134 results on '"Robert P. Igo"'
Search Results
2. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries
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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, and Me Research Team, Gen Tamiya, Yukihiro Shiga, Masayuki Yamamoto, Toru Nakazawa, Hannah Currant, Ewan Birney, Xin Wang, Adam Auton, Michelle K. Lupton, Nicholas G. Martin, Adeyinka Ashaye, Olusola Olawoye, Susan E. Williams, Stephen Akafo, Michele Ramsay, Kazuki Hashimoto, Yoichiro Kamatani, Masato Akiyama, Yukihide Momozawa, Paul J. Foster, Peng T. Khaw, James E. Morgan, Nicholas G. Strouthidis, Peter Kraft, Jae H. Kang, Chi Pui Pang, Francesca Pasutto, Paul Mitchell, Andrew J. Lotery, Aarno Palotie, Cornelia van Duijn, Jonathan L. Haines, Chris Hammond, Louis R. Pasquale, Caroline C. W. Klaver, Michael Hauser, Chiea Chuen Khor, David A. Mackey, Michiaki Kubo, Ching-Yu Cheng, Jamie E. Craig, Stuart MacGregor, and Janey L. Wiggs
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Science - 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.
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- 2021
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3. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract
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Ekaterina Yonova-Doing, Wanting Zhao, Robert P. Igo, Chaolong Wang, Periasamy Sundaresan, Kristine E. Lee, Gyungah R. Jun, Alexessander Couto Alves, Xiaoran Chai, Anita S. Y. Chan, Mei Chin Lee, Allan Fong, Ava G. Tan, Chiea Chuen Khor, Emily Y. Chew, Pirro G. Hysi, Qiao Fan, Jacqueline Chua, Jaeyoon Chung, Jiemin Liao, Johanna M. Colijn, Kathryn P. Burdon, Lars G. Fritsche, Maria K. Swift, Maryam H. Hilmy, Miao Ling Chee, Milly Tedja, Pieter W. M. Bonnemaijer, Preeti Gupta, Queenie S. Tan, Zheng Li, Eranga N. Vithana, Ravilla D. Ravindran, Soon-Phaik Chee, Yuan Shi, Wenting Liu, Xinyi Su, Xueling Sim, Yang Shen, Ya Xing Wang, Hengtong Li, Yih-Chung Tham, Yik Ying Teo, Tin Aung, Kerrin S. Small, Paul Mitchell, Jost B. Jonas, Tien Yin Wong, Astrid E. Fletcher, Caroline C. W. Klaver, Barbara E. K. Klein, Jie Jin Wang, Sudha K. Iyengar, Christopher J. Hammond, and Ching-Yu Cheng
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Biology (General) ,QH301-705.5 - Abstract
Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.
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- 2020
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4. Statistical driver genes as a means to uncover missing heritability for age-related macular degeneration
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Andrea R. Waksmunski, Michelle Grunin, Tyler G. Kinzy, Robert P. Igo, Jonathan L. Haines, and Jessica N. Cooke Bailey
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Genome-wide association study ,Pathway analysis ,Statistical driver gene ,GREML ,Heritability ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Age-related macular degeneration (AMD) is a progressive retinal disease contributing to blindness worldwide. Multiple estimates for AMD heritability (h 2 ) exist; however, a substantial proportion of h 2 is not attributable to known genomic loci. The International AMD Genomics Consortium (IAMDGC) gathered the largest dataset of advanced AMD (ADV) cases and controls available and identified 34 loci containing 52 independent risk variants defining known AMD h 2 . To better define AMD heterogeneity, we used Pathway Analysis by Randomization Incorporating Structure (PARIS) on the IAMDGC data and identified 8 statistical driver genes (SDGs), including 2 novel SDGs not discovered by the IAMDGC. We chose to further investigate these pathway-based risk genes and determine their contribution to ADV h 2 , as well as the differential ADV subtype h 2 . Methods We performed genomic-relatedness-based restricted maximum-likelihood (GREML) analyses on ADV, geographic atrophy (GA), and choroidal neovascularization (CNV) subtypes to investigate the h 2 of genotyped variants on the full DNA array chip, 34 risk loci (n = 2758 common variants), 52 variants from the IAMDGC 2016 GWAS, and the 8 SDGs, specifically the novel 2 SDGs, PPARA and PLCG2. Results Via GREML, full chip h 2 was 44.05% for ADV, 46.37% for GA, and 62.03% for CNV. The lead 52 variants’ h 2 (ADV: 14.52%, GA: 8.02%, CNV: 13.62%) and 34 loci h 2 (ADV: 13.73%, GA: 8.81%, CNV: 12.89%) indicate that known variants contribute ~ 14% to ADV h 2 . SDG variants account for a small percentage of ADV, GA, and CNV heritability, but estimates based on the combination of SDGs and the 34 known loci are similar to those calculated for known loci alone. We identified modest epistatic interactions among variants in the 2 SDGs and the 52 IAMDGC variants, including modest interactions between variants in PPARA and PLCG2. Conclusions Pathway analyses, which leverage biological relationships among genes in a pathway, may be useful in identifying additional loci that contribute to the heritability of complex disorders in a non-additive manner. Heritability analyses of these loci, especially amongst disease subtypes, may provide clues to the importance of specific genes to the genetic architecture of AMD.
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- 2020
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5. Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy
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Natalie A. Afshari, Robert P. Igo, Nathan J. Morris, Dwight Stambolian, Shiwani Sharma, V. Lakshmi Pulagam, Steven Dunn, John F. Stamler, Barbara J. Truitt, Jacqueline Rimmler, Abraham Kuot, Christopher R. Croasdale, Xuejun Qin, Kathryn P. Burdon, S. Amer Riazuddin, Richard Mills, Sonja Klebe, Mollie A. Minear, Jiagang Zhao, Elmer Balajonda, George O. Rosenwasser, Keith H Baratz, V. Vinod Mootha, Sanjay V. Patel, Simon G. Gregory, Joan E. Bailey-Wilson, Marianne O. Price, Francis W. Price, Jamie E. Craig, John H. Fingert, John D. Gottsch, Anthony J. Aldave, Gordon K. Klintworth, Jonathan H. Lass, Yi-Ju Li, and Sudha K. Iyengar
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Science - Abstract
Fuchs endothelial corneal dystrophy (FECD) is one of the most common reasons for corneal transplantation, and is known to cluster in families. Here, the authors discover new genetic loci associated with FECD with sex-specific effects and implications for disease mechanism.
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- 2017
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6. Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error
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Qiao Fan, Virginie J. M. Verhoeven, Robert Wojciechowski, Veluchamy A. Barathi, Pirro G. Hysi, Jeremy A. Guggenheim, René Höhn, Veronique Vitart, Anthony P. Khawaja, Kenji Yamashiro, S Mohsen Hosseini, Terho Lehtimäki, Yi Lu, Toomas Haller, Jing Xie, Cécile Delcourt, Mario Pirastu, Juho Wedenoja, Puya Gharahkhani, Cristina Venturini, Masahiro Miyake, Alex W. Hewitt, Xiaobo Guo, Johanna Mazur, Jenifer E. Huffman, Katie M. Williams, Ozren Polasek, Harry Campbell, Igor Rudan, Zoran Vatavuk, James F. Wilson, Peter K. Joshi, George McMahon, Beate St Pourcain, David M. Evans, Claire L. Simpson, Tae-Hwi Schwantes-An, Robert P. Igo, Alireza Mirshahi, Audrey Cougnard-Gregoire, Céline Bellenguez, Maria Blettner, Olli Raitakari, Mika Kähönen, Ilkka Seppälä, Tanja Zeller, Thomas Meitinger, Janina S. Ried, Christian Gieger, Laura Portas, Elisabeth M. van Leeuwen, Najaf Amin, André G. Uitterlinden, Fernando Rivadeneira, Albert Hofman, Johannes R. Vingerling, Ya Xing Wang, Xu Wang, Eileen Tai-Hui Boh, M. Kamran Ikram, Charumathi Sabanayagam, Preeti Gupta, Vincent Tan, Lei Zhou, Candice E. H. Ho, Wan’e Lim, Roger W. Beuerman, Rosalynn Siantar, E-Shyong Tai, Eranga Vithana, Evelin Mihailov, Chiea-Chuen Khor, Caroline Hayward, Robert N. Luben, Paul J. Foster, Barbara E. K. Klein, Ronald Klein, Hoi-Suen Wong, Paul Mitchell, Andres Metspalu, Tin Aung, Terri L. Young, Mingguang He, Olavi Pärssinen, Cornelia M. van Duijn, Jie Jin Wang, Cathy Williams, Jost B. Jonas, Yik-Ying Teo, David A. Mackey, Konrad Oexle, Nagahisa Yoshimura, Andrew D. Paterson, Norbert Pfeiffer, Tien-Yin Wong, Paul N. Baird, Dwight Stambolian, Joan E. Bailey Wilson, Ching-Yu Cheng, Christopher J. Hammond, Caroline C. W. Klaver, Seang-Mei Saw, and Consortium for Refractive Error and Myopia (CREAM)
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Science - Abstract
This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.
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- 2016
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7. Younger Age and Albuminuria are Associated with Proliferative Diabetic Retinopathy and Diabetic Macular Edema in the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study
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Gayatri Susarla, A.N. Rizza, Ashley Li, Samuel Han, Rehana Khan, Weilin Chan, Ines Lains, Atitaya Apivatthakakul, Kim Brustoski, Vikas Khetan, Rajiv Raman, Robert P. Igo, Sudha K. Iyengar, Sinnakaruppan Mathavan, and Lucia Sobrin
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Glycated Hemoglobin ,Male ,Diabetic Retinopathy ,Macular Edema ,Sensory Systems ,Cellular and Molecular Neuroscience ,Ophthalmology ,Cholesterol ,Diabetes Mellitus, Type 2 ,Risk Factors ,Albuminuria ,Humans ,Prospective Studies ,Triglycerides - Published
- 2022
8. A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration
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Rosie Clark, Samantha Sze-Yee Lee, Ran Du, Yining Wang, Sander C.M. Kneepkens, Jason Charng, Yu Huang, Michael L. Hunter, Chen Jiang, J.Willem L. Tideman, Ronald B. Melles, Caroline C.W. Klaver, David A. Mackey, Cathy Williams, Hélène Choquet, Kyoko Ohno-Matsui, Jeremy A. Guggenheim, Joan E. Bailey-Wilson, Paul N. Baird, Veluchamy A. Barathi, Ginevra Biino, Kathryn P. Burdon, Harry Campbell, Li Jia Chen, Ching-Yu Cheng, Emily Y. Chew, Jamie E. Craig, Margaret M. Deangelis, Cécile Delcourt, Xiaohu Ding, Qiao Fan, Maurizio Fossarello, Paul J. Foster, Puya Gharahkhani, Xiaobo Guo, Annechien E.G. Haarman, Toomas Haller, Christopher J. Hammond, Xikun Han, Caroline Hayward, Mingguang He, Alex W. Hewitt, Quan Hoang, Pirro G. Hysi, Adriana I. Iglesias, Robert P. Igo, Sudha K. Iyengar, Jost B. Jonas, Mika Kähönen, Jaakko Kaprio, Anthony P. Khawaja, Barbara E. Klein, Jonathan H. Lass, Kris Lee, Terho Lehtimäki, Deyana Lewis, Qing Li, Shi-Ming Li, Leo-Pekka Lyytikäinen, Stuart MacGregor, Nicholas G. Martin, Akira Meguro, Andres Metspalu, Candace Middlebrooks, Masahiro Miyake, Nobuhisa Mizuki, Anthony Musolf, Stefan Nickels, Konrad Oexle, Chi Pui Pang, Olavi Pärssinen, Andrew D. Paterson, Norbert Pfeiffer, Ozren Polasek, Jugnoo S. Rahi, Olli Raitakari, Igor Rudan, Srujana Sahebjada, Seang-Mei Saw, Claire L. Simpson, Dwight Stambolian, E-Shyong Tai, Milly S. Tedja, J. Willem L. Tideman, Akitaka Tsujikawa, Cornelia M. van Duijn, Virginie J.M. Verhoeven, Veronique Vitart, Ningli Wang, Ya Xing Wang, Juho Wedenoja, Wen Bin Wei, Katie M. Williams, James F. Wilson, Robert Wojciechowski, Jason C.S. Yam, Kenji Yamashiro, Maurice K.H. Yap, Seyhan Yazar, Shea Ping Yip, Terri L. Young, Xiangtian Zhou, Naomi Allen, Tariq Aslam, Denize Atan, Sarah Barman, Jenny Barrett, Paul Bishop, Graeme Black, Catey Bunce, Roxana Carare, Usha Chakravarthy, Michelle Chan, Sharon Chua, Valentina Cipriani, Alexander Day, Parul Desai, Bal Dhillon, Andrew Dick, Alexander Doney, Cathy Egan, Sarah Ennis, Paul Foster, Marcus Fruttiger, John Gallacher, David Garway-Heath, Jane Gibson, Dan Gore, Jeremy Guggenheim, Chris Hammond, Alison Hardcastle, Simon Harding, Ruth Hogg, Pirro Hysi, Pearse A. Keane, Peng Tee Khaw, Anthony Khawaja, Gerassimos Lascaratos, Thomas Littlejohns, Andrew Lotery, Phil Luthert, Tom MacGillivray, Sarah Mackie, Bernadette McGuinness, Gareth McKay, Martin McKibbin, Danny Mitry, Tony Moore, James Morgan, Zaynah Muthy, Eoin O'Sullivan, Chris Owen, Praveen Patel, Euan Paterson, Tunde Peto, Axel Petzold, Nikolas Pontikos, Jugnoo Rahi, Alicja Rudnicka, Jay Self, Panagiotis Sergouniotis, Sobha Sivaprasad, David Steel, Irene Stratton, Nicholas Strouthidis, Cathie Sudlow, Robyn Tapp, Caroline Thaung, Dhanes Thomas, Emanuele Trucco, Adnan Tufail, Stephen Vernon, Ananth Viswanathan, Katie Williams, Jayne Woodside, Max Yates, Jennifer Yip, Yalin Zheng, Neurology, Ophthalmology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Epidemiology, Clinical Genetics, and Erasmus MC other
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All institutes and research themes of the Radboud University Medical Center ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] - Abstract
Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).
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- 2023
9. Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy
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Jie Jin Wang, Robert P. Igo, Barry I. Freedman, Jerome I. Rotter, Kathyrn P. Burdon, Alan D. Penman, Albert V. Smith, Xiaohui Li, Jamie E. Craig, Paul Mitchell, Brian L. Yaspan, Mary Frances Cotch, John M. Rouhana, Ayellet V. Segrè, Barbara E.K. Klein, Ashley Li, Richard A. Jensen, Gayatri Susarla, Lynn K. Stanwyck, Sudha K. Iyengar, Maggie C.Y. Ng, Ching J. Chen, Kent D. Taylor, Donald W. Bowden, Lucia Sobrin, Tien Yin Wong, Emily Y. Chew, Sharon G. Adler, Samuela Pollack, and Jane Z. Kuo
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Lipid catabolic process ,Clinical Sciences ,Genome-wide association study ,Type 2 diabetes ,Biology ,Ophthalmology & Optometry ,Polymorphism, Single Nucleotide ,Article ,Opthalmology and Optometry ,Risk Factors ,Diabetes Mellitus ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Humans ,Interferon gamma ,Polymorphism ,Aetiology ,Eye Disease and Disorders of Vision ,Gene ,Metabolic and endocrine ,Lipid Transport ,Diabetic Retinopathy ,Catabolism ,Diabetes ,Human Genome ,Single Nucleotide ,medicine.disease ,Ophthalmology ,Diabetes Mellitus, Type 2 ,Public Health and Health Services ,Lipid digestion ,Type 2 ,Biotechnology ,Genome-Wide Association Study ,medicine.drug - Abstract
To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses.MethodsWe analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was
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- 2022
10. A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa.
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Rafal S Sobota, Catherine M Stein, Nuri Kodaman, Isaac Maro, Wendy Wieland-Alter, Robert P Igo, Albert Magohe, LaShaunda L Malone, Keith Chervenak, Noemi B Hall, Mecky Matee, Harriet Mayanja-Kizza, Moses Joloba, Jason H Moore, William K Scott, Timothy Lahey, W Henry Boom, C Fordham von Reyn, Scott M Williams, and Giorgio Sirugo
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Genetics ,QH426-470 - Abstract
One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an "experiment of nature" design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease.
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- 2017
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11. Genomic Disorders in CKD across the Lifespan
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Miguel Verbitsky, Sarathbabu Krishnamurthy, Priya Krithivasan, Daniel Hughes, Atlas Khan, Maddalena Marasà, Natalie Vena, Pavan Khosla, Junying Zhang, Tze Y. Lim, Joseph T. Glessner, Chunhua Weng, Ning Shang, Yufeng Shen, George Hripcsak, Hakon Hakonarson, Iuliana Ionita-Laza, Brynn Levy, Eimear E. Kenny, Ruth J.F. Loos, Krzysztof Kiryluk, Simone Sanna-Cherchi, David R. Crosslin, Susan Furth, Bradley A. Warady, Robert P. Igo, Sudha K. Iyengar, Craig S. Wong, Afshin Parsa, Harold I. Feldman, and Ali G. Gharavi
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Nephrology ,General Medicine - Abstract
Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility.We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II (We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk.Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.
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- 2022
12. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract
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Preeti Gupta, Maryam Hazly Hilmy, Jie Jin Wang, Jiemin Liao, Allan Fong, Maria K. Swift, Johanna M. Colijn, Paul Mitchell, Ya Xing Wang, Anita S Y Chan, Barbara E.K. Klein, Pirro G. Hysi, Jaeyoon Chung, Emily Y. Chew, Wanting Zhao, Yang Shen, Ava Grace Tan, Hengtong Li, Eranga N. Vithana, Gyungah Jun, Wenting Liu, Tin Aung, Qiao Fan, Yuan Shi, Ekaterina Yonova-Doing, Soon-Phaik Chee, Sudha K. Iyengar, Yik Ying Teo, Periasamy Sundaresan, Chiea Chuen Khor, Zheng Li, Kathryn P. Burdon, Miao Ling Chee, Yih Chung Tham, Christopher J Hammond, Xiaoran Chai, Kerrin S. Small, Queenie S. Tan, Jacqueline Chua, Jost B. Jonas, Astrid E. Fletcher, Alexessander Couto Alves, Pieter W.M. Bonnemaijer, Ravilla D. Ravindran, Mei Chin Lee, Milly S. Tedja, Robert P. Igo, Kristine E. Lee, Tien Y Wong, Xinyi Su, Caroline C W Klaver, Xueling Sim, Ching-Yu Cheng, Chaolong Wang, Lars G. Fritsche, Epidemiology, and Ophthalmology
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0301 basic medicine ,Genotype ,genetic structures ,QH301-705.5 ,Medicine (miscellaneous) ,Genome-wide association study ,Disease ,Bioinformatics ,Polymorphism, Single Nucleotide ,Genome-wide association studies ,Cataract ,Article ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Genetic variation ,Humans ,Medicine ,Genetic Predisposition to Disease ,Allele ,Biology (General) ,Alleles ,Genetic Association Studies ,Genetic association ,business.industry ,SOXB1 Transcription Factors ,Genetic Variation ,medicine.disease ,eye diseases ,030104 developmental biology ,Age-related nuclear cataract ,030221 ophthalmology & optometry ,Congenital cataracts ,Lens diseases ,sense organs ,General Agricultural and Biological Sciences ,business ,Genome-Wide Association Study - Abstract
Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye., Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.
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- 2020
13. Distribution of rare LOXL1 missense alleles, haplotypes and diplotypes suggests association with reduced risk of glaucoma-related exfoliation syndrome
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J. H. Kang, R. Ritch, Tyler G. Kinzy, Tin Aung, Richard K. Lee, Louis R. Pasquale, Robert P. Igo, Chiea Chuen Khor, J. N. Cooke Bailey, Haines Jl, Margaret A. Pericak-Vance, Janey L. Wiggs, and Arthur J. Sit
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Minor allele frequency ,Genetics ,Loss of heterozygosity ,Exact test ,Haplotype ,Genotype ,Missense mutation ,Allele ,Biology ,Exome ,eye diseases - Abstract
PurposeCommon LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele has been associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study was to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States.MethodsLOXL1 rare (minor allele frequency less than 1%) variants were identified from Humanexome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls. Distribution of rare variants, haplotypes (defined using IMPUTE2) and diplotypes were examined using the Fisher’s exact test. Rare variant allele distribution was confirmed in an independent set of primary open angle glaucoma (POAG) controls and multi-ethnic datasets. Correlation of LOXL1 common allele homozygosity with disease risk used data from gnomAD (gnomad.broadinstitute.org/) and an existing multi-ethnic meta-analysis.ResultsFour rare LOXL1 missense alleles were identified, and all were more common in controls (combined P= 7.6E-4), with two of these located in a LOXL1 intrinsic disordered region (IDR) known to be involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases (OR= 0.33, P=1.7E-8). Heterozygous diplotypes were significantly associated with reduced risk overall (OR= 0.45 P= 1.7 E-89) with the largest effects observed for diplotypes with more than one heterozygous genotype (OR= 0.05, P= 1.0E-39). A homozygous diplotype was associated with increased disease risk (OR= 6.8, P= 4.7E-157) and homozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (Pearson= 0.92, PConclusionsUsing exome array data from XFS/XFG cases and controls from the United States, we identify 4 rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes are associated with reduced risk of XFS/XFG. The diplotype results also demonstrate that LOXL1 allelic heterozygosity is protective while homozygosity is associated with increased disease risk. These results suggest that LOXL1 minor allele frequency variation among populations, with corresponding variation in genotype heterozgyosity and homozygosity, determines the XFS/XFG association effects and that genotypic effects may also impact protein aggregation involving intrinsic disordered regions.
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- 2021
14. Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).
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Sudha K Iyengar, John R Sedor, Barry I Freedman, W H Linda Kao, Matthias Kretzler, Benjamin J Keller, Hanna E Abboud, Sharon G Adler, Lyle G Best, Donald W Bowden, Allison Burlock, Yii-Der Ida Chen, Shelley A Cole, Mary E Comeau, Jeffrey M Curtis, Jasmin Divers, Christiane Drechsler, Ravi Duggirala, Robert C Elston, Xiuqing Guo, Huateng Huang, Michael Marcus Hoffmann, Barbara V Howard, Eli Ipp, Paul L Kimmel, Michael J Klag, William C Knowler, Orly F Kohn, Tennille S Leak, David J Leehey, Man Li, Alka Malhotra, Winfried März, Viji Nair, Robert G Nelson, Susanne B Nicholas, Stephen J O'Brien, Madeleine V Pahl, Rulan S Parekh, Marcus G Pezzolesi, Rebekah S Rasooly, Charles N Rotimi, Jerome I Rotter, Jeffrey R Schelling, Michael F Seldin, Vallabh O Shah, Adam M Smiles, Michael W Smith, Kent D Taylor, Farook Thameem, Denyse P Thornley-Brown, Barbara J Truitt, Christoph Wanner, E Jennifer Weil, Cheryl A Winkler, Philip G Zager, Robert P Igo, Robert L Hanson, Carl D Langefeld, and Family Investigation of Nephropathy and Diabetes (FIND)
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Genetics ,QH426-470 - Abstract
Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
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- 2015
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15. Erratum to Gene Set Enrichment Analyses Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy. Am J Ophthalmol 2022;233:111-123
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Lucia Sobrin, Gayatri Susarla, Lynn Stanwyck, John M. Rouhana, Ashley Li, Samuela Pollack, Robert P. Igo, Richard A. Jensen, Xiaohui Li, Maggie C.Y. Ng, Albert V. Smith, Jane Z. Kuo, Kent D. Taylor, Barry I. Freedman, Donald W. Bowden, Alan Penman, Ching J. Chen, Jamie E. Craig, Sharon G. Adler, Emily Y. Chew, Mary Frances Cotch, Brian Yaspan, Paul Mitchell, Jie Jin Wang, Barbara E.K. Klein, Tien Y. Wong, Jerome I. Rotter, Kathyrn P. Burdon, Sudha K. Iyengar, and Ayellet V. Segrè
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Ophthalmology - Published
- 2022
16. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium
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Heather M. Highland, Francisco Rothhammer, Kristin L. Young, Andres Ruiz-Linares, Yujie Wang, Roberta McKean-Cowdin, Fernando Pires Hartwig, Noël P. Burtt, Ye Feng, Mark O. Goodarzi, Adrienne M. Stilp, Andrea R. V. R. Horimoto, Charleston W. K. Chiang, Michael Preuss, Adam G. Lilly, Gabriela Torres-Mejía, V. Saroja Voruganti, Donna E. Lehman, LáShauntá M. Glover, Roelof A.J. Smit, Yii-Der Ida Chen, Carl Langfeld, Xiuqing Guo, Rebecca Rohde, Estela Blanco, Samuel Canizales-Quinteros, Ravindranath Duggirala, Tamar Sofer, Sheila Gahagan, Anny H. Xiang, Ruth J. F. Loos, Hung-Hsin Chen, Sobha Puppala, Giovanni Poletti, Yang Hai, Claudia Schumann, Victor Acuña-Alonzo, Sharon G. Adler, Kari E. North, José Eduardo Krieger, Xinruo Zhang, Christopher A. Haiman, Alexandre C. Pereira, Thomas A. Buchanan, Xiaoyi Raymond Gao, Matthew A. Allison, Zorayr Arzumanyan, Jennifer A. Smith, Jie Yao, Marta Guindo-Martínez, Carmen R. Isasi, Clicerio González-Villalpando, Anthony G. Commuzzie, Nancy J. Cox, Kent D. Taylor, Victoria L. Buchanan, Carla Gallo, Esther M. John, Humberto García-Ortiz, David V. Conti, Lynne E. Wagenknecht, Carlos A. Aguilar-Salinas, Jose C. Florez, Willa A. Hsueh, Craig L. Hanis, Susanne B. Nicholas, Struan F.A. Grant, José de Jesús Peralta Romero, Lindsay Fernández-Rhodes, Alvin G. Thomas, Jerome I. Rotter, Maria Cátira Bortolini, Anne E. Justice, Hakon Hakonarson, Darryl Nousome, Nicholette Allred, Leslie J. Raffel, Nancy F. Butte, Wanying Zhu, Joanne E. Curran, Miguel Cruz, Xiaohui Li, Kevin Sandow, Minhui Chen, Poojan Shrestha, Eli Ipp, Teresa Tusie, Minjung Kho, Bernando Horta, Kelvin Lam, Stephanie M. Gogarten, Pauline Genter, John Blangero, Robert P. Igo, Mariaelisa Graff, Rolando González-José, Kaye Roll, Shelley A. Cole, Josep M. Mercader, Jingyi Tan, Esteban J. Parra, Jennifer E. Below, Sudha K. Iyengar, Qibin Qi, Elad Ziv, Gabriel Bedoya, Sara Pulit, Lorena Orozco, Fouad Kandeel, Astride Audirac-Chalifour, Laura Fejerman, Jerry L. Nadler, Daeeun Kim, Kaustubh Adhikari, George Papnicolaou, and Jonathan P. Bradfield
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Linkage disequilibrium ,medicine ,Locus (genetics) ,Genome-wide association study ,Anthropometry ,Overweight ,medicine.symptom ,Biology ,Population stratification ,Body mass index ,Demography ,Genetic association - Abstract
Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite notable anthropometric variability with ancestry proportions, and a high burden of growth stunting and overweight/obesity in Hispanic/Latino populations. This address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults, to identify and fine-map common genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,769) and validated our findings in 9 additional studies (HISLA Stage 2, n=9,336). We conducted a trans-ethnic GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one novel BMI locus, as well two novel BMI signals and another novel height signal, each within established anthropometric loci. In our trans-ethnic meta- analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI. We replicated >60 established anthropometric loci in Hispanic/Latino populations at genome-wide significance—representing up to 30% of previously-reported index SNP anthropometric associations. Trans-ethnic meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our novel findings demonstrate that future studies may also benefit from leveraging differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.
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- 2021
17. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry
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Carly J. van der Heide, Jessica N. Cooke Bailey, Susan Williams, Dan Milea, José Paulo Cabral de Vasconcellos, Sadiq M. Abdullahi, Douglas E. Gaasterland, Ifeoma N. Asimadu, Sayoko E. Moroi, Hasnaa Lamari, Sarah J. Garnai, Janey L. Wiggs, Donald L. Budenz, R. Rand Allingham, Julia E. Richards, Jonathan L. Haines, Jerome I. Rotter, Michael G. Anderson, Xiuqing Guo, Robert M. Feldman, Michael A. Hauser, Yii-Der Ida Chen, Hugo Freire Nunes, Leon W. Herndon, John F. Ervin, Stephen Akafo, Radha Ayyagari, Thomas J. Hoffmann, Rachel W. Kuchtey, Michèle Ramsay, Prisca Biangoup Nyamsi, Zheng Li, Eric Jorgenson, Kar Seng Sim, Ebenezer Obeng-Nyarkoh, William C. Bromley, Christopher A. Girkin, Robert N. Weinreb, Alberta A H J Thiadens, Serge Resnikoff, William E. Sponsel, Maggie C.Y. Ng, Christine M. Hulette, Donald W. Bowden, Saydou Bakayoko, Jeffrey M. Liebmann, Harvey Dubiner, Suhanya Okeke, Abba Hydara, Ruth J. F. Loos, Adeyinka O. Ashaye, Olusegun Olaniyi, Mahmoud B. Alhassan, Khaled K. Abu-Amero, Christopher J Hammond, Tin Aung, John H. Fingert, Robert P. Igo, Shih-Hsiu Wang, Rui Barroso Schimiti, Pratap Challa, Robert F. Mullins, Rodolfo A. Perez-Grossmann, Nouhoum Guirou, Margaret A. Pericak-Vance, Anthony Okeke, Pieter W.M. Bonnemaijer, Paulo Vinicius Svidnicki, Abdoulaye Napo, Louise R. Pasquale, Joyce Kabwe, Chiea Chuen Khor, Mônica Barbosa de Melo, Girish N. Nadkarni, CM Chuka-Okosa, Neil Risch, Nkiru Kizor-Akaraiwe, Miles J. Flamme-Wiese, Cornelia M. van Duijn, N J Uche, Joseph Msosa, Olusola Olawoye, Linda M. Zangwill, Mariana B. Oliveira, Caroline C W Klaver, Allison E. Ashley Koch, Vital Paulino Costa, Ngoy Janvier Kilangalanga, Trevor R. Carmichael, Xue Qin, Kent D. Taylor, Yutao Liu, Dianne A. Cruz, Epidemiology, and Ophthalmology
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Male ,medicine.medical_specialty ,Genotype ,genetic structures ,Open angle glaucoma ,Population ,Black People ,Glaucoma ,Genome-wide association study ,Polymorphism, Single Nucleotide ,01 natural sciences ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,03 medical and health sciences ,0302 clinical medicine ,Meta-Analysis as Topic ,Risk Factors ,Interquartile range ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,030212 general & internal medicine ,0101 mathematics ,education ,Adaptor Proteins, Signal Transducing ,Aged ,Original Investigation ,education.field_of_study ,Amyloid beta-Peptides ,business.industry ,010102 general mathematics ,Case-control study ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Immunohistochemistry ,eye diseases ,Case-Control Studies ,Female ,Risk assessment ,business ,Glaucoma, Open-Angle ,Genome-Wide Association Study - Abstract
Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
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- 2019
18. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control
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Mark I. McCarthy, Weihua Meng, Brian L. Yaspan, M Imamura, Mark W. Christiansen, Niina Sandholm, Yii-Der Ida Chen, Sharon G. Adler, Lucia Sobrin, Craig L. Hanis, Valeriya Lyssenko, Shiro Maeda, Yang Hai, Paul Mitchell, Roberta McKean-Cowdin, Xiuqing Guo, John R. Sedor, David S. Siscovick, Sudha K. Iyengar, Heather Hancock, Jane Z. Kuo, Barbara E.K. Klein, David-Alexandre Tregouet, Elisabet Agardh, Kent D. Taylor, Andrew D. Morris, S. Mohsen Hosseini, Andrew D. Paterson, I-Te Lee, Wayne Huey-Herng Sheu, Emma Ahlqvist, Kathryn P. Burdon, Leif Groop, Ayellet V. Segrè, Samy Hadjadj, Samaneh Davoudi, Lynn K. Stanwyck, Emily Y. Chew, Xiaohui Li, Michael A. Grassi, Jie Jin Wang, Samuela Pollack, Albert V. Smith, Kyu Hyung Park, Michiaki Kubo, Mary Frances Cotch, Yucheng Jia, Ching J. Chen, Colin N. A. Palmer, Helen M. Colhoun, Alan D. Penman, R. Varma, Per-Henrik Groop, Tien Yin Wong, Barry I. Freedman, Eli Ipp, Alex S. F. Doney, Gavin Tan, Ronald Klein, Kaanan P. Shah, Jamie E Craig, Donald W. Bowden, Jerome I. Rotter, Robert P. Igo, Darryl Nousome, Ching-Yu Cheng, Michel Marre, Maggie C.Y. Ng, Latchezar Dimitrov, Jeeyun Ahn, Atsushi Takahashi, Richard A. Jensen, Aaron Leong, Jihye Kim, Iiro Toppila, Elizabeth J. Rossin, Alkes L. Price, Diabetes and Obesity Research Program, University of Helsinki, Department of Medicine, Nefrologian yksikkö, Research Programs Unit, Clinicum, HUS Abdominal Center, and Per Henrik Groop / Principal Investigator
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Blood Glucose ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genotype ,Endocrinology, Diabetes and Metabolism ,LOCI ,030209 endocrinology & metabolism ,Genome-wide association study ,VARIANTS ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Meta-Analysis as Topic ,RESOURCE ,Internal medicine ,Diabetes mellitus ,REVEALS ,Genetic variation ,Internal Medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,CHINESE PATIENTS ,Allele ,METAANALYSIS ,POLYMORPHISMS ,Glycemic ,Glycated Hemoglobin ,Diabetic Retinopathy ,business.industry ,Diabetic retinopathy ,medicine.disease ,PREVALENCE ,3. Good health ,SEVERITY ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,3121 General medicine, internal medicine and other clinical medicine ,Multiple comparisons problem ,RISK-FACTORS ,Medical genetics ,Erratum ,business ,Genome-Wide Association Study ,Protein Binding - Abstract
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value
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- 2018
19. Association between genes regulating neural pathways for quantitative traits of speech and language disorders
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Yvonne Wren, Jessica Tag, Panos Roussos, Catherine M. Stein, Sudha K. Iyengar, Penelope Benchek, Barbara A. Lewis, H. Gerry Taylor, Gabrielle Miller, Barbara Truitt, Wen Zhang, Robert P. Igo, E. Ricky Chan, Lisa Freebairn, Michael D. Osterman, and Heather Voss-Hoynes
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0301 basic medicine ,Longitudinal study ,Vocabulary ,media_common.quotation_subject ,Genome-wide association study ,QH426-470 ,Genome-wide association studies ,Article ,Developmental psychology ,03 medical and health sciences ,0302 clinical medicine ,Phonological awareness ,Reading (process) ,Genetics ,Association (psychology) ,Molecular Biology ,Genetics (clinical) ,media_common ,Spelling ,030104 developmental biology ,Differentially methylated regions ,Medicine ,Psychiatric disorders ,Psychology ,030217 neurology & neurosurgery - Abstract
Speech sound disorders (SSD) manifest as difficulties in phonological memory and awareness, oral motor function, language, vocabulary, reading, and spelling. Families enriched for SSD are rare, and typically display a cluster of deficits. We conducted a genome-wide association study (GWAS) in 435 children from 148 families in the Cleveland Family Speech and Reading study (CFSRS), examining 16 variables representing 6 domains. Replication was conducted using the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 18 significant loci (combined p −8) that we pursued bioinformatically. We prioritized 5 novel gene regions with likely functional repercussions on neural pathways, including those which colocalized with differentially methylated regions in our sample. Polygenic risk scores for receptive language, expressive vocabulary, phonological awareness, phonological memory, spelling, and reading decoding associated with increasing clinical severity. In summary, neural-genetic influence on SSD is primarily multigenic and acts on genomic regulatory elements, similar to other neurodevelopmental disorders.
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- 2021
20. A genome-wide search for linkage of estimated glomerular filtration rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND).
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Farook Thameem, Robert P Igo, Barry I Freedman, Carl Langefeld, Robert L Hanson, Jeffrey R Schelling, Robert C Elston, Ravindranath Duggirala, Susanne B Nicholas, Katrina A B Goddard, Jasmin Divers, Xiuqing Guo, Eli Ipp, Paul L Kimmel, Lucy A Meoni, Vallabh O Shah, Michael W Smith, Cheryl A Winkler, Philip G Zager, William C Knowler, Robert G Nelson, Madeline V Pahl, Rulan S Parekh, W H Linda Kao, Rebekah S Rasooly, Sharon G Adler, Hanna E Abboud, Sudha K Iyengar, John R Sedor, and Family Investigation of Nephropathy and Diabetes Research Group
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Medicine ,Science - Abstract
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4 × 10(-5)) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5 × 10(-4)) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5 × 10(-4)) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
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- 2013
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21. Methylome-wide Analysis Reveals Epigenetic Marks Associated With Resistance to Tuberculosis in Human Immunodeficiency Virus-Infected Individuals From East Africa
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Robert P. Igo, Rafal S. Sobota, Timothy Lahey, Jacquelaine Bartlett, Harriet Mayanja-Kizza, William K. Scott, Keith A. Chervenak, Catherine M. Stein, Penelope Benchek, C. Fordham von Reyn, Giorgio Sirugo, Scott M. Williams, William S. Bush, Carmen J. Marsit, and W. Henry Boom
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0301 basic medicine ,Tuberculosis ,Genome-wide association study ,Single-nucleotide polymorphism ,HIV Infections ,Biology ,Tanzania ,Epigenesis, Genetic ,Mycobacterium tuberculosis ,03 medical and health sciences ,Epigenome ,Major Articles and Brief Reports ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Humans ,Uganda ,Epigenetics ,Disease Resistance ,HIV ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Infectious Diseases ,Infectious disease (medical specialty) ,DNA methylation ,Immunology ,030217 neurology & neurosurgery ,Biomarkers ,Genome-Wide Association Study - Abstract
Background Tuberculosis (TB) is the most deadly infectious disease globally and is highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation. We hypothesized that HIV-infected individuals exposed to Mtb who remain disease free carry epigenetic changes that strongly protect them from active TB. Methods We conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania and integrated data from our GWAS. Results We identified 3 regions of interest that included markers that were differentially methylated between TB cases and controls with latent TB infection: chromosome 1 (RNF220, P = 4 × 10–5), chromosome 2 (between COPS8 and COL6A3, P = 2.7 × 10–5), and chromosome 5 (CEP72, P = 1.3 × 10–5). These methylation results co-localized with associated single-nucleotide polymorphisms (SNPs), methylation QTLs, and methylation × SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung. Conclusions Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.
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- 2020
22. Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa
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Harriet Mayanja-Kizza, Scott M. Williams, William S. Bush, Jacquelaine Bartlett, Catherine M. Stein, Robert P. Igo, Giorgio Sirugo, William K. Scott, Keith A. Chervenak, Penelope Bencheck, C. Fordham von Reyn, Rafal S. Sobota, Timothy Lahey, Carmen J. Marsit, and W. Henry Boom
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Regulation of gene expression ,Tuberculosis ,Infectious disease (medical specialty) ,DNA methylation ,Immunology ,medicine ,SNP ,Single-nucleotide polymorphism ,Methylation ,Epigenetics ,Biology ,medicine.disease - Abstract
BackgroundTuberculosis (TB) is the most deadly infectious disease globally and highly prevalent in the developing world, especially sub-Saharan Africa. Even though a third of humans are exposed to Myocbacterium tuberculosis (Mtb), most infected immunocompetent individuals do not develop active TB. In contrast, for individuals infected with both TB and the human immunodeficiency virus (HIV), the risk of active disease is 10% or more per year. Previously, we identified in a genome-wide association study a region on chromosome 5 that was associated with resistance to TB. This region included epigenetic marks that could influence gene regulation so we hypothesized that HIV-infected individuals exposed to Mtb, who remain disease free, carry epigenetic changes that strongly protect them from active TB. To test this hypothesis, we conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania.ResultsIn 221 HIV-infected adults from Uganda and Tanzania, we identified 3 regions of interest that included markers that were differentially methylated between TB cases and LTBI controls, that also included methylation QTLs and associated SNPs: chromosome 1 (RNF220, p=4×10−5), chromosome 2 (between COPS8 and COL6A3 genes, p=2.7×10−5), and chromosome 5 (CEP72, p=1.3×10−5). These methylation results colocalized with associated SNPs, methylation QTLs, and methylation × SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung.ConclusionEpigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.
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- 2020
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23. A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease
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Peter Kraft, Adriana Iglesias, Steffen Uebe, Alberta A H J Thiadens, Jessica N. Cooke Bailey, Paul Mitchell, Olusola Olawoye, Michele Ramsay, Caroline C.W. Klaver, Eranga N. Vithana, Ayub Qassim, Mark James Simcoe, Pirro G. Hysi, Xin Wang, Angela J. Cree, Juha Karjalainen, René Höhn, Cornelia van Duijn, Andrew J. Lotery, Veronique Vitart, Anthony P Khawaja, Terri L. Young, James E. Morgan, UK Biobank Eye, Yukihiro Shiga, Owen M. Siggs, Yukihide Momozawa, Stephen Akafo, Puya Gharahkhani, Robert P. Igo, Masato Akiama, Gen Tamiya, Sarah A. Pendergrass, Navya Shilpa Josyula, Chris Hammond, David A. Mackey, FinnGen study, Chiea Chuen Khor, Francesca Pasutto, Ewan Birney, Pieter W.M. Bonnemaijer, Aarno Palotie, Susan E. Williams, John Rouhana, Nishani Amersinghe, Peng T. Khaw, Stuart MacGregor, Ching-Yu Cheng, Yoichito Kamatani, Calvin Chi Pui Pang, Xikun Han, Alex W. Hewitt, Louis R. Pasquale, Jae Hee Kang, Eric Jorgenson, Ronald B. Melles, Michael Hauser, Li Jia Chen, Jonathan Haines, Masayuki Yamamoto, Alicia Poplawski, Ayellet V. Segrè, Jue-Sheng Ong, Kazuki Hashimoto, Hélène Choquet, Hannah Currant, Jamie E. Craig, Robert Luben, Adam Auton, Tin Aung, Paul J. Foster, Toru Nakazawa, Nicholas G. Strouthidis, Michiaki Kubo, K. Saidas Nair, Janey L. Wiggs, and Adeyinka O. Ashaye
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Genetics ,0303 health sciences ,genetic structures ,Open angle glaucoma ,Glaucoma ,Genome-wide association study ,Disease ,Biology ,medicine.disease ,eye diseases ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Meta-analysis ,medicine ,sense organs ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology ,Genetic association - Abstract
We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer’s disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.
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- 2020
24. Contributors
- Author
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Mohamed H. Abdel-Rahman, Elizabeth D. Au, Milam A. Brantley, Kinga M. Bujakowska, Colleen M. Cebulla, Rui Chen, Jessica N. Cooke Bailey, Frederick H. Davidorf, Eiko K. de Jong, Anneke I. den Hollander, Rachayata Dharmat, Patty P.A. Dhooge, Michael H. Farkas, Kavin Fatehchand, John H. Fingert, Xiaoyi Raymond Gao, Maartje J. Geerlings, Jonathan L. Haines, Carel B. Hoyng, Robert P. Igo, Hacer Isildak, Tadeusz J. Kaczynski, Mariam Lotfy Khaled, Yutao Liu, Leighanne R. Main, Matthew A Miller, Matthew P. Ohr, Robert Pilarski, Emily Place, Claudio Punzo, Riccardo Sangermano, Stephen G. Schwartz, Hilary Scott, Ruifang Sui, Dyon Valkenburg, Carly J. van der Heide, Naomi Wagner, Andrea R. Waksmunski, Hui Wang, Katie Weihbrecht, and Hannah Youngblood
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- 2020
25. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression
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Henry Marshall, Paul R. Healey, Stuart MacGregor, Paul Mitchell, Cornelia M. van Duijn, Tyler G. Kinzy, Nicholas H Andrew, Stephen Best, Angela J. Cree, Louis R. Pasquale, Xikun Han, Alex W. Hewitt, Andrea L Vincent, Robert J Casson, Christopher J Hammond, Jiyuan An, Paul J. Foster, Matthew Law, Tiger Zhou, Sobha Sivaprasad, Veronique Vitart, Mark M. Hassall, Peng T. Khaw, Francesca Pasutto, Andrew J. Lotery, Tin Aung, Robert P. Igo, Puya Gharahkhani, Kathryn P. Burdon, Nicholas G. Martin, Ashish Agar, Ivan Goldberg, Neeru A. Vallabh, Pirro G. Hysi, David A. Mackey, Jonathan B Ruddle, Colin E. Willoughby, John Landers, Jue-Sheng Ong, Ananth C. Viswanathan, Bronwyn Ridge, Anthony P Khawaja, Emmanuelle Souzeau, Grant W. Montgomery, Richard A. Mills, Jamie E Craig, Janey L. Wiggs, Jost B. Jonas, Caroline C W Klaver, Ayub Qassim, Graham L. Radford-Smith, Stuart L. Graham, Jonathan L. Haines, Andrew White, Anna Galanopoulos, Owen M. Siggs, Robert Wojciechowski, René Hoehn, Jessica N. Cooke Bailey, Ophthalmology, and Epidemiology
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Multifactorial Inheritance ,medicine.medical_specialty ,Intraocular pressure ,Open angle glaucoma ,genetic structures ,medicine.medical_treatment ,Population ,Glaucoma ,Penetrance ,Trabeculectomy ,Biology ,Polymorphism, Single Nucleotide ,Article ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetic model ,Odds Ratio ,Genetics ,medicine ,Glaucoma surgery ,Humans ,Genetic Predisposition to Disease ,Eye Proteins ,education ,Intraocular Pressure ,Myocilin ,Glycoproteins ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Australia ,Optic Nerve ,medicine.disease ,United Kingdom ,United States ,eye diseases ,Cytoskeletal Proteins ,Case-Control Studies ,Disease Progression ,sense organs ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Contains fulltext : 218893.pdf (Publisher’s version ) (Closed access) Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 x 10(-)(6)). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
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- 2020
26. Genetic risk scores in complex eye disorders
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Jessica N. Cooke Bailey and Robert P. Igo
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Disease susceptibility ,Disease progression ,Trait ,Eye disorder ,Polygenic risk score ,Disease ,Biology ,Genetic risk ,Allele ,Bioinformatics - Abstract
Genetic risk scores (GRS) in their simplest form summarize the burden of risk-associated alleles at established genetic loci shown to be statistically associated with a disease or trait to predict likelihood of disease or trait variation. More complex forms incorporate clinical and/or environmental modifiers (i) to predict disease susceptibility, (ii) to predict disease progression, and/or (iii) to classify individuals into treatment categories. Because many common ocular diseases and traits have a known genetic component, various GRS have been proposed drawing on information from one to thousands of genetic variants. Polygenic risk scores, incorporating thousands of markers, are emerging in studies of ocular traits. Currently, genetic/polygenic risk scores require further research regarding their utility to warrant incorporation into clinical settings. We herein summarize the breadth of literature around GRS in common ocular diseases.
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- 2020
27. Differing roles for TCF4 and COL8A2 in central corneal thickness and fuchs endothelial corneal dystrophy.
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Robert P Igo, Laura J Kopplin, Peronne Joseph, Barbara Truitt, Jeremy Fondran, David Bardenstein, Anthony J Aldave, Christopher R Croasdale, Marianne O Price, Miriam Rosenwasser, Jonathan H Lass, Sudha K Iyengar, and FECD Genetics Multi-center Study Group
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Medicine ,Science - Abstract
Fuchs endothelial corneal dystrophy (FECD) is the most common late-onset, vision-threatening corneal dystrophy in the United States, affecting about 4% of the population. Advanced FECD involves a thickening of the cornea from stromal edema and changes in Descemet membrane. To understand the relationship between FECD and central corneal thickness (CCT), we characterized common genetic variation in COL8A2 and TCF4, genes previously implicated in CCT and/or FECD. Other genes previously associated with FECD (PITX2, ZEB1, SLC4A11), and genes only known to affect CCT (COL5A1, FOXO1, AVGR8, ZNF469) were also interrogated. FECD probands, relatives and controls were recruited from 32 clinical sites; a total of 532 cases and 204 controls were genotyped and tested for association of FECD case/control status, a 7-step FECD severity scale and CCT, adjusting for age and sex. Association of FECD grade with TCF4 was highly significant (OR= 6.01 at rs613872; p = 4.8×10(-25)), and remained significant when adjusted for changes in CCT (OR= 4.84; p = 2.2×10(-16)). Association of CCT with TCF4 was also significant (p = 6.1×10(-7)), but was abolished with adjustment for FECD grade (p = 0.92). After adjusting for FECD grade, markers in other genes examined were modestly associated (p ∼ 0.001) with FECD and/or CCT. Thus, common variants in TCF4 appear to influence FECD directly, and CCT secondarily via FECD. Additionally, changes in corneal thickness due to the effect of other loci may modify disease severity, age-at-onset, or other biomechanical characteristics.
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- 2012
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28. Fine-mapping analysis of a chromosome 2 region linked to resistance to Mycobacterium tuberculosis infection in Uganda reveals potential regulatory variants
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Catherine M. Stein, Ezekiel Mupere, Li Tao, Thomas R. Hawn, Noemi B. Hall, Jacob B. Hall, Barbara Truitt, La Shaunda L. Malone, William S. Bush, Robert P. Igo, W. Henry Boom, Moses Joloba, Audrey H. Schnell, and Feiyou Qiu
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Male ,0301 basic medicine ,Tuberculosis ,Adolescent ,genetic association ,Immunology ,Tuberculin ,HIV Infections ,Histone Deacetylase 1 ,Single-nucleotide polymorphism ,genetics of immunity ,Polymorphism, Single Nucleotide ,Article ,Body Mass Index ,Mycobacterium tuberculosis ,Transcriptome ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Uganda ,Child ,Gene ,Wasting ,Genetics (clinical) ,Disease Resistance ,Zinc Finger E-box Binding Homeobox 2 ,biology ,Tuberculin Test ,Glycosyltransferases ,biology.organism_classification ,medicine.disease ,3. Good health ,030104 developmental biology ,tuberculosis ,Chromosomes, Human, Pair 2 ,Female ,Histone deacetylase ,medicine.symptom ,early clearance of Mycobacterium tuberculosis ,Genome-Wide Association Study ,Signal Transduction ,030215 immunology - Abstract
Tuberculosis (TB) is a major public health burden worldwide, and more effective treatment is sorely needed. Consequently, uncovering causes of resistance to Mycobacterium tuberculosis (Mtb) infection is of special importance for vaccine design. Resistance to Mtb infection can be defined by a persistently negative tuberculin skin test (PTST–) despite living in close and sustained exposure to an active TB case. While susceptibility to Mtb is, in part, genetically determined, relatively little work has been done to uncover genetic factors underlying resistance to Mtb infection. We examined a region on chromosome 2q previously implicated in our genomewide linkage scan by a targeted, high-density association scan for genetic variants enhancing PTST– in two independent Ugandan TB household cohorts (n = 747 and 471). We found association with SNPs in neighboring genes ZEB2 and GTDC1 (peak meta p = 1.9 × 10–5) supported by both samples. Bioinformatic analysis suggests these variants may affect PTST– by regulating the histone deacetylase (HDAC) pathway, supporting previous results from transcriptomic analyses. An apparent protective effect of PTST– against body-mass wasting suggests a link between resistance to Mtb infection and healthy body composition. Our results provide insight into how humans may escape latent Mtb infection despite heavy exposure.
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- 2018
29. Genetic Risk Scores
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Robert P. Igo, Tyler G. Kinzy, and Jessica N. Cooke Bailey
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Genetic Markers ,Multifactorial Inheritance ,Phenotype ,Genotype ,Risk Factors ,Genetics ,Humans ,Disease ,Genetic Predisposition to Disease ,Genetics (clinical) ,Software ,Article - Abstract
Genome-wide variation data with millions of genetic markers have become commonplace. However, the potential for interpretation and application of these data for clinical assessment of outcomes of interest, and prediction of disease risk, is currently not fully realized. Many common complex diseases now have numerous, well-established risk loci and likely harbor many genetic determinants with effects too small to be detected at genome-wide levels of statistical significance. A simple and intuitive approach for converting genetic data to a predictive measure of disease susceptibility is to aggregate the effects of these loci into a single measure, the genetic risk score. Here, we describe some common methods and software packages for calculating genetic risk scores and polygenic risk scores, with focus on studies of common complex diseases. We review the basic information needed, as well as important considerations for constructing genetic risk scores, including specific requirements for phenotypic and genetic data, and limitations in their application. © 2019 by John WileySons, Inc.
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- 2019
30. Differential Long-Term Outcomes for Individuals With Histories of Preschool Speech Sound Disorders
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Robert P. Igo, Sudha K. Iyengar, Catherine M. Stein, Barbara A. Lewis, Lisa Freebairn, Jessica Tag, H. Gerry Taylor, and Allison A vrich Ciesla
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Male ,Linguistics and Language ,Adolescent ,media_common.quotation_subject ,MEDLINE ,Speech Sound Disorder ,Literacy ,Developmental psychology ,030507 speech-language pathology & audiology ,03 medical and health sciences ,Speech and Hearing ,0302 clinical medicine ,Developmental and Educational Psychology ,Long term outcomes ,otorhinolaryngologic diseases ,Humans ,Conversation ,Language Development Disorders ,Longitudinal Studies ,Child ,Research Articles ,media_common ,Retrospective Studies ,Speech sound ,Repetition (rhetorical device) ,Differential (mechanical device) ,Retrospective cohort study ,Otorhinolaryngology ,Child, Preschool ,Female ,0305 other medical science ,Psychology ,030217 neurology & neurosurgery - Abstract
Purpose The goal of this study was to determine whether adolescent outcomes for individuals with histories of early speech sound disorders (SSD) could be differentiated by speech and language skills at earlier ages (preschool, 4–6 years, and school age, 7–10 years). Method The study used a retrospective longitudinal design. Participants with and without histories of early SSD were classified in adolescence as having no SSD, resolved SSD, low multisyllabic word (MSW; difficulty with MSW repetition but no errors in conversational speech), or persistent speech disorders (errors in both conversational speech and MSW repetition). Analysis of variance was employed to determine whether early speech, language, and literacy skills distinguished these adolescent outcome groups. Results Preschool and school-age skills differed for adolescents whose SSD had resolved from those who had persistent speech errors. Adolescents with errors solely in production of MSWs (Low MSW) did not differ in early speech and language skills from adolescents who had difficulty with both MSWs and persistent errors in conversation. Conclusions Speech and language assessments earlier in childhood can help establish risks for persistent SSD and other language and literacy difficulties in adolescence. Early identification of these clinically relevant subgroups of SSD may allow for early targeted interventions. Supplemental Material https://doi.org/10.23641/asha.9932279
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- 2019
31. Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes
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Janey L. Wiggs, C.M. vanDuijn, Vincent Laville, Adriana I Iglesias, Daniel I. Chasman, Bernard Rosner, Jessica N. Cooke Bailey, James F. Wilson, Michael A. Hauser, Jae H. Kang, William G. Christen, Christopher J Hammond, Hugues Aschard, Puya Gharahkhani, John H. Fingert, Alex W. Hewitt, Stuart MacGregor, Frank B. Hu, Peter Kraft, Louis R. Pasquale, Robert P. Igo, Yeunjoo E. Song, David A. Mackey, Pirro G. Hysi, Jonathan L. Haines, UK Biobank, Anthony P Khawaja, Clara C. Cousins, Reka Nagy, Veronique Vitart, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Edinburgh, Case Western Reserve University [Cleveland], Harvard T.H. Chan School of Public Health, QIMR Berghofer Medical Research Institute, University of Melbourne, University of Tasmania [Hobart, Australia] (UTAS), The University of Western Australia (UWA), King‘s College London, University of Oxford [Oxford], University of Iowa [Iowa City], Duke University [Durham], University of Cambridge [UK] (CAM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Orkney Complex Disease Study was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), a Royal Society URF to Dr Wilson, the MRC Human Genetics Unit quinquennial programme 'QTL in Health and Disease,' Arthritis Research UK, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947)., The Viking Health Study – Shetland (VIKING) was supported by the MRC Human Genetics Unit quinquennial programme grant 'QTL in Health and Disease.', European Project: 35103,EUROSPAN, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Clinical Genetics, and Ophthalmology
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Male ,Linkage disequilibrium ,genetic structures ,Glaucoma ,Genome-wide association study ,Type 2 diabetes ,0302 clinical medicine ,MESH: Aged, 80 and over ,MESH: Incidence ,Aged, 80 and over ,2. Zero hunger ,MESH: Aged ,0303 health sciences ,[STAT.AP]Statistics [stat]/Applications [stat.AP] ,MESH: Middle Aged ,Incidence ,MESH: Tonometry, Ocular ,Middle Aged ,Pedigree ,3. Good health ,Europe ,Phenotype ,MESH: Young Adult ,Female ,[STAT.ME]Statistics [stat]/Methodology [stat.ME] ,Glaucoma, Open-Angle ,MESH: Diabetes Mellitus, Type 2 ,Adult ,medicine.medical_specialty ,Adolescent ,MESH: Pedigree ,Biology ,MESH: Phenotype ,Genetic correlation ,Article ,Tonometry, Ocular ,Young Adult ,03 medical and health sciences ,MESH: Cross-Sectional Studies ,SDG 3 - Good Health and Well-being ,MESH: Intraocular Pressure ,Genetic linkage ,Ophthalmology ,medicine ,MESH: United States ,Humans ,Intraocular Pressure ,Aged ,030304 developmental biology ,MESH: Adolescent ,MESH: Humans ,MESH: Adult ,Heritability ,medicine.disease ,United States ,Human genetics ,eye diseases ,MESH: Male ,Cross-Sectional Studies ,Diabetes Mellitus, Type 2 ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,MESH: Genome-Wide Association Study ,030221 ophthalmology & optometry ,MESH: Glaucoma, Open-Angle ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,sense organs ,MESH: Europe ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,MESH: Female ,Genome-Wide Association Study - Abstract
Purpose A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. Design Cross-sectional study. Methods We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (rg) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT, and select diabetes-related traits based on individual level phenotype data in 2 Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines. Results Overall, there was little rg between diabetes- and glaucoma-related traits. Specifically, we found a nonsignificant negative correlation between T2D and POAG (rg = −0.14; P = .16). Using Sequential Oligogenic Linkage Analysis Routines, the genetic correlations between measured IOP, CCT, FBS, fasting insulin, and hemoglobin A1c were null. In contrast, genetic correlations between IOP and POAG (rg ≥ 0.45; P ≤ 3.0 × 10−4) and between CDR and POAG were high (rg = 0.57; P = 2.8 × 10−10). However, genetic correlations between corneal properties (CCT, CRF, and CH) and POAG were low (rg range −0.18 to 0.11) and nonsignificant (P ≥ .07). Conclusion These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.
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- 2019
32. Association of Smoking, Alcohol Consumption, Blood Pressure, Body Mass Index, and Glycemic Risk Factors With Age-Related Macular Degeneration
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Itay Chowers, Stacy M Meuer, R. Theodore Smith, Bamini Gopinath, Brendan J Vote, Thierry Léveillard, David A Mackey, Dwight Stambolian, Jamie E Craig, José-Alain Sahel, David J Hunter, Michael L Klein, Jane Romm, Robyn H Guymer, Mingyao Li, J. L. Haines, Emily L. Moore, J Allie McGrath, Chloe M. Stanton, Danni Lin, Jessica N Cooke Bailey, Anton Orlin, Anita Agarwal, Frank G Holz, Debra A Schaumberg, Valerie Kuan, Christine A. Curcio, Ken Flagg, Sudha K Iyengar, Sebanti Sengupta, Bal Dhillon, Joanna E. Merriam, Janette Hall, Bernhard H F Weber, Caroline Brandl, Donald Zack, Eric Souied, Yara T. E. Lechanteur, Christina A Rennie, Mathias Gorski, Murray H Brilliant, Denise J. Morgan, Barbara Truitt, Daniel E Weeks, Thomas Langmann, Aroon D. Hingorani, Gerald Liew, Andrea J Richardson, Neal S Peachey, John Blangero, Alasdair Warwick, Humma Shahid, Eiko K de Jong, Kari E Branham, S. V. Goverdhan, Paul Mitchell, Angela J Cree, Margaux A. Morrison, Rebecca J Sardell, Ian J Constable, Michael A. Hauser, Zhenglin Yang, Reneé Laux, G. Rudolph, David Cho, Jie Jin Wang, Albert Caramoy, Jaclyn L Kovach, Alexander Brucker, Frédéric Blond, Hongrong Luo, Michael B Gorin, Robert P Igo, Caroline C W Klaver, Lebriz Ersoy, Timothy Isaacs, Adnan Tufail, Gabriëlle H.S. Buitendijk, Nicholas Katsanis, Stephen Burgess, Carel B Hoyng, Reecha Sofat, Ivana K Kim, Mohammad Othman, Ian L McAllister, Giuliana Silvestri, Helena Hai Liang, Margaret DeAngelis, Matthew P Johnson, Ava G Tan, Felix Grassmann, Lindsay A Farrer, Alex W Hewitt, Hong Ouyang, Cindy Wen, Henry Ferreyra, Milam A Brantley, Melinda Cain, Caroline Hayward, Kristine E. Lee, Linn Gieser, Isabelle Audo, Evangelia E Tsironi, Nicole T.M. Saksens, Hendrik P N Scholl, Stephen G Schwartz, Matthias Olden, Saddek Mohand-Said, Scott J Hebbring, Joshua D Hoffman, Shira Hagbi-Levi, Anthony T Moore, Mustapha Benchaboune, Lars G Fritsche, Margaret A Pericak-Vance, Iris M Heid, Kyu Hyung Park, Jennifer L Bragg-Gresham, Hélène Blanché, Alexis Boleda, Rando Allikmets, John R Heckenlively, Kathryn P Burdon, Elisa Bala, Rinki Ratnapriya, Kimberly F Doheny, Xiaowei Zhan, Sascha Fauser, Claudia N von Strachwitz, Ronald Klein, Johanna R. Foerster, Wilmar Igl, Andrew J Lotery, Klaus Stark, Matthew Brooks, Jane C Khan, Emily Y Chew, Paul N Baird, Cornelia M Van Duijn, Chelsea E. Myers, Anneke I den Hollander, Monique D Courtenay, Zhiguang Su, Yingda Jiang, William K Scott, Tammy M Martin, Armin Wolf, Jeeyun Ahn, John C. Merriam, Eric A Postel, Guanping Mao, Emmanuelle Souzeau, Barbara E K Klein, Terrie Kitchner, Stewart Lake, Anand Swaroop, Valentina Cipriani, Tina Schick, Stephanie A. Hagstrom, Alan M. Kwong, Daniel Chen, Gonçalo R. Abecasis, Matthew Schu, Michelle Grunin, John R.W. Yates, Peter Campochiaro, Kang Zhang, and Jean-François Deleuze
- Subjects
Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Alcohol Drinking ,medicine.medical_treatment ,Visual Acuity ,Angiogenesis Inhibitors ,Blood Pressure ,Type 2 diabetes ,Blindness ,Lower risk ,Body Mass Index ,Risk Factors ,Internal medicine ,Mendelian randomization ,Humans ,Medicine ,Risk factor ,Glycemic ,business.industry ,Smoking ,Odds ratio ,Mendelian Randomization Analysis ,medicine.disease ,Ophthalmology ,Diabetes Mellitus, Type 2 ,Wet Macular Degeneration ,Smoking cessation ,business ,Body mass index ,Genome-Wide Association Study - Abstract
Importance Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD. Objective To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. Design, Setting, Participants This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P
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- 2021
33. A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.
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Theru A Sivakumaran, Robert P Igo, Jeffrey M Kidd, Andy Itsara, Laura J Kopplin, Wei Chen, Stephanie A Hagstrom, Neal S Peachey, Peter J Francis, Michael L Klein, Emily Y Chew, Vedam L Ramprasad, Wan-Ting Tay, Paul Mitchell, Mark Seielstad, Dwight E Stambolian, Albert O Edwards, Kristine E Lee, Dmitry V Leontiev, Gyungah Jun, Yang Wang, Liping Tian, Feiyou Qiu, Alice K Henning, Thomas LaFramboise, Parveen Sen, Manoharan Aarthi, Ronnie George, Rajiv Raman, Manmath Kumar Das, Lingam Vijaya, Govindasamy Kumaramanickavel, Tien Y Wong, Anand Swaroop, Goncalo R Abecasis, Ronald Klein, Barbara E K Klein, Deborah A Nickerson, Evan E Eichler, and Sudha K Iyengar
- Subjects
Medicine ,Science - Abstract
Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.
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- 2011
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34. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci
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Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K, Khan, Muhammad Imran, Olawoye, Olusola O, Ashaye, Adeyinka O, Ugbede, Idakwo, Onakoya, Adeola, Kizor Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J, Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Grossmann, Rodolfo Perez, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A, Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W, Coote, Michael, Crowston, Jonathan G, Astakhov, Sergei Y, Akopov, Eugeny L, Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al Obeidan, Saleh A, Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q, Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O, Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su Ling, Hillmer, Axel M, Cheng, Ching Yu, Escudero Domínguez, Francisco A, González Sarmiento, Rogelio, Martinon Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Nari, Sakuntabhai, Anavaj, Nguyn, Hip X, Nguyn, Giang T. T, Nguyn, Trình V, Zenz, Werner, Binder, Alexander, Klobassa, Daniela S, Hibberd, Martin L, Davila, Sonia, Herms, Stefan, Nöthen, Markus M, Moebus, Susanne, Rautenbach, Robyn M, Ziskind, Ari, Carmichael, Trevor R, Ramsay, Michele, Álvarez, Lydia, García, Montserrat, González Iglesias, Héctor, Rodríguez Calvo, Pedro P, Cueto, Luis Fernández Vega, Oguz, Çilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasım, Burcu, Wilson, M. Roy, Coleman, Anne L, Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W, Kuchtey, John, Curtin, Karen, Chaya, Craig J, Crandall, Alan, Zangwill, Linda M, Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I, Vesti, Eija, Fingert, John H, Lee, Richard K, Sit, Arthur J, Shingleton, Bradford J, Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak Vance, Margaret A, Raychaudhuri, Soumya, Heegaard, Steffen, Kivelä, Tero, Reis, André, Kruse, Friedrich E, Weinreb, Robert N, Pasquale, Louis R, Haines, Jonathan L, Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N, Micheal, Shazia, Topouzis, Foti, Craig, Jamie E, Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L, Pasutto, Francesca, Khor, Chiea Chuen, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Helsinki
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0301 basic medicine ,Male ,Calcium Channels/genetics ,Messenger ,Medizin ,PSEUDOEXFOLIATION SYNDROME ,Genome-wide association study ,BLOOD-PRESSURE ,Disease ,Exfoliation Syndrome ,Eye ,Exfoliation Syndrome/ethnology/genetics ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,0302 clinical medicine ,PARKINSONS-DISEASE ,80 and over ,ta319 ,Missense mutation ,Genetics ,Aged, 80 and over ,Amino Acid Oxidoreductases/genetics/physiology ,Alleles ,Amino Acid Oxidoreductases ,Amino Acid Substitution ,Asian Continental Ancestry Group ,Calcium Channels ,Cell Adhesion ,Extracellular Matrix ,Female ,Gene Expression Profiling ,Genetic Predisposition to Disease ,Haplotypes ,Humans ,Molecular Chaperones ,RNA, Messenger ,Spheroids, Cellular ,Genome-Wide Association Study ,Mutation, Missense ,Point Mutation ,Metaanalysis ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,3. Good health ,ALZHEIMERS-DISEASE ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Molecular Chaperones/biosynthesis/genetics ,Biology ,SYNONYMOUS MUTATIONS ,ta3111 ,Article ,03 medical and health sciences ,Asian People ,Asian Continental Ancestry Group/genetics ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,Allele ,Risk factor ,GENOME-WIDE ASSOCIATION ,Eye/metabolism ,Aged ,Genetic association ,[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE] ,Haplotype ,Individuals ,Glaucoma ,Odds ratio ,Extracellular Matrix/metabolism ,RNA, Messenger/biosynthesis ,MACULAR DEGENERATION ,RISK LOCI ,eye diseases ,COMMON SEQUENCE VARIANTS ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Mutation ,030221 ophthalmology & optometry ,RNA ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Cellular ,Spheroids ,Missense ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,Polymorphisms ,purl.org/pe-repo/ocde/ford#1.06.07 [https] ,INFLAMMATORY-BOWEL-DISEASE - Abstract
International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
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- 2017
35. Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy
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Kathryn P. Burdon, Marianne O. Price, Natalie A. Afshari, Simon G. Gregory, Jiagang Zhao, S. Amer Riazuddin, Sanjay V. Patel, Elmer Balajonda, Sudha K. Iyengar, Christopher R. Croasdale, Jamie E Craig, Venkateswara Mootha, Gordon K. Klintworth, Barbara Truitt, John F. Stamler, George O D Rosenwasser, Shiwani Sharma, Abraham Kuot, Jonathan H. Lass, Mollie A. Minear, Richard A. Mills, Steven P. Dunn, Sonja Klebe, Keith H. Baratz, John H. Fingert, Anthony J. Aldave, Xuejun Qin, Dwight Stambolian, V. Lakshmi Pulagam, John D. Gottsch, Joan E. Bailey-Wilson, Francis W. Price, Nathan Morris, Yi-Ju Li, Robert P. Igo, and J. B. Rimmler
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0301 basic medicine ,Science ,General Physics and Astronomy ,Locus (genetics) ,Genome-wide association study ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Cornea ,medicine ,Humans ,Genetics ,Multidisciplinary ,Fuchs' Endothelial Dystrophy ,Reproducibility of Results ,General Chemistry ,TCF4 ,eye diseases ,3. Good health ,Transplantation ,Corneal Disorder ,030104 developmental biology ,medicine.anatomical_structure ,ROC Curve ,Genetic Loci ,030221 ophthalmology & optometry ,Etiology ,sense organs ,Fuchs Endothelial Corneal Dystrophy ,Genome-Wide Association Study - Abstract
The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P, Fuchs endothelial corneal dystrophy (FECD) is one of the most common reasons for corneal transplantation, and is known to cluster in families. Here, the authors discover new genetic loci associated with FECD with sex-specific effects and implications for disease mechanism.
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- 2017
36. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis
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Douglas J Rhee, Bernard Rosner, Louis R. Pasquale, Yeunjoo E. Song, Hugues Aschard, Caroline C W Klaver, Allison E. Ashley-Koch, Jessica N. Cooke Bailey, Felipe A. Medeiros, Gadi Wollstein, Jonathan L. Haines, Pirro G. Hysi, Terry Gaasterland, Lisa A Hark, Richard K. Lee, Vikas Gulati, Douglas Vollrath, R. Rand Allingham, Margaret A. Pericak-Vance, Anthony P Khawaja, Julia E. Richards, William K. Scott, Murray H. Brilliant, Ching-Yu Cheng, Robert P. Igo, Joel S. Schuman, Daniel I. Chasman, Michael A. Hauser, Yutao Liu, Tony Realini, Robert N. Weinreb, Jae H. Kang, Robert Ritch, C.M. vanDuijn, Kuldev Singh, Sayoko E. Moroi, Arthur J. Sit, Donald L. Budenz, Peter Kraft, Donald J. Zack, John H. Fingert, Janey L. Wiggs, William G. Christen, Adriana I Iglesias, Shane Haven, Harvard Medical School [Boston] (HMS), Centre d'Études Biologiques de Chizé - UMR 7372 (CEBC), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), King‘s College London, Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Singapore Eye Research Institute [Singapore] (SERI), Lawrence Livermore National Laboratory (LLNL), Epidemiology, Ophthalmology, Institut National de la Recherche Agronomique (INRA)-La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-École normale supérieure - Rennes (ENS Rennes)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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Male ,0301 basic medicine ,Aging ,Linkage disequilibrium ,Intraocular pressure ,genetic structures ,Glaucoma ,Blood Pressure ,Genome-wide association study ,Neurodegenerative ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Linkage Disequilibrium ,0302 clinical medicine ,Medicine ,Genetics (clinical) ,Genetics & Heredity ,Genetics ,[STAT.AP]Statistics [stat]/Applications [stat.AP] ,MESH: Genetic Predisposition to Disease ,MESH: Blood Pressure ,3. Good health ,Open-Angle ,MESH: Linkage Disequilibrium ,Female ,[STAT.ME]Statistics [stat]/Methodology [stat.ME] ,Glaucoma, Open-Angle ,medicine.medical_specialty ,Open angle glaucoma ,Clinical Sciences ,International Glaucoma Genetics Consortium ,Genetic correlation ,Article ,03 medical and health sciences ,MESH: Intraocular Pressure ,Ophthalmology ,Humans ,Genetic Predisposition to Disease ,Eye Disease and Disorders of Vision ,Intraocular Pressure ,MESH: Humans ,business.industry ,Human Genome ,Neurosciences ,Heritability ,medicine.disease ,MESH: Male ,eye diseases ,030104 developmental biology ,Blood pressure ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,030221 ophthalmology & optometry ,MESH: Glaucoma, Open-Angle ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,sense organs ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,business ,MESH: Female - Abstract
Item does not contain fulltext Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 x 10(-27)) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 x 10(-5)); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.
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- 2017
37. Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish
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Renee Laux, Yeunjoo E. Song, Laura Caywood, Andrea R. Waksmunski, Jonathan L. Haines, William K. Scott, Michael Prough, Robert P. Igo, Jessica N. Cooke Bailey, Dwight Stambolian, Margaret A. Pericak-Vance, Larry D. Adams, Denise Fuzzell, and Sarada Fuzzell
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Male ,Linkage disequilibrium ,Indiana ,genetic structures ,Genetic Linkage ,Quantitative Trait Loci ,Locus (genetics) ,Biology ,03 medical and health sciences ,Macular Degeneration ,Gene Frequency ,Chromosome 18 ,Genetic linkage ,Fatty acid binding ,Genetics ,Humans ,Genetic Predisposition to Disease ,Endopeptidase inhibitor activity ,Allele ,Allele frequency ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,030304 developmental biology ,Aged ,Ohio ,Original Investigation ,Aged, 80 and over ,0303 health sciences ,030305 genetics & heredity ,Computational Biology ,Genetic Variation ,eye diseases ,3. Good health ,Pedigree ,Gene Ontology ,Female ,sense organs ,Amish - Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness in the world. While dozens of independent genomic variants are associated with AMD, about one-third of AMD heritability is still unexplained. To identify novel variants and loci for AMD, we analyzed Illumina HumanExome chip data from 87 Amish individuals with early or late AMD, 79 unaffected Amish individuals, and 15 related Amish individuals with unknown AMD affection status. We retained 37,428 polymorphic autosomal variants across 175 samples for association and linkage analyses. After correcting for multiple testing (n = 37,428), we identified four variants significantly associated with AMD: rs200437673 (LCN9, p = 1.50 × 10−11), rs151214675 (RTEL1, p = 3.18 × 10−8), rs140250387 (DLGAP1, p = 4.49 × 10−7), and rs115333865 (CGRRF1, p = 1.05 × 10−6). These variants have not been previously associated with AMD and are not in linkage disequilibrium with the 52 known AMD-associated variants reported by the International AMD Genomics Consortium based on physical distance. Genome-wide significant linkage peaks were observed on chromosomes 8q21.11–q21.13 (maximum recessive HLOD = 4.03) and 18q21.2–21.32 (maximum dominant HLOD = 3.87; maximum recessive HLOD = 4.27). These loci do not overlap with loci previously linked to AMD. Through gene ontology enrichment analysis with ClueGO in Cytoscape, we determined that several genes in the 1-HLOD support interval of the chromosome 8 locus are involved in fatty acid binding and triglyceride catabolic processes, and the 1-HLOD support interval of the linkage region on chromosome 18 is enriched in genes that participate in serine-type endopeptidase inhibitor activity and the positive regulation of epithelial to mesenchymal transition. These results nominate novel variants and loci for AMD that require further investigation. Electronic supplementary material The online version of this article (10.1007/s00439-019-02050-4) contains supplementary material, which is available to authorized users.
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- 2019
38. Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye
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Mineo Ozaki, Marcelo T. Nicolela, Theofanis Pappas, Fotis Topouzis, Andrés Fernández-Vega Cueto, Panayiota Founti, Eray Atalay, Nilgun Yildirim, Chie Sotozono, Christina Keskini, Yosai Mori, Luis Fernández-Vega Cueto, Andrew C. Orr, Murat Irkec, Yuanhan Li, Deepak P. Edward, Satoko Nakano, Yury S. Astakhov, Tsutomu Ohashi, Daniel Gaston, George Chichua, Evangelia S Panagiotou, Ursula Schlötzer-Schrehardt, Jae H. Kang, Sergo Tabagari, Federico Martinón-Torres, Akitoshi Yoshida, Lesya M. Shuba, Masaru Inatani, Ken Hayashi, Takako Sugimoto, Shamira A. Perera, Takanori Mizoguchi, Kar Seng Sim, Friedrich E. Kruse, Shin-ichi Manabe, Andreas Giessl, Joseph Saunders, Ewa Kosior-Jarecka, Christian Y. Mardin, Wai Leong Tam, Hui Meng Soo, Makoto Aihara, Yoshiaki Kiuchi, Tomomi Higashide, Wee Yang Meah, Rahat Husain, Tin Aung, Sergei Y. Astakhov, Zheng Li, Dimitrios G. Mikropoulos, André Reis, Eleftherios Anastasopoulos, Jessica N. Cooke Bailey, Anastasios G. P. Konstas, Toshiya Sakurai, Dilek Aktas, Montserrat García, Bilge Batu, Hideki Chuman, Shigeru Kinoshita, Matthias Zenkel, Ying Swan Ho, Nevbahar Tamçelik, Masakazu Nakano, Jonathan L. Haines, Nino Kobakhidze, Kazuhiko Mori, Esther Kai Lay Peh, Francesca Pasutto, Georg Mossböck, Anthi Chatzikyriakidou, Robert P. Igo, Etsuo Chihara, Kazuhisa Sugiyama, Janey L. Wiggs, Michael V. Dubina, Shuwen Chen, Paul E Rafuse, Xiao Yin Chen, Trevor R. Carmichael, Kei Tashiro, Miguel Coca-Prados, Claus Hellerbrand, Shigeyasu Kazama, Çilingir Oguz, Alexandros Lambropoulos, Patrick Tan, Michael A. Hauser, Burcu Kasım, Michèle Ramsay, Morio Ueno, Kana Tokumo, Kenji Inoue, Robert Ritch, Tomasz Zarnowski, Toshiaki Kubota, Sonia Davila, Steffen Heegaard, Ryuichi Ideta, Lydia Álvarez, Yoko Ikeda, Chiea Chuen Khor, Susan Williams, Satoshi Ishiko, Louis R. Pasquale, Eugeny L. Akopov, Antonio Salas, Alina Popa-Cherecheanu, Monisha E. Nongpiur, Héctor González-Iglesias, Urszula Lukasik, Jia Nee Foo, Augustine Cheong, Zhenxun Wang, Mei Chin Lee, Anita Chan, and Kazunori Miyata
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Risk ,Loxl1 ,medicine.medical_specialty ,Glaucoma ,Gene ,01 natural sciences ,Exfoliation syndrome ,03 medical and health sciences ,Low-Frequency ,0302 clinical medicine ,Interquartile range ,Internal medicine ,medicine ,Disease ,030212 general & internal medicine ,0101 mathematics ,Exfoliation (botany) ,Exome sequencing ,Original Investigation ,business.industry ,Protein ,010102 general mathematics ,Case-control study ,General Medicine ,Odds ratio ,medicine.disease ,Pseudoexfoliation Syndrome ,Susceptibility ,Cohort ,business - Abstract
IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 x 10(-6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 x 10(-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4%[interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings. National Research Foundation of SingaporeNational Research Foundation, Singapore [NRF-NRFI2018-01]; US National Eye Institute of the National Institutes of Health [R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, EY015473]; Glaucoma Research Foundation of Canada [X052, CIRG17may053]; National Medical Research Council of SingaporeNational Medical Research Council, Singapore The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.
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- 2021
39. Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4
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Oleg Butovsky, Milica A. Margeta, Janey L. Wiggs, Sophia M Letcher, Jessica N. Cooke Bailey, Jonathan L. Haines, Robert P. Igo, and Louis R. Pasquale
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Adult ,Male ,0301 basic medicine ,Apolipoprotein E ,Oncology ,medicine.medical_specialty ,Genotype ,genetic structures ,Open angle glaucoma ,Apolipoprotein E4 ,microglia ,Glaucoma ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,TREM2 ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Alleles ,Intraocular Pressure ,business.industry ,DNA ,Odds ratio ,Middle Aged ,medicine.disease ,eye diseases ,glaucoma ,030104 developmental biology ,Female ,sense organs ,Alzheimer's disease ,business ,Glaucoma, Open-Angle ,APOE ,030217 neurology & neurosurgery - Abstract
Purpose Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegeneration-associated molecular signature. Methods APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex. Results In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.74–0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70–0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58–0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05). Conclusions We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.
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- 2020
40. Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for coevolution?
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Kyle Fluegge, Harriet Mayanja-Kizza, Moses Joloba, Noemi B. Hall, Scott M. Williams, Eddie M. Wampande, Giorgio Sirugo, Michael L. McHenry, Robert P. Igo, Jacquelaine Bartlett, Catherine M. Stein, Penelope Benchek, Sarah A. Tishkoff, W. Henry Boom, Christian Wejse, and Sebastien Gagneux
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Male ,Bacterial Diseases ,RNA viruses ,Cancer Research ,Heredity ,Pathogenesis ,Disease ,QH426-470 ,Pathology and Laboratory Medicine ,Biological Coevolution ,0302 clinical medicine ,Immunodeficiency Viruses ,Genotype ,Medicine and Health Sciences ,Cation Transport Proteins ,Genetics (clinical) ,SLC11A1 ,Genetics ,0303 health sciences ,biology ,Interleukin-12 Subunit p40 ,Middle Aged ,Actinobacteria ,Genetic Mapping ,Infectious Diseases ,Medical Microbiology ,Viral Pathogens ,Host-Pathogen Interactions ,Viruses ,Female ,Pathogens ,Research Article ,Adult ,Evolutionary Processes ,Tuberculosis ,Adolescent ,Variant Genotypes ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Microbiology ,Evolution, Molecular ,Molecular Genetics ,Mycobacterium tuberculosis ,03 medical and health sciences ,Retroviruses ,medicine ,Humans ,SNP ,Allele ,Microbial Pathogens ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Aged ,030304 developmental biology ,Evolutionary Biology ,Bacteria ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Human Genetics ,Tropical Diseases ,biology.organism_classification ,medicine.disease ,biology.protein ,Genome, Bacterial ,030217 neurology & neurosurgery ,Coevolution - Abstract
Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB., Author summary Susceptibility to tuberculosis (TB) is affected by genetic variation in both the human host and the causative bacterium, Mycobacterium tuberculosis. However, prior studies of the genetics of each species have not explained a large part of TB risk. The possibility exists that risk can be better estimated from patterns of variation in the two species as a unit, such that some combinations provide increased risk, or in the presence of TB, increased disease severity. We hypothesized that alleles in the two species that have co-existed for long periods are more likely to reduce disease severity so as to promote prolonged co-occurrence. We tested this by studying TB severity in two patient cohorts from Uganda for which paired MTB-human DNA were available. We examined severity, as measured by the Bandim TBscore, and assessed whether there was an interaction between MTB lineage and SNPs in the host with this metric. Our results indicate that the most recent TB lineage (L4.6/Uganda) when found together with an ancestral allele in SLC11A1 resulted in more severe disease. This finding is consistent with the conclusion that MTB and human have coevolved to modulate TB severity.
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- 2020
41. Erratum. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 2019;68:441—456
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Aaron Leong, Yii-Der Ida Chen, Iiro Toppila, Elizabeth J. Rossin, Alan D. Penman, I-Te Lee, Kathryn P. Burdon, Yucheng Jia, Sudha K. Iyengar, Helen M. Colhoun, Michael A. Grassi, Jie Jin Wang, Tien Yin Wong, Barry I. Freedman, Kaanan P. Shah, Ching J. Chen, Weihua Meng, Brian L. Yaspan, Samaneh Davoudi, David S. Siscovick, Per-Henrik Groop, Samy Hadjadj, Michel Marre, Ching-Yu Cheng, John R. Sedor, Xiuqing Guo, Albert V. Smith, Robert P. Igo, Kyu Hyung Park, Jerome I. Rotter, Andrew D. Paterson, Samuela Pollack, Sharon G. Adler, Alkes L. Price, Emily Y. Chew, Emma Ahlqvist, Eli Ipp, Jamie E Craig, Richard A. Jensen, Barbara E.K. Klein, Maggie C.Y. Ng, Leif Groop, Craig L. Hanis, Xiaohui Li, Atsushi Takahashi, Roberta McKean-Cowdin, Mark P. Christiansen, Lynn K. Stanwyck, Paul Mitchell, Shiro Maeda, Alex S. F. Doney, Darryl Nousome, Ronald Klein, Yang Hai, Mark I. McCarthy, Niina Sandholm, Kent D. Taylor, Andrew D. Morris, Rohit Varma, David-Alexandre Trégouët, Jihye Kim, Valeriya Lyssenko, Colin N. A. Palmer, Mary Frances Cotch, Jane Z. Kuo, Elisabet Agardh, S. Mohsen Hosseini, Michiaki Kubo, Jeeyun Ahn, Gavin Tan, Minako Imamura, Lucia Sobrin, Heather Hancock, Wayne Huey-Herng Sheu, Donald W. Bowden, Ayellet V. Segrè, and Latchezar Dimitrov
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Pediatrics ,medicine.medical_specialty ,Complications ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genome-wide association study ,Diabetic retinopathy ,medicine.disease ,Diabetes mellitus ,Internal Medicine ,medicine ,Duration (project management) ,business ,Glycemic - Abstract
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value
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- 2020
42. Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis
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John H. Fingert, Robert Ritch, Baojian Fan, Peter Kraft, Paul R. Lichter, Murray H. Brilliant, Jessica N. Cooke Bailey, Jonathan L. Haines, Kuldev Singh, Louis R. Pasquale, Richard K. Lee, Robert N. Weinreb, Arthur J. Sit, Jonathan S. Myers, Yutao Liu, S.E. Moroi, Donald L. Budenz, Tahani Boumenna, Douglas J Rhee, Julia E. Richards, Margaret A. Pericak-Vance, Terry Gaasterland, Robert P. Igo, Douglas Vollrath, Jae H. Kang, William K. Scott, Michael A. Hauser, Anthony Realini, Gadi Wollstein, Douglas E. Gaasterland, Donald J. Zack, Janey L. Wiggs, and Joel S. Schuman
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medicine.medical_specialty ,genetic structures ,Open angle glaucoma ,business.industry ,Brief Report ,Glaucoma ,Odds ratio ,Disease ,Ophthalmology & Optometry ,medicine.disease ,eye diseases ,Genetic load ,Ophthalmology ,Opthalmology and Optometry ,Polymorphism (computer science) ,Internal medicine ,Cohort ,medicine ,Allele ,business - Abstract
IMPORTANCE: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. OBJECTIVE: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. MAIN OUTCOMES AND MEASURES: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. RESULTS: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10(−66)). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = −0.36; 95% CI, −0.56 to −0.16; P = 4.0 × 10(−4)). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10(−4)). CONCLUSIONS AND RELEVANCE: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.
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- 2019
43. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma
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Janey L. Wiggs, UK Biobank Eye, Jessica N. Cooke Bailey, Jonathan L. Haines, Ching-Yu Cheng, Pirro G. Hysi, Mark James Simcoe, Anthony P Khawaja, Paul J. Foster, Christopher J Hammond, Peng T. Khaw, Louis R. Pasquale, Yeunjoo E. Song, Robert A. Scott, Robert Wojciechowski, Nicholas J. Wareham, Robert P. Igo, Khawaja, Anthony P [0000-0001-6802-8585], Cooke Bailey, Jessica N [0000-0002-4001-8702], Simcoe, Mark [0000-0003-2432-0810], Pasquale, Louis R [0000-0002-5835-3496], Haines, Jonathan L [0000-0002-4351-4728], Foster, Paul J [0000-0002-4755-177X], Wiggs, Janey L [0000-0003-1890-3278], Hammond, Chris J [0000-0002-3227-2620], Hysi, Pirro G [0000-0001-5752-2510], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Adult ,Male ,Intraocular pressure ,Open angle glaucoma ,genetic structures ,Glaucoma ,Genome-wide association study ,Disease ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Risk factor ,Intraocular Pressure ,Aged ,Middle Aged ,medicine.disease ,eye diseases ,3. Good health ,030104 developmental biology ,Genetic Loci ,Cohort ,030221 ophthalmology & optometry ,Female ,sense organs ,Glaucoma, Open-Angle ,Cohort study ,Genome-Wide Association Study - Abstract
Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.
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- 2018
44. AMISH EYE STUDY: Baseline Spectral Domain Optical Coherence Tomography Characteristics of Age-Related Macular Degeneration
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Denise Fuzzell, Jessica N. Cooke Bailey, Dwight Stambolian, Yeunjoo E. Song, Violet Horst, Debra Dana, Robert P. Igo, Swetha Bindu Velaga, Samuel Pan, Margaret A. Pericak-Vance, Jonathan L. Haines, William K. Scott, Srinivas R. Sadda, Laura Caywood, Muneeswar Gupta Nittala, Larry D. Adams, Renee Laux, Rebecca J. Sardell, and Sarada Fuzzell
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0301 basic medicine ,Male ,medicine.medical_specialty ,genetic structures ,Population ,Retinal Drusen ,Drusen ,Fundus (eye) ,Article ,03 medical and health sciences ,Macular Degeneration ,0302 clinical medicine ,Optical coherence tomography ,Ophthalmology ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,education ,Aged ,Aged, 80 and over ,Observer Variation ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Reproducibility of Results ,General Medicine ,Macular degeneration ,Middle Aged ,medicine.disease ,eye diseases ,030104 developmental biology ,medicine.anatomical_structure ,Cohort ,030221 ophthalmology & optometry ,Female ,Choroid ,sense organs ,business ,Amish ,Biomarkers ,Tomography, Optical Coherence - Abstract
PURPOSE: To describe spectral domain optical coherence tomography (SD-OCT) findings in an Amish cohort to assess SD-OCT markers for early age-related macular degeneration (AMD). METHODS: The authors performed a family-based prospective cohort study of 1,146 elderly Amish subjects (age range 50–99 years) (2,292 eyes) who had a family history of at least 1 individual with AMD. All subjects underwent complete ophthalmic examinations, SD-OCT using both Cirrus and Spectralis (20 × 20° scan area) instruments, fundus auto-fluorescence, infrared imaging, and color fundus photography. Spectral domain optical coherence tomography characteristics were analyzed in subjects with AMD (with and without subretinal drusenoid deposits [SDDs]) and normal healthy cohorts. RESULTS: Participants’ mean age was 65.2 years (SD ± 11). Color fundus photographic findings in 596 (53%) subjects (1,009 eyes) were consistent with AMD; the remaining 478 (43%) subjects showed no signs of AMD. The choroid was significantly thinner on OCT (242 ± 76 μm, P < 0.001) in those with AMD compared with those without (263 ± 63 μm). Subretinal drusenoid deposits were found in 143 eyes (7%); 11 of the 143 eyes (8%) had no other manifestations of AMD. Drusen volume (P < 0.001) and area of geographic atrophy (P < 0.001) were significantly greater, and choroid was significantly (P < 0.001) thinner in subjects with SDDs versus those without SDDs. CONCLUSION: The authors describe spectral domain optical coherence tomography characteristics in an elderly Amish population with and without AMD, including the frequency of SDD. Although relatively uncommon in this population, the authors confirmed that SDDs can be found in the absence of other features of AMD and that eyes with SDDs have thinner choroids.
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- 2018
45. Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma
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David C. Whiteman, Jessica N. Cooke Bailey, William K. Scott, Michael Coote, Ivan Goldberg, Mark J Walland, David J. Lynn, Paul R. Healey, Paul Mitchell, John Landers, Terry Gaasterland, Kathryn P. Burdon, Arthur J. Sit, Jonathan B Ruddle, Nicholas G. Martin, Douglas Vollrath, R. Rand Allingham, Richard K. Lee, Julia E. Richards, Yutao Liu, David A. Mackey, Kuldev Singh, Mitchell Lawlor, Doug Rhee, Stuart MacGregor, Jamie E Craig, Robert Ritch, Graham L. Radford-Smith, Donald L. Budenz, Murray H. Brilliant, Robert P. Igo, John R. Grigg, Robert J Casson, Janey L. Wiggs, Bronwyn Ridge, Stuart L. Graham, Stephen Best, Louis R. Pasquale, S.E. Moroi, Peter Kraft, Anthony Realini, Lisa A Hark, Mona S Awadalla, Gadi Wollstein, Jesse Gale, Donald J. Zack, Owen M. Siggs, Puya Gharahkhani, Andrea L Vincent, Tiger Zhou, Alex W. Hewitt, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michael A. Hauser, Shiwani Sharma, John H. Fingert, Andrew White, Grant W. Montgomery, Douglas E. Gaasterland, Paul R. Lichter, Richard A. Mills, Joel S. Schuman, Jae H. Kang, Matthew Law, and Jonathan L. Haines
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Male ,0301 basic medicine ,Intraocular pressure ,genetic structures ,Optic disk ,lcsh:Medicine ,Muscle Proteins ,Glaucoma ,Genome-wide association study ,0302 clinical medicine ,Risk Factors ,lcsh:Science ,Genetics ,Multidisciplinary ,LIM Domain Proteins ,Middle Aged ,Retinoic Acid 4-Hydroxylase ,3. Good health ,Phenotype ,Female ,Glaucoma, Open-Angle ,Genotype ,Open angle glaucoma ,Endophenotypes ,LIM-Homeodomain Proteins ,Optic Disk ,Locus (genetics) ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Article ,Tonometry, Ocular ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,gamma-Crystallins ,Intraocular Pressure ,Aged ,lcsh:R ,Calcium-Binding Proteins ,Membrane Proteins ,Macular degeneration ,medicine.disease ,eye diseases ,030104 developmental biology ,Case-Control Studies ,030221 ophthalmology & optometry ,lcsh:Q ,sense organs ,Visual Fields ,Genome-Wide Association Study ,Transcription Factors - Abstract
Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
- Published
- 2018
46. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets
- Author
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R. Rand Allingham, Douglas J Rhee, Julia E. Richards, Donald J. Zack, Mariusz Butkiewicz, Margaret A. Pericak-Vance, Janey L. Wiggs, Richard K. Lee, William K. Scott, Hugues Aschard, Lisa A Hark, Arthur J. Sit, Alex W. Hewitt, Felipe A. Medeiros, Gadi Wollstein, Sayoko E. Moroi, Louis R. Pasquale, Jessica N. Cooke Bailey, Murray H. Brilliant, Stuart MacGregor, Donald L. Budenz, William G. Christen, John H. Fingert, Yeunjoo E. Song, Jamie E Craig, Thasarat S. Vajaranant, Tony Realini, David A. Sullivan, Daniel I. Chasman, Peter Kraft, Jonathan L. Haines, Robert P. Igo, Jae H. Kang, Robert N. Weinreb, Joel S. Schuman, Kuldev Singh, Robert Ritch, Kathryn P. Burdon, Yutao Liu, Puya Gharahkhani, David A. Mackey, Michael A. Hauser, Terry Gaasterland, Douglas Vollrath, Bernard Rosner, Allison E. Ashley-Koch, Harvard Medical School [Boston] (HMS), University of California [San Diego] (UC San Diego), University of California, and Harvard T.H. Chan School of Public Health
- Subjects
Male ,0301 basic medicine ,primary open-angle glaucoma ,genetic structures ,Datasets as Topic ,Genome-wide association study ,Ophthalmology & Optometry ,Medical and Health Sciences ,MESH: Genotype ,0302 clinical medicine ,Gene Frequency ,genetics ,MESH: Datasets as Topic ,Low Tension Glaucoma ,MESH: Low Tension Glaucoma ,Genetics ,[STAT.AP]Statistics [stat]/Applications [stat.AP] ,MESH: Middle Aged ,MESH: Polymorphism, Single Nucleotide ,Single Nucleotide ,Middle Aged ,Biological Sciences ,Pathway analysis ,pathway analysis ,Open-Angle ,Female ,[STAT.ME]Statistics [stat]/Methodology [stat.ME] ,Glaucoma, Open-Angle ,Metabolic Networks and Pathways ,Genotype ,Open angle glaucoma ,MESH: Testosterone ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium ,03 medical and health sciences ,MESH: Intraocular Pressure ,MESH: Gene Frequency ,Humans ,Polymorphism ,1000 Genomes Project ,Estrogen Metabolism ,Allele frequency ,Intraocular Pressure ,MESH: Humans ,Glaucoma ,Testosterone (patch) ,eye diseases ,MESH: Male ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,MESH: Metabolic Networks and Pathways ,testosterone ,MESH: Genome-Wide Association Study ,030221 ophthalmology & optometry ,MESH: Glaucoma, Open-Angle ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,sense organs ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,MESH: Female ,Genome-Wide Association Study - Abstract
Author(s): Bailey, Jessica N Cooke; Gharahkhani, Puya; Kang, Jae H; Butkiewicz, Mariusz; Sullivan, David A; Weinreb, Robert N; Aschard, Hugues; Allingham, R Rand; Ashley-Koch, Allison; Lee, Richard K; Moroi, Sayoko E; Brilliant, Murray H; Wollstein, Gadi; Schuman, Joel S; Fingert, John H; Budenz, Donald L; Realini, Tony; Gaasterland, Terry; Scott, William K; Singh, Kuldev; Sit, Arthur J; Igo, Robert P; Song, Yeunjoo E; Hark, Lisa; Ritch, Robert; Rhee, Douglas J; Vollrath, Douglas; Zack, Donald J; Medeiros, Felipe; Vajaranant, Thasarat S; Chasman, Daniel I; Christen, William G; Pericak-Vance, Margaret A; Liu, Yutao; Kraft, Peter; Richards, Julia E; Rosner, Bernard A; Hauser, Michael A; Craig, Jamie E; Burdon, Kathryn P; Hewitt, Alex W; Mackey, David A; Haines, Jonathan L; MacGregor, Stuart; Wiggs, Janey L; Pasquale, Louis R; Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium | Abstract: Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
- Published
- 2018
47. Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration
- Author
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Manoharan Aarthi, Theru A. Sivakumaran, Manmath Kumar Das, Stephanie A. Hagstrom, Liping Tian, Rajiv Raman, Gonçalo R. Abecasis, Vedam L. Ramprasad, Deborah A. Nickerson, Mark Seielstad, Emily Y. Chew, Parveen Sen, Wei Chen, Michael L. Klein, Lingam Vijaya, Jeffrey M. Kidd, Paul Mitchell, Evan E. Eichler, Yang Wang, Dwight Stambolian, Neal S. Peachey, Peter J. Francis, Ronnie George, Barbara E.K. Klein, Feiyou Qiu, Wan Ting Tay, A. K. Henning, Gyungah Jun, Dmitry V. Leontiev, Laura J. Kopplin, Tien Yin Wong, Albert O. Edwards, Robert P. Igo, Kristine E. Lee, Thomas LaFramboise, Anand Swaroop, Sudha K. Iyengar, Andy Itsara, Govindasamy Kumaramanickavel, and Ronald Klein
- Subjects
Multidisciplinary ,General Science & Technology ,Science ,Philosophy ,Age related ,Medicine ,Theology - Abstract
Author(s): Sivakumaran, Theru A; Igo, Robert P; Kidd, Jeffrey M; Itsara, Andy; Kopplin, Laura J; Chen, Wei; Hagstrom, Stephanie A; Peachey, Neal S; Francis, Peter J; Klein, Michael L; Chew, Emily Y; Ramprasad, Vedam L; Tay, Wan-Ting; Mitchell, Paul; Seielstad, Mark; Stambolian, Dwight E; Edwards, Albert O; Lee, Kristine E; Leontiev, Dmitry V; Jun, Gyungah; Wang, Yang; Tian, Liping; Qiu, Feiyou; Henning, Alice K; LaFramboise, Thomas; Sen, Parveen; Aarthi, Manoharan; George, Ronnie; Raman, Rajiv; Das, Manmath Kumar; Vijaya, Lingam; Kumaramanickavel, Govindasamy; Wong, Tien Y; Swaroop, Anand; Abecasis, Goncalo R; Klein, Ronald; Klein, Barbara EK; Nickerson, Deborah A; Eichler, Evan E; Iyengar, Sudha K | Abstract: [This corrects the article DOI: 10.1371/journal.pone.0025598.].
- Published
- 2018
48. AmpliSeq transcriptome analysis of human alveolar and monocyte-derived macrophages over time in response to Mycobacterium tuberculosis infection
- Author
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Catherine M. Stein, Larry S. Schlesinger, Abul K. Azad, Maciej Pietrzak, Katherine Hartmann, Audrey C. Papp, Amanda C. de C. Williams, Wolfgang Sadee, Robert P. Igo, and Samuel K. Handelman
- Subjects
0301 basic medicine ,Bacterial Diseases ,Time Factors ,Physiology ,Gene Expression ,lcsh:Medicine ,Transcriptome ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Gene cluster ,Gene expression ,Medicine and Health Sciences ,lcsh:Science ,Multidisciplinary ,Genomics ,3. Good health ,Body Fluids ,Interleukin-10 ,Infectious Diseases ,Blood ,Multigene Family ,Cellular Types ,Anatomy ,Transcriptome Analysis ,Research Article ,Sequence analysis ,Immune Cells ,Immunology ,Biology ,03 medical and health sciences ,Macrophages, Alveolar ,Genetics ,Genome-Wide Association Studies ,Tuberculosis ,Humans ,Gene Regulation ,Gene ,Blood Cells ,Sequence Analysis, RNA ,Macrophages ,Gene Expression Profiling ,lcsh:R ,RNA ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Cell Biology ,Mycobacterium tuberculosis ,Genome Analysis ,Tropical Diseases ,Molecular biology ,Triggering Receptor Expressed on Myeloid Cells-1 ,Gene expression profiling ,030104 developmental biology ,Genetic Loci ,Expression quantitative trait loci ,lcsh:Q ,030215 immunology - Abstract
Human alveolar macrophages (HAM) are primary bacterial niche and immune response cells during Mycobacterium tuberculosis (M.tb) infection, and human blood monocyte-derived macrophages (MDM) are a model for investigating M.tb-macrophage interactions. Here, we use a targeted RNA-Seq method to measure transcriptome-wide changes in RNA expression patterns of freshly obtained HAM (used within 6 h) and 6 day cultured MDM upon M.tb infection over time (2, 24 and 72 h), in both uninfected and infected cells from three donors each. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit (AmpliSeq) uses primers targeting 18,574 mRNAs and 2,228 non-coding RNAs (ncRNAs) for a total of 20,802 transcripts. AmpliSeqTM yields highly precise and reproducible gene expression profiles (R2 >0.99). Taking advantage of AmpliSeq's reproducibility, we establish well-defined quantitative RNA expression patterns of HAM versus MDM, including significant M.tb-inducible genes, in networks and pathways that differ in part between MDM and HAM. A similar number of expressed genes are detected at all time-points between uninfected MDM and HAM, in common pathways including inflammatory and immune functions, but canonical pathway differences also exist. In particular, at 2 h, multiple genes relevant to the immune response are preferentially expressed in either uninfected HAM or MDM, while the HAM RNA profiles approximate MDM profiles over time in culture, highlighting the unique RNA expression profile of freshly obtained HAM. MDM demonstrate a greater transcriptional response than HAM upon M.tb infection, with 2 to >10 times more genes up- or down-regulated. The results identify key genes involved in cellular responses to M.tb in two different human macrophage types. Follow-up bioinformatics analysis indicates that approximately 30% of response genes have expression quantitative trait loci (eQTLs in GTEx), common DNA variants that can influence host gene expression susceptibility or resistance to M.tb, illustrated with the TREM1 gene cluster and IL-10.
- Published
- 2018
49. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility
- Author
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S.E. Moroi, Christopher J Hammond, Peter Kraft, Terri L. Young, Tin Aung, Unnar Thorsteinsdottir, R. Rand Allingham, Francesca Pasutto, Murray H. Brilliant, Robert P. Igo, Joel S. Schuman, Paul R. Lichter, Adriana I. Iglesias Gonzalez, Jessica N. Cooke Bailey, Jonathan L. Haines, Chiea Chuen Khor, Robert Ritch, René Hoehn, John H. Fingert, Puya Gharahkhani, Terry Gaasterland, Calvin C P Pang, Cheng Yu Cheng, Louis R. Pasquale, Lisa A Hark, Andrew J. Lotery, Douglas Vollrath, Yutao Liu, David A. Mackey, Stuart MacGregor, William K. Scott, Pirro G. Hysi, Alex W. Hewitt, Jae H. Kang, Cornelia M. van Duijn, Arthur J. Sit, Margaret A. Pericak-Vance, Michael A. Hauser, Peter Bonnemaijer, Veronique Vitart, Kuldev Singh, D. L. Budenz, Doaa Nabih Maria, Gudmar Thorleifsson, Julia R. Richards, Kari Stefansson, Sumana R Chintalapudi, Doug Rhee, Richard K. Lee, Anthony P Khawaja, Anthony Realini, Robert W. Williams, Eranga N. Vithana, Gadi Wollstein, Fridbert Jonansson, Jamie E Craig, Xiang Di Wang, Tanja Zeller, Douglas E. Gaasterland, Donald J. Zack, Caroline C W Klaver, Janey L. Wiggs, Monica M. Jablonski, Psychiatry, Epidemiology, Clinical Genetics, and Ophthalmology
- Subjects
0301 basic medicine ,Male ,Intraocular pressure ,Candidate gene ,genetic structures ,General Physics and Astronomy ,Glaucoma ,Genome-wide association study ,Disease ,Bioinformatics ,Cohort Studies ,Mice ,0302 clinical medicine ,lcsh:Science ,Multidisciplinary ,biology ,3. Good health ,Mice, Inbred DBA ,CACNA2D1 ,Female ,Glaucoma, Open-Angle ,Open angle glaucoma ,Science ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Genetic variation ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Intraocular Pressure ,Aged ,business.industry ,General Chemistry ,medicine.disease ,eye diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,030221 ophthalmology & optometry ,biology.protein ,lcsh:Q ,Calcium Channels ,sense organs ,business ,Genome-Wide Association Study - Abstract
Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets., Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.
- Published
- 2017
50. Autosomal dominant hereditary spastic paraplegia with axonal sensory motor polyneuropathy maps to chromosome 21q 22.3
- Author
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Yuqun A. Luo, Robert P. Igo, Leema Reddy Peddareddygari, Philip A. Hanna, Michio Hirano, Raji P. Grewal, and Sungho Won
- Subjects
Adult ,Male ,Genetics ,Candidate gene ,Chromosomes, Human, Pair 21 ,Spastic Paraplegia, Hereditary ,Hereditary spastic paraplegia ,General Neuroscience ,Haplotype ,Locus (genetics) ,General Medicine ,Middle Aged ,Biology ,medicine.disease ,Genome ,Genetic analysis ,Pedigree ,medicine ,Humans ,Female ,Candidate Gene Analysis ,Gene ,Aged - Abstract
Hereditary spastic paraplegia (HSP) are a genetically and clinically heterogeneous group of disorders. At present, 19 autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy.A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis.All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum logarithm of odds score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease-producing mutations were detected.We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motor polyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56.
- Published
- 2015
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