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  1. Article: Ancestry-specific regulatory and disease architectures are likely due to cell-type-specific gene-by-environment interactions.

    Wang, Juehan / Gazal, Steven

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: Multi-ancestry genome-wide association studies (GWAS) have highlighted the existence of variants with ancestry-specific effect sizes. Understanding where and why these ancestry-specific effects occur is fundamental to understanding the genetic basis of ... ...

    Abstract Multi-ancestry genome-wide association studies (GWAS) have highlighted the existence of variants with ancestry-specific effect sizes. Understanding where and why these ancestry-specific effects occur is fundamental to understanding the genetic basis of human diseases and complex traits. Here, we characterized genes differentially expressed across ancestries (ancDE genes) at the cell-type level by leveraging single-cell RNA-seq data in peripheral blood mononuclear cells for 21 individuals with East Asian (EAS) ancestry and 23 individuals with European (EUR) ancestry (172K cells); then, we tested if variants surrounding those genes were enriched in disease variants with ancestry-specific effect sizes by leveraging ancestry-matched GWAS of 31 diseases and complex traits (average
    Language English
    Publishing date 2023-10-21
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.20.23297214
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: A scalable variational approach to characterize pleiotropic components across thousands of human diseases and complex traits using GWAS summary statistics.

    Zhang, Zixuan / Jung, Junghyun / Kim, Artem / Suboc, Noah / Gazal, Steven / Mancuso, Nicholas

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: Genome-wide association studies (GWAS) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling ... ...

    Abstract Genome-wide association studies (GWAS) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling these approaches to ultra large-scale biobanks has been challenging. Here, we propose FactorGo, a scalable variational factor analysis model to identify and characterize pleiotropic components using biobank GWAS summary data. In extensive simulations, we observe that FactorGo outperforms the state-of-the-art (model-free) approach tSVD in capturing latent pleiotropic factors across phenotypes, while maintaining a similar computational cost. We apply FactorGo to estimate 100 latent pleiotropic factors from GWAS summary data of 2,483 phenotypes measured in European-ancestry Pan-UK BioBank individuals (N=420,531). Next, we find that factors from FactorGo are more enriched with relevant tissue-specific annotations than those identified by tSVD (P=2.58E-10), and validate our approach by recapitulating brain-specific enrichment for BMI and the height-related connection between reproductive system and muscular-skeletal growth. Finally, our analyses suggest novel shared etiologies between rheumatoid arthritis and periodontal condition, in addition to alkaline phosphatase as a candidate prognostic biomarker for prostate cancer. Overall, FactorGo improves our biological understanding of shared etiologies across thousands of GWAS.
    Language English
    Publishing date 2023-03-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.27.23287801
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A scalable approach to characterize pleiotropy across thousands of human diseases and complex traits using GWAS summary statistics.

    Zhang, Zixuan / Jung, Junghyun / Kim, Artem / Suboc, Noah / Gazal, Steven / Mancuso, Nicholas

    American journal of human genetics

    2023  Volume 110, Issue 11, Page(s) 1863–1874

    Abstract: Genome-wide association studies (GWASs) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling ... ...

    Abstract Genome-wide association studies (GWASs) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling these approaches to ultra-large-scale biobanks has been challenging. Here, we propose FactorGo, a scalable variational factor analysis model to identify and characterize pleiotropic components using biobank GWAS summary data. In extensive simulations, we observe that FactorGo outperforms the state-of-the-art (model-free) approach tSVD in capturing latent pleiotropic factors across phenotypes while maintaining a similar computational cost. We apply FactorGo to estimate 100 latent pleiotropic factors from GWAS summary data of 2,483 phenotypes measured in European-ancestry Pan-UK BioBank individuals (N = 420,531). Next, we find that factors from FactorGo are more enriched with relevant tissue-specific annotations than those identified by tSVD (p = 2.58E-10) and validate our approach by recapitulating brain-specific enrichment for BMI and the height-related connection between reproductive system and muscular-skeletal growth. Finally, our analyses suggest shared etiologies between rheumatoid arthritis and periodontal condition in addition to alkaline phosphatase as a candidate prognostic biomarker for prostate cancer. Overall, FactorGo improves our biological understanding of shared etiologies across thousands of GWASs.
    MeSH term(s) Male ; Humans ; Genome-Wide Association Study/methods ; Multifactorial Inheritance ; Phenotype ; Brain ; Arthritis, Rheumatoid/genetics ; Polymorphism, Single Nucleotide/genetics ; Genetic Pleiotropy
    Language English
    Publishing date 2023-10-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2023.09.015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 107: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Genome-wide classification of epigenetic activity reveals regions of enriched heritability in immune-related traits.

    Stricker, Miriam / Zhang, Weijiao / Cheng, Wei-Yi / Gazal, Steven / Dendrou, Calliope / Nahkuri, Satu / Palamara, Pier Francesco

    Cell genomics

    2023  Volume 4, Issue 3, Page(s) 100508

    Language English
    Publishing date 2023-11-23
    Publishing country United States
    Document type Published Erratum
    ISSN 2666-979X
    ISSN (online) 2666-979X
    DOI 10.1016/j.xgen.2024.100508
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Improved multi-ancestry fine-mapping identifies

    Lu, Zeyun / Wang, Xinran / Carr, Matthew / Kim, Artem / Gazal, Steven / Mohammadi, Pejman / Wu, Lang / Gusev, Alexander / Pirruccello, James / Kachuri, Linda / Mancuso, Nicholas

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: Multi-ancestry statistical fine-mapping ... ...

    Abstract Multi-ancestry statistical fine-mapping of
    Language English
    Publishing date 2024-04-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.15.24305836
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Partitioning gene-mediated disease heritability without eQTLs.

    Weiner, Daniel J / Gazal, Steven / Robinson, Elise B / O'Connor, Luke J

    American journal of human genetics

    2022  Volume 109, Issue 3, Page(s) 405–416

    Abstract: Unknown SNP-to-gene regulatory architecture complicates efforts to link noncoding GWAS associations with genes implicated by sequencing or functional studies. eQTLs are often used to link SNPs to genes, but expression in bulk tissue explains a small ... ...

    Abstract Unknown SNP-to-gene regulatory architecture complicates efforts to link noncoding GWAS associations with genes implicated by sequencing or functional studies. eQTLs are often used to link SNPs to genes, but expression in bulk tissue explains a small fraction of disease heritability. A simple but successful approach has been to link SNPs with nearby genes via base pair windows, but genes may often be regulated by SNPs outside their window. We propose the abstract mediation model (AMM) to estimate (1) the fraction of heritability mediated by the closest or k
    MeSH term(s) Gene Expression Regulation/genetics ; Genome-Wide Association Study ; Humans ; Phenotype ; Polymorphism, Single Nucleotide/genetics
    Language English
    Publishing date 2022-02-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2022.01.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 107: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: Genome-wide classification of epigenetic activity reveals regions of enriched heritability in immune-related traits

    Miriam Stricker / Weijiao Zhang / Wei-Yi Cheng / Steven Gazal / Calliope Dendrou / Satu Nahkuri / Pier Francesco Palamara

    Cell Genomics, Vol 4, Iss 1, Pp 100469- (2024)

    2024  

    Abstract: Summary: Epigenetics underpins the regulation of genes known to play a key role in the adaptive and innate immune system (AIIS). We developed a method, EpiNN, that leverages epigenetic data to detect AIIS-relevant genomic regions and used it to detect 2, ... ...

    Abstract Summary: Epigenetics underpins the regulation of genes known to play a key role in the adaptive and innate immune system (AIIS). We developed a method, EpiNN, that leverages epigenetic data to detect AIIS-relevant genomic regions and used it to detect 2,765 putative AIIS loci. Experimental validation of one of these loci, DNMT1, provided evidence for a novel AIIS-specific transcription start site. We built a genome-wide AIIS annotation and used linkage disequilibrium (LD) score regression to test whether it predicts regional heritability using association statistics for 176 traits. We detected significant heritability effects (average |τ∗|=1.65) for 20 out of 26 immune-relevant traits. In a meta-analysis, immune-relevant traits and diseases were 4.45× more enriched for heritability than other traits. The EpiNN annotation was also depleted of trans-ancestry genetic correlation, indicating ancestry-specific effects. These results underscore the effectiveness of leveraging supervised learning algorithms and epigenetic data to detect loci implicated in specific classes of traits and diseases.
    Keywords heritability ; immune system ; machine learning ; epigenetics ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
    Subject code 006
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Genome-wide classification of epigenetic activity reveals regions of enriched heritability in immune-related traits.

    Stricker, Miriam / Zhang, Weijiao / Cheng, Wei-Yi / Gazal, Steven / Dendrou, Calliope / Nahkuri, Satu / Palamara, Pier Francesco

    Cell genomics

    2023  Volume 4, Issue 1, Page(s) 100469

    Abstract: Epigenetics underpins the regulation of genes known to play a key role in the adaptive and innate immune system (AIIS). We developed a method, EpiNN, that leverages epigenetic data to detect AIIS-relevant genomic regions and used it to detect 2,765 ... ...

    Abstract Epigenetics underpins the regulation of genes known to play a key role in the adaptive and innate immune system (AIIS). We developed a method, EpiNN, that leverages epigenetic data to detect AIIS-relevant genomic regions and used it to detect 2,765 putative AIIS loci. Experimental validation of one of these loci, DNMT1, provided evidence for a novel AIIS-specific transcription start site. We built a genome-wide AIIS annotation and used linkage disequilibrium (LD) score regression to test whether it predicts regional heritability using association statistics for 176 traits. We detected significant heritability effects (average |τ
    MeSH term(s) Phenotype ; Linkage Disequilibrium/genetics ; Quantitative Trait Loci ; Genomics ; Epigenesis, Genetic/genetics
    Language English
    Publishing date 2023-12-28
    Publishing country United States
    Document type Meta-Analysis ; Journal Article
    ISSN 2666-979X
    ISSN (online) 2666-979X
    DOI 10.1016/j.xgen.2023.100469
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Rhinovirus infection of airway epithelial cells uncovers the non-ciliated subset as a likely driver of genetic susceptibility to childhood-onset asthma.

    Djeddi, Sarah / Fernandez-Salinas, Daniela / Huang, George X / Aguiar, Vitor R C / Mohanty, Chitrasen / Kendziorski, Christina / Gazal, Steven / Boyce, Joshua / Ober, Carole / Gern, James / Barrett, Nora / Gutierrez-Arcelus, Maria

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: Asthma is a complex disease caused by genetic and environmental factors. Epidemiological studies have shown that in children, wheezing during rhinovirus infection (a cause of the common cold) is associated with asthma development during childhood. This ... ...

    Abstract Asthma is a complex disease caused by genetic and environmental factors. Epidemiological studies have shown that in children, wheezing during rhinovirus infection (a cause of the common cold) is associated with asthma development during childhood. This has led scientists to hypothesize there could be a causal relationship between rhinovirus infection and asthma or that RV-induced wheezing identifies individuals at increased risk for asthma development. However, not all children who wheeze when they have a cold develop asthma. Genome-wide association studies (GWAS) have identified hundreds of genetic variants contributing to asthma susceptibility, with the vast majority of likely causal variants being non-coding. Integrative analyses with transcriptomic and epigenomic datasets have indicated that T cells drive asthma risk, which has been supported by mouse studies. However, the datasets ascertained in these integrative analyses lack airway epithelial cells. Furthermore, large-scale transcriptomic T cell studies have not identified the regulatory effects of most non-coding risk variants in asthma GWAS, indicating there could be additional cell types harboring these "missing regulatory effects". Given that airway epithelial cells are the first line of defense against rhinovirus, we hypothesized they could be mediators of genetic susceptibility to asthma. Here we integrate GWAS data with transcriptomic datasets of airway epithelial cells subject to stimuli that could induce activation states relevant to asthma. We demonstrate that epithelial cultures infected with rhinovirus significantly upregulate childhood-onset asthma-associated genes. We show that this upregulation occurs specifically in non-ciliated epithelial cells. This enrichment for genes in asthma risk loci, or 'asthma heritability enrichment' is also significant for epithelial genes upregulated with influenza infection, but not with SARS-CoV-2 infection or cytokine activation. Additionally, cells from patients with asthma showed a stronger heritability enrichment compared to cells from healthy individuals. Overall, our results suggest that rhinovirus infection is an environmental factor that interacts with genetic risk factors through non-ciliated airway epithelial cells to drive childhood-onset asthma.
    Language English
    Publishing date 2024-02-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.02.24302068
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: SNP-to-gene linking strategies reveal contributions of enhancer-related and candidate master-regulator genes to autoimmune disease.

    Dey, Kushal K / Gazal, Steven / van de Geijn, Bryce / Kim, Samuel Sungil / Nasser, Joseph / Engreitz, Jesse M / Price, Alkes L

    Cell genomics

    2022  Volume 2, Issue 7

    Abstract: We assess contributions to autoimmune disease of genes whose regulation is driven by enhancer regions (enhancer-related) and genes that regulate other genes ... ...

    Abstract We assess contributions to autoimmune disease of genes whose regulation is driven by enhancer regions (enhancer-related) and genes that regulate other genes in
    Language English
    Publishing date 2022-07-19
    Publishing country United States
    Document type Journal Article
    ISSN 2666-979X
    ISSN (online) 2666-979X
    DOI 10.1016/j.xgen.2022.100145
    Database MEDical Literature Analysis and Retrieval System OnLINE

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