNA can provide insights into AD pathology and prognostic/diagnostic ... ...

    Abstract Background: Alzheimer's dementia (AD) pathogenesis involves complex mechanisms, including microRNA (miRNA) dysregulation. Integrative network and machine learning analysis of miRNA can provide insights into AD pathology and prognostic/diagnostic biomarkers.
    Methods: We performed co-expression network analysis to identify network modules associated with AD, its neuropathology markers, and cognition using brain tissue miRNA profiles from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) (N = 702) as a discovery dataset. We performed association analysis of hub miRNAs with AD, its neuropathology markers, and cognition. After selecting target genes of the hub miRNAs, we performed association analysis of the hub miRNAs with their target genes and then performed pathway-based enrichment analysis. For replication, we performed a consensus miRNA co-expression network analysis using the ROS/MAP dataset and an independent dataset (N = 16) from the Gene Expression Omnibus (GEO). Furthermore, we performed a machine learning approach to assess the performance of hub miRNAs for AD classification.
    Results: Network analysis identified a glucose metabolism pathway-enriched module (M3) as significantly associated with AD and cognition. Five hub miRNAs (miR-129-5p, miR-433, miR-1260, miR-200a, and miR-221) of M3 had significant associations with AD clinical and/or pathologic traits, with miR129-5p by far the strongest across all phenotypes. Gene-set enrichment analysis of target genes associated with their corresponding hub miRNAs identified significantly enriched biological pathways including ErbB, AMPK, MAPK, and mTOR signaling pathways. Consensus network analysis identified two AD-associated consensus network modules and two hub miRNAs (miR-129-5p and miR-221). Machine learning analysis showed that the AD classification performance (area under the curve (AUC) = 0.807) of age, sex, and APOE ε4 carrier status was significantly improved by 6.3% with inclusion of five AD-associated hub miRNAs.
    Conclusions: Integrative network and machine learning analysis identified miRNA signatures, especially miR-129-5p, as associated with AD, its neuropathology markers, and cognition, enhancing our understanding of AD pathogenesis and leading to better performance of AD classification as potential diagnostic/prognostic biomarkers.
    MeSH term(s) Humans ; Alzheimer Disease/genetics ; Reactive Oxygen Species ; Cognitive Dysfunction ; MicroRNAs/genetics ; Biomarkers
    Chemical Substances Reactive Oxygen Species ; MicroRNAs ; Biomarkers ; Mirn129 microRNA, human ; MIRN433 microRNA, human
    Language English
    Publishing date 2024-01-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2506521-X
    ISSN 1758-9193 ; 1758-9193
    ISSN (online) 1758-9193
    ISSN 1758-9193
    DOI 10.1186/s13195-023-01366-8
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  3. Article ; Online: Genome-wide association study identifies susceptibility loci of brain atrophy to NFIA and ST18 in Alzheimer's disease.

    Kim, Bo-Hyun / Nho, Kwangsik / Lee, Jong-Min

    Neurobiology of aging

    2021  Volume 102, Page(s) 200.e1–200.e11

    Abstract: To identify genetic variants influencing cortical atrophy in Alzheimer's disease (AD), we performed genome-wide association studies (GWAS) of mean cortical thicknesses in 17 AD-related brain. In this study, we used neuroimaging and genetic data of 919 ... ...

    Abstract To identify genetic variants influencing cortical atrophy in Alzheimer's disease (AD), we performed genome-wide association studies (GWAS) of mean cortical thicknesses in 17 AD-related brain. In this study, we used neuroimaging and genetic data of 919 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, which include 268 cognitively normal controls, 488 mild cognitive impairment, 163 AD individuals. We performed GWAS with 3,041,429 single nucleotide polymorphisms (SNPs) for cortical thickness. The results of GWAS indicated that rs10109716 in ST18 (ST18 C2H2C-type zinc finger transcription factor) and rs661526 in NFIA (nuclear factor I A) genes are significantly associated with mean cortical thicknesses of the left inferior frontal gyrus and left parahippocampal gyrus, respectively. The rs661526 regulates the expression levels of NFIA in the substantia nigra and frontal cortex and rs10109716 regulates the expression levels of ST18 in the thalamus. These results suggest a crucial role of identified genes for cortical atrophy and could provide further insights into the genetic basis of AD.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Atrophy/genetics ; Cerebral Cortex/metabolism ; Cerebral Cortex/pathology ; Female ; Gene Expression ; Genetic Loci/genetics ; Genome-Wide Association Study ; Humans ; Male ; NFI Transcription Factors/genetics ; NFI Transcription Factors/metabolism ; Polymorphism, Single Nucleotide ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
    Chemical Substances NFI Transcription Factors ; NFIA protein, human ; Repressor Proteins ; ST18 protein, human
    Language English
    Publishing date 2021-02-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 604505-4
    ISSN 1558-1497 ; 0197-4580
    ISSN (online) 1558-1497
    ISSN 0197-4580
    DOI 10.1016/j.neurobiolaging.2021.01.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Myelin repair in Alzheimer's disease: a review of biological pathways and potential therapeutics.

    Hirschfeld, Lauren Rose / Risacher, Shannon L / Nho, Kwangsik / Saykin, Andrew J

    Translational neurodegeneration

    2022  Volume 11, Issue 1, Page(s) 47

    Abstract: This literature review investigates the significant overlap between myelin-repair signaling pathways and pathways known to contribute to hallmark pathologies of Alzheimer's disease (AD). We discuss previously investigated therapeutic targets of amyloid, ... ...

    Abstract This literature review investigates the significant overlap between myelin-repair signaling pathways and pathways known to contribute to hallmark pathologies of Alzheimer's disease (AD). We discuss previously investigated therapeutic targets of amyloid, tau, and ApoE, as well as other potential therapeutic targets that have been empirically shown to contribute to both remyelination and progression of AD. Current evidence shows that there are multiple AD-relevant pathways which overlap significantly with remyelination and myelin repair through the encouragement of oligodendrocyte proliferation, maturation, and myelin production. There is a present need for a single, cohesive model of myelin homeostasis in AD. While determining a causative pathway is beyond the scope of this review, it may be possible to investigate the pathological overlap of myelin repair and AD through therapeutic approaches.
    MeSH term(s) Humans ; Myelin Sheath/metabolism ; Myelin Sheath/pathology ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Oligodendroglia/metabolism ; Oligodendroglia/pathology ; Remyelination ; Apolipoproteins E/metabolism
    Chemical Substances Apolipoproteins E
    Language English
    Publishing date 2022-10-26
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 2653701-1
    ISSN 2047-9158
    ISSN 2047-9158
    DOI 10.1186/s40035-022-00321-1
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  5. Article: Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation.

    Varathan, Pradeep / Xie, Linhui / He, Bing / Saykin, Andrew J / Nho, Kwangsik / Yan, Jingwen

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: Alzheimer's disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWAS) have led to a significant set of SNPs associated with AD and related traits. GWAS hits ...

    Abstract Alzheimer's disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWAS) have led to a significant set of SNPs associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed with even the strongest associations in the GWAS, the lead SNPs have been historically the focus of the field, with the remaining associations inferred as redundant. Recent deep genome annotation tools enable the prediction of function from a segment of DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits on the chromatin functions, and whether it will be altered by the genomic context (i.e., alleles of neighborhood SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impact on the downstream functions. Although some GWAS lead SNPs showed dominating functional effect regardless of the neighborhood SNP alleles, several other ones do get enhanced loss or gain of function under certain genomic context, suggesting potential extra information hidden in the LD blocks.
    Language English
    Publishing date 2023-10-23
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.23.23297399
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  6. Article: Anti-Amyloid Therapy, AD, and ARIA: Untangling the Role of CAA.

    Sin, Mo-Kyung / Zamrini, Edward / Ahmed, Ali / Nho, Kwangsik / Hajjar, Ihab

    Journal of clinical medicine

    2023  Volume 12, Issue 21

    Abstract: Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid β plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals ... ...

    Abstract Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid β plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid β plays a key role in the pathogenesis of AD and of CAA. Amyloid β accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid β accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid β level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications.
    Language English
    Publishing date 2023-10-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm12216792
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  7. Article ; Online: Discovering Precision AD Biomarkers with Varying Prognosis Effects in Genetics Driven Subpopulations.

    Lee, Brian N / Wang, Junwen / Nho, Kwangsik / Saykin, Andrew J / Shen, Li

    AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science

    2023  Volume 2023, Page(s) 340–349

    Abstract: Alzheimer's Disease (AD) is a highly heritable neurodegenerative disorder characterized by memory impairments. Understanding how genetic factors contribute to AD pathology may inform interventions to slow or prevent the progression of AD. We performed ... ...

    Abstract Alzheimer's Disease (AD) is a highly heritable neurodegenerative disorder characterized by memory impairments. Understanding how genetic factors contribute to AD pathology may inform interventions to slow or prevent the progression of AD. We performed stratified genetic analyses of 1,574 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants to examine associations between levels of quantitative traits (QT's) and future diagnosis. The Chow test was employed to determine if an individual's genetic profile affects identified predictive relationships between QT's and future diagnosis. Our chow test analysis discovered that cognitive and PET-based biomarkers differentially predicted future diagnosis when stratifying on allelic dosage of AD loci. Post-hoc bootstrapped and association analyses of biomarkers confirmed differential effects, emphasizing the necessity of stratified models to realize individualized AD diagnosis prediction. This novel application of the Chow test allows for the quantification and direct comparison of genetic-based differences. Our findings, as well as the identified QT-future diagnosis relationships, warrant future investigation from a biological context.
    Language English
    Publishing date 2023-06-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2676378-3
    ISSN 2153-4063 ; 2153-4063
    ISSN (online) 2153-4063
    ISSN 2153-4063
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Author Correction: Predicting Alzheimer's disease progression using multi-modal deep learning approach.

    Lee, Garam / Nho, Kwangsik / Kang, Byungkon / Sohn, Kyung-Ah / Kim, Dokyoon

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 12466

    Language English
    Publishing date 2023-08-01
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-39138-x
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  9. Article ; Online: Alternative Splicing Regulation of an Alzheimer's Risk Variant in CLU.

    Han, Seonggyun / Nho, Kwangsik / Lee, Younghee

    International journal of molecular sciences

    2020  Volume 21, Issue 19

    Abstract: Clusterin ( ...

    Abstract Clusterin (
    MeSH term(s) Alternative Splicing ; Alzheimer Disease/genetics ; Brain/metabolism ; Brain/pathology ; Clusterin/genetics ; Cohort Studies ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; RNA/analysis ; Sex Factors
    Chemical Substances CLU protein, human ; Clusterin ; RNA (63231-63-0)
    Language English
    Publishing date 2020-09-25
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21197079
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  10. Article ; Online: Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of

    Han, Seonggyun / Na, Yirang / Koh, Insong / Nho, Kwangsik / Lee, Younghee

    International journal of molecular sciences

    2021  Volume 22, Issue 18

    Abstract: ... ...

    Abstract TREM2
    MeSH term(s) Aged ; Alternative Splicing/genetics ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Brain/metabolism ; Brain/pathology ; Exons/genetics ; Female ; Gene Frequency/genetics ; Genetic Predisposition to Disease ; Genetic Variation/genetics ; Humans ; Male ; Membrane Glycoproteins/genetics ; RNA Splicing/genetics ; RNA-Seq ; Receptors, Immunologic/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Whole Genome Sequencing
    Chemical Substances Membrane Glycoproteins ; Receptors, Immunologic ; TREM2 protein, human
    Language English
    Publishing date 2021-09-13
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22189865
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