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  1. Article ; Online: Interaction of background genetic risk, psychotropic medications, and primary angle closure glaucoma in the UK Biobank.

    Sayuri Sekimitsu / Jiali Wang / Tobias Elze / Ayellet V Segrè / Janey L Wiggs / Nazlee Zebardast

    PLoS ONE, Vol 17, Iss 6, p e

    2022  Volume 0270530

    Abstract: Background/aims Psychotropic medications have been reported as a risk factor for angle closure disease. However, the interaction between background genetic risk for primary angle closure glaucoma (PACG) and susceptibility to angle closure disease among ... ...

    Abstract Background/aims Psychotropic medications have been reported as a risk factor for angle closure disease. However, the interaction between background genetic risk for primary angle closure glaucoma (PACG) and susceptibility to angle closure disease among psychotropic medication users has not been investigated. Here we demonstrate the utility of a genome-wide polygenic risk score (PRS) in identifying and risk-stratifying subjects with PACG and investigate the association between PACG genetic burden and exposure to psychotropic medications on prevalent angle closure. Methods This analysis used the UK Biobank dataset, a prospective cohort study of 502,506 UK residents. We constructed a PACG PRS for participants using genome-wide association study summary statistics from a multiethnic meta-analysis using the Lassosum method. Results Among the 441,054 participants, 959 (0.22%) were identified as PACG cases. Individuals with PACG had higher PRS compared to those without PACG (0.24±1.03 SD vs. 0.00±1.00 SD, p<0.001) and PACG prevalence increased with each decile of higher PRS. Among individuals using psychotropic medication, those with PACG had higher average PRS (0.31±1.00 SD vs. 0.00±1.00 SD, p<0.001) and were more likely to have a PRS in upper deciles of polygenic risk (p = 0.04). At each decile of PRS, psychotropic medication use was associated with increased risk of PACG. These effects were more pronounced and significant in higher deciles. Conclusion We demonstrate the utility of a PRS for identifying individuals at higher risk of PACG. Additionally, we demonstrate an important relationship where the association between psychotropic medications use and PACG diagnosis varies across the polygenic risk spectrum.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

    Andrew R. Hamel / Wenjun Yan / John M. Rouhana / Aboozar Monovarfeshani / Xinyi Jiang / Puja A. Mehta / Jayshree Advani / Yuyang Luo / Qingnan Liang / Skanda Rajasundaram / Arushi Shrivastava / Katherine Duchinski / Sreekar Mantena / Jiali Wang / Tavé van Zyl / Louis R. Pasquale / Anand Swaroop / Puya Gharahkhani / Anthony P. Khawaja /
    Stuart MacGregor / International Glaucoma Genetics Consortium (IGGC) / Rui Chen / Veronique Vitart / Joshua R. Sanes / Janey L. Wiggs / Ayellet V. Segrè

    Nature Communications, Vol 15, Iss 1, Pp 1-

    2024  Volume 25

    Abstract: Abstract Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is ... ...

    Abstract Abstract Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.
    Keywords Science ; Q
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: ForestPMPlot

    Eun Yong Kang / Yurang Park / Xiao Li / Ayellet V. Segrè / Buhm Han / Eleazar Eskin

    G3: Genes, Genomes, Genetics, Vol 6, Iss 7, Pp 1793-

    A Flexible Tool for Visualizing Heterogeneity Between Studies in Meta-analysis

    2016  Volume 1798

    Abstract: Meta-analysis has become a popular tool for genetic association studies to combine different genetic studies. A key challenge in meta-analysis is heterogeneity, or the differences in effect sizes between studies. Heterogeneity complicates the ... ...

    Abstract Meta-analysis has become a popular tool for genetic association studies to combine different genetic studies. A key challenge in meta-analysis is heterogeneity, or the differences in effect sizes between studies. Heterogeneity complicates the interpretation of meta-analyses. In this paper, we describe ForestPMPlot, a flexible visualization tool for analyzing studies included in a meta-analysis. The main feature of the tool is visualizing the differences in the effect sizes of the studies to understand why the studies exhibit heterogeneity for a particular phenotype and locus pair under different conditions. We show the application of this tool to interpret a meta-analysis of 17 mouse studies, and to interpret a multi-tissue eQTL study.
    Keywords GWAS ; genetic association studies ; heterogeneity ; meta-analysis ; Genetics ; QH426-470 ; Biology (General) ; QH301-705.5 ; Science ; Q
    Language English
    Publishing date 2016-07-01T00:00:00Z
    Publisher Genetics Society of America
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Exploiting the GTEx resources to decipher the mechanisms at GWAS loci

    Alvaro N. Barbeira / Rodrigo Bonazzola / Eric R. Gamazon / Yanyu Liang / YoSon Park / Sarah Kim-Hellmuth / Gao Wang / Zhuoxun Jiang / Dan Zhou / Farhad Hormozdiari / Boxiang Liu / Abhiram Rao / Andrew R. Hamel / Milton D. Pividori / François Aguet / GTEx GWAS Working Group / Lisa Bastarache / Daniel M. Jordan / Marie Verbanck /
    Ron Do / GTEx Consortium / Matthew Stephens / Kristin Ardlie / Mark McCarthy / Stephen B. Montgomery / Ayellet V. Segrè / Christopher D. Brown / Tuuli Lappalainen / Xiaoquan Wen / Hae Kyung Im

    Genome Biology, Vol 22, Iss 1, Pp 1-

    2021  Volume 24

    Abstract: Abstract The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation ... ...

    Abstract Abstract The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2519 out of 5385) of the GWAS loci examined.
    Keywords Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: High-resolution mutation mapping reveals parallel experimental evolution in yeast.

    Ayellet V Segrè / Andrew W Murray / Jun-Yi Leu

    PLoS Biology, Vol 4, Iss 8, p e

    2006  Volume 256

    Abstract: Understanding the genetic basis of evolutionary adaptation is limited by our ability to efficiently identify the genomic locations of adaptive mutations. Here we describe a method that can quickly and precisely map the genetic basis of naturally and ... ...

    Abstract Understanding the genetic basis of evolutionary adaptation is limited by our ability to efficiently identify the genomic locations of adaptive mutations. Here we describe a method that can quickly and precisely map the genetic basis of naturally and experimentally evolved complex traits using linkage analysis. A yeast strain that expresses the evolved trait is crossed to a distinct strain background and DNA from a large pool of progeny that express the trait of interest is hybridized to oligonucleotide microarrays that detect thousands of polymorphisms between the two strains. Adaptive mutations are detected by linkage to the polymorphisms from the evolved parent. We successfully tested our method by mapping five known genes to a precision of 0.2-24 kb (0.1-10 cM), and developed computer simulations to test the effect of different factors on mapping precision. We then applied this method to four yeast strains that had independently adapted to a fluctuating glucose-galactose environment. All four strains had acquired one or more missense mutations in GAL80, the repressor of the galactose utilization pathway. When transferred into the ancestral strain, the gal80 mutations conferred the fitness advantage that the evolved strains show in the transition from glucose to galactose. Our results show an example of parallel adaptation caused by mutations in the same gene.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2006-07-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

    Puya Gharahkhani / Eric Jorgenson / Pirro Hysi / Anthony P. Khawaja / Sarah Pendergrass / Xikun Han / Jue Sheng Ong / Alex W. Hewitt / Ayellet V. Segrè / John M. Rouhana / Andrew R. Hamel / Robert P. Igo / Helene Choquet / Ayub Qassim / Navya S. Josyula / Jessica N. Cooke Bailey / Pieter W. M. Bonnemaijer / Adriana Iglesias / Owen M. Siggs /
    Terri L. Young / Veronique Vitart / Alberta A. H. J. Thiadens / Juha Karjalainen / Steffen Uebe / Ronald B. Melles / K. Saidas Nair / Robert Luben / Mark Simcoe / Nishani Amersinghe / Angela J. Cree / Rene Hohn / Alicia Poplawski / Li Jia Chen / Shi-Song Rong / Tin Aung / Eranga Nishanthie Vithana / NEIGHBORHOOD consortium / ANZRAG consortium / Biobank Japan project / FinnGen study / UK Biobank Eye and Vision Consortium / GIGA study group / 23 and Me Research Team / Gen Tamiya / Yukihiro Shiga / Masayuki Yamamoto / Toru Nakazawa / Hannah Currant / Ewan Birney / Xin Wang

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 16

    Abstract: Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci ... ...

    Abstract Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.
    Keywords Science ; Q
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: A genome-wide association search for type 2 diabetes genes in African Americans.

    Nicholette D Palmer / Caitrin W McDonough / Pamela J Hicks / Bong H Roh / Maria R Wing / S Sandy An / Jessica M Hester / Jessica N Cooke / Meredith A Bostrom / Megan E Rudock / Matthew E Talbert / Joshua P Lewis / DIAGRAM Consortium / MAGIC Investigators / Assiamira Ferrara / Lingyi Lu / Julie T Ziegler / Michele M Sale / Jasmin Divers /
    Daniel Shriner / Adebowale Adeyemo / Charles N Rotimi / Maggie C Y Ng / Carl D Langefeld / Barry I Freedman / Donald W Bowden / Benjamin F Voight / Laura J Scott / Valgerdur Steinthorsdottir / Andrew P Morris / Christian Dina / Ryan P Welch / Eleftheria Zeggini / Cornelia Huth / Yurii S Aulchenko / Gudmar Thorleifsson / Laura J McCulloch / Teresa Ferreira / Harald Grallert / Najaf Amin / Guanming Wu / Cristen J Willer / Soumya Raychaudhuri / Steve A McCarroll / Claudia Langenberg / Oliver M Hofmann / Josée Dupuis / Lu Qi / Ayellet V Segrè / Mandy van Hoek

    PLoS ONE, Vol 7, Iss 1, p e

    2012  Volume 29202

    Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African ... ...

    Abstract African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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