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115 results on '"Hysi, P G"'

2. A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation

Author

Gorman, Bryan R., Francis, Michael, Nealon, Cari L., Halladay, Christopher W., Duro, Nalvi, Markianos, Kyriacos, Genovese, Giulio, Hysi, Pirro G., Choquet, Hélène, Afshari, Natalie A., Li, Yi-Ju, Gaziano, J. Michael, Hung, Adriana M., Wu, Wen-Chih, Greenberg, Paul B., Pyarajan, Saiju, Lass, Jonathan H., Peachey, Neal S., and Iyengar, Sudha K.

Published
2024
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4. Circulating metabolites modulated by diet are associated with depression

Author

van der Spek, Ashley, Stewart, Isobel D., Kühnel, Brigitte, Pietzner, Maik, Alshehri, Tahani, Gauß, Friederike, Hysi, Pirro G., MahmoudianDehkordi, Siamak, Heinken, Almut, Luik, Annemarie I., Ladwig, Karl-Heinz, Kastenmüller, Gabi, Menni, Cristina, Hertel, Johannes, Ikram, M. Arfan, de Mutsert, Renée, Suhre, Karsten, Gieger, Christian, Strauch, Konstantin, Völzke, Henry, Meitinger, Thomas, Mangino, Massimo, Flaquer, Antonia, Waldenberger, Melanie, Peters, Annette, Thiele, Ines, Kaddurah-Daouk, Rima, Dunlop, Boadie W., Rosendaal, Frits R., Wareham, Nicholas J., Spector, Tim D., Kunze, Sonja, Grabe, Hans Jörgen, Mook-Kanamori, Dennis O., Langenberg, Claudia, van Duijn, Cornelia M., and Amin, Najaf

Published
2023
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5. Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

Author

Musolf, Anthony M., Haarman, Annechien E. G., Luben, Robert N., Ong, Jue-Sheng, Patasova, Karina, Trapero, Rolando Hernandez, Marsh, Joseph, Jain, Ishika, Jain, Riya, Wang, Paul Zhiping, Lewis, Deyana D., Tedja, Milly S., Iglesias, Adriana I., Li, Hengtong, Cowan, Cameron S., Biino, Ginevra, Klein, Alison P., Duggal, Priya, Mackey, David A., Hayward, Caroline, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Pärssinen, Olavi, Cheng, Ching-Yu, Saw, Seang-Mei, Stambolian, Dwight, Hysi, Pirro G., Khawaja, Anthony P., Vitart, Veronique, Hammond, Christopher J., van Duijn, Cornelia M., Verhoeven, Virginie J. M., Klaver, Caroline C. W., and Bailey-Wilson, Joan E.

Published
2023
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6. New Polygenic Risk Score to Predict High Myopia in Singapore Chinese Children

Author

Lanca, Carla, Kassam, Irfahan, Patasova, Karina, Foo, Li-Lian, Li, Jonathan, Ang, Marcus, Hoang, Quan V, Teo, Yik-Ying, Hysi, Pirro G, and Saw, Seang-Mei

Subjects
Pediatric, Clinical Research, Prevention, Good Health and Well Being, Adolescent, Child, China, Cohort Studies, Humans, Myopia, Risk Factors, Singapore, high myopia, polygenic risk score, teenagers, East Asian, Biomedical Engineering, Opthalmology and Optometry
Abstract

PurposeThe purpose of this study was to develop an Asian polygenic risk score (PRS) to predict high myopia (HM) in Chinese children in the Singapore Cohort of Risk factors for Myopia (SCORM) cohort.MethodsWe included children followed from 6 to 11 years old until teenage years (12-18 years old). Cycloplegic autorefraction, ultrasound biometry, Illumina HumanHap 550, or 550 Duo Beadarrays, demographics, and environmental factors data were obtained. The PRS was generated from the Consortium for Refractive Error and Myopia genomewide association study (n = 542,934) and the Strabismus, Amblyopia, and Refractive Error in Singapore children Study (n = 500). The Growing Up in Singapore Towards healthy Outcomes Cohort study (n = 339) was the replication cohort. The outcome was teenage HM (≤ -5.00 D) with predictive performance assessed using the area under the curve (AUC).ResultsMean baseline age ± SD was 7.85 ± 0.84 (n = 1004) and 571 attended the teenage visit; 23.3% had HM. In multivariate analysis, the PRS was associated with a myopic spherical equivalent with an incremental R2 of 0.041 (95% confidence interval [CI] = 0.010, 0.073; P < 0.001). AUC for HM (0.77 [95% CI = 0.71-0.83]) performed better (P = 0.02) with the PRS compared with a model without (0.72 [95% CI = 0.65, 0.78]). Children at the top 25% PRS risk had a 2.34-fold-greater risk of HM (95% CI = 1.53, 3.55; P < 0.001).ConclusionsThe new Asian PRS improved the predictive performance to detect children at risk of HM.Translational relevanceClinicians may use the PRS with other predictive factors to identify high risk children and guide interventions to reduce the risk of HM later in life.

Published
2021

7. A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

Author

Hardcastle, Alison J, Liskova, Petra, Bykhovskaya, Yelena, McComish, Bennet J, Davidson, Alice E, Inglehearn, Chris F, Li, Xiaohui, Choquet, Hélène, Habeeb, Mahmoud, Lucas, Sionne EM, Sahebjada, Srujana, Pontikos, Nikolas, Lopez, Karla E Rojas, Khawaja, Anthony P, Ali, Manir, Dudakova, Lubica, Skalicka, Pavlina, Van Dooren, Bart TH, Geerards, Annette JM, Haudum, Christoph W, Faro, Valeria Lo, Tenen, Abi, Simcoe, Mark J, Patasova, Karina, Yarrand, Darioush, Yin, Jie, Siddiqui, Salina, Rice, Aine, Farraj, Layal Abi, Chen, Yii-Der Ida, Rahi, Jugnoo S, Krauss, Ronald M, Theusch, Elisabeth, Charlesworth, Jac C, Szczotka-Flynn, Loretta, Toomes, Carmel, Meester-Smoor, Magda A, Richardson, Andrea J, Mitchell, Paul A, Taylor, Kent D, Melles, Ronald B, Aldave, Anthony J, Mills, Richard A, Cao, Ke, Chan, Elsie, Daniell, Mark D, Wang, Jie Jin, Rotter, Jerome I, Hewitt, Alex W, MacGregor, Stuart, Klaver, Caroline CW, Ramdas, Wishal D, Craig, Jamie E, Iyengar, Sudha K, O'Brart, David, Jorgenson, Eric, Baird, Paul N, Rabinowitz, Yaron S, Burdon, Kathryn P, Hammond, Chris J, Tuft, Stephen J, and Hysi, Pirro G

Abstract

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Published
2021

8. Rare and common genetic determinants of metabolic individuality and their effects on human health

Author

Surendran, Praveen, Stewart, Isobel D., Au Yeung, Victoria P. W., Pietzner, Maik, Raffler, Johannes, Wörheide, Maria A., Li, Chen, Smith, Rebecca F., Wittemans, Laura B. L., Bomba, Lorenzo, Menni, Cristina, Zierer, Jonas, Rossi, Niccolò, Sheridan, Patricia A., Watkins, Nicholas A., Mangino, Massimo, Hysi, Pirro G., Di Angelantonio, Emanuele, Falchi, Mario, Spector, Tim D., Soranzo, Nicole, Michelotti, Gregory A., Arlt, Wiebke, Lotta, Luca A., Denaxas, Spiros, Hemingway, Harry, Gamazon, Eric R., Howson, Joanna M. M., Wood, Angela M., Danesh, John, Wareham, Nicholas J., Kastenmüller, Gabi, Fauman, Eric B., Suhre, Karsten, Butterworth, Adam S., and Langenberg, Claudia

Published
2022
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9. Association of Pharmacogenetic Markers With Atazanavir Exposure in HIV‐Infected Women

Author

Tamraz, Bani, Huang, Yong, French, Audrey L, Kassaye, Seble, Anastos, Kathryn, Nowicki, Marek J, Gange, Stephen, Gustafson, Deborah R, Bacchetti, Peter, Greenblatt, Ruth M, Hysi, Pirro G, Aouizerat, Bradley E, and Study, Women's Interagency HIV

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, ATP Binding Cassette Transporter, Subfamily B, Area Under Curve, Atazanavir Sulfate, Chromatography, High Pressure Liquid, Citrus sinensis, Cytochrome P-450 CYP3A Inhibitors, Diarrhea, Dose-Response Relationship, Drug, Female, Genotype, HIV Infections, HIV Protease Inhibitors, Hair, Heroin Dependence, Humans, Hydrogen-Ion Concentration, Longitudinal Studies, MicroRNAs, Polymorphism, Single Nucleotide, Racial Groups, Receptors, Cell Surface, Tandem Mass Spectrometry, Women's Interagency HIV Study, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

SORCS2 rs73208473 was recently associated with decreased atazanavir (ATV) concentration in the hair of women with seropositive HIV. Herein, we report on a pharmacogenetic study of women with seropositive HIV demonstrating a similar association between rs73208473 and dose-adjusted plasma ATV concentration in African Americans.

Published
2020

10. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author

Bonnemaijer, Pieter WM, Leeuwen, Elisabeth M van, Iglesias, Adriana I, Gharahkhani, Puya, Vitart, Veronique, Khawaja, Anthony P, Simcoe, Mark, Höhn, René, Cree, Angela J, Igo, Rob P, Gerhold-Ay, Aslihan, Nickels, Stefan, Wilson, James F, Hayward, Caroline, Boutin, Thibaud S, Polašek, Ozren, Aung, Tin, Khor, Chiea Chuen, Amin, Najaf, Lotery, Andrew J, Wiggs, Janey L, Cheng, Ching-Yu, Hysi, Pirro G, Hammond, Christopher J, Thiadens, Alberta AHJ, MacGregor, Stuart, Klaver, Caroline CW, and Duijn, Cornelia M van

Subjects
Genetics, Eye Disease and Disorders of Vision, Neurodegenerative, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Computational Biology, Gene Expression Profiling, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Humans, Molecular Sequence Annotation, Optic Disk, Optic Nerve Diseases, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Signal Transduction, International Glaucoma Genetics Consortium, NEIGHBORHOOD consortium, UK Biobank Eye and Vision Consortium, Genome-wide association studies, Optic nerve diseases
Abstract

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Published
2019

11. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author

Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study - GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, Wellcome Trust Case Control Consortium 2 (WTCCC2), NEIGHBORHOOD consortium, Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart

Subjects
Blue Mountains Eye Study - GWAS group, Wellcome Trust Case Control Consortium 2, NEIGHBORHOOD consortium, Eye Disease and Disorders of Vision
Abstract

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

12. Ascorbic acid metabolites are involved in intraocular pressure control in the general population.

Author

Hysi, Pirro G, Khawaja, Anthony P, Menni, Cristina, Tamraz, Bani, Wareham, Nick, Khaw, Kay-Tee, Foster, Paul J, Benet, Leslie Z, Spector, Tim D, and Hammond, Chris J

Subjects
Humans, Glaucoma, Ascorbic Acid, Intraocular Pressure, Adult, Aged, Middle Aged, Female, Male, Metabolomics, Metabolome, Public Health Surveillance, Ascorbate metabolism, Intraocular pressure, Multi-omics, Neurodegenerative, Prevention, Aging, Eye Disease and Disorders of Vision, Neurosciences, Multi-omits, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Pharmacology and Pharmaceutical Sciences
Abstract

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma.

Published
2019

13. Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Author

Bonnemaijer, Pieter WM, Iglesias, Adriana I, Nadkarni, Girish N, Sanyiwa, Anna J, Hassan, Hassan G, Cook, Colin, GIGA Study Group, Simcoe, Mark, Taylor, Kent D, Schurmann, Claudia, Belbin, Gillian M, Kenny, Eimear E, Bottinger, Erwin P, van de Laar, Suzanne, Wiliams, Susan EI, Akafo, Stephen K, Ashaye, Adeyinka O, Zangwill, Linda M, Girkin, Christopher A, Ng, Maggie CY, Rotter, Jerome I, Weinreb, Robert N, Li, Zheng, Allingham, R Rand, Eyes of Africa Genetics Consortium, Nag, Abhishek, Hysi, Pirro G, Meester-Smoor, Magda A, Wiggs, Janey L, NEIGHBORHOOD Consortium, Hauser, Michael A, Hammond, Christopher J, Lemij, Hans G, Loos, Ruth JF, van Duijn, Cornelia M, Thiadens, Alberta AHJ, and Klaver, Caroline CW

Subjects
GIGA Study Group, Eyes of Africa Genetics Consortium, NEIGHBORHOOD Consortium, Humans, Glaucoma, Open-Angle, Vesicular Transport Proteins, Aged, Aged, 80 and over, Middle Aged, African Continental Ancestry Group, Female, Male, Thioredoxin Reductase 2, Genome-Wide Association Study, Genetic Loci, Neurodegenerative, Human Genome, Aging, Eye Disease and Disorders of Vision, Genetics, Neurosciences, 2.1 Biological and endogenous factors, Genetics & Heredity, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine
Abstract

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

Published
2018

14. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author

Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study—GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart

Subjects
Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Cornea, Humans, Marfan Syndrome, Corneal Diseases, Corneal Dystrophies, Hereditary, Keratoconus, Eye Diseases, Hereditary, Glaucoma, Open-Angle, Myopia, Ehlers-Danlos Syndrome, Proteoglycans, Gene Expression, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Asian Continental Ancestry Group, European Continental Ancestry Group, Transforming Growth Factor beta2, Genome-Wide Association Study, Loeys-Dietz Syndrome, Mendelian Randomization Analysis, Decorin, Lumican, Fibrillin-1, ADAMTS Proteins, Corneal Dystrophies, Hereditary, Eye Diseases, Glaucoma, Open-Angle, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Genome, Human
Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Published
2018

15. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author

de Vries, Paul S, Sabater-Lleal, Maria, Chasman, Daniel I, Trompet, Stella, Ahluwalia, Tarunveer S, Teumer, Alexander, Kleber, Marcus E, Chen, Ming-Huei, Wang, Jie Jin, Attia, John R, Marioni, Riccardo E, Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A, Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M, Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J, Rumley, Ann, Mulas, Antonella, de Craen, Anton JM, Grotevendt, Anne, Taylor, Kent D, Delgado, Graciela E, Kifley, Annette, Lopez, Lorna M, Berentzen, Tina L, Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C, Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek PM, Draisma, Harmen HM, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J, Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G, McEvoy, Mark A, Starr, John M, Hysi, Pirro G, Hernandez, Dena G, Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Psaty, Bruce M, Uitterlinden, André G, de Geus, Eco JC, Stott, David J, Binder, Harald, Hofman, Albert, Franco, Oscar H, Rotter, Jerome I, Ferrucci, Luigi, Spector, Tim D, Deary, Ian J, März, Winfried, Greinacher, Andreas, Wild, Philipp S, Cucca, Francesco, Boomsma, Dorret I, Watkins, Hugh, Tang, Weihong, Ridker, Paul M, Jukema, Jan W, Scott, Rodney J, Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J, Smith, Nicholas L, Strachan, David P, and Dehghan, Abbas

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Genome-Wide Association Study, HapMap Project, Humans, General Science & Technology
Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017

16. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Author

Bailey, Jessica N Cooke, Loomis, Stephanie J, Kang, Jae H, Allingham, R Rand, Gharahkhani, Puya, Khor, Chiea Chuen, Burdon, Kathryn P, Aschard, Hugues, Chasman, Daniel I, Igo, Robert P, Hysi, Pirro G, Glastonbury, Craig A, Ashley-Koch, Allison, Brilliant, Murray, Brown, Andrew A, Budenz, Donald L, Buil, Alfonso, Cheng, Ching-Yu, Choi, Hyon, Christen, William G, Curhan, Gary, De Vivo, Immaculata, Fingert, John H, Foster, Paul J, Fuchs, Charles, Gaasterland, Douglas, Gaasterland, Terry, Hewitt, Alex W, Hu, Frank, Hunter, David J, Khawaja, Anthony P, Lee, Richard K, Li, Zheng, Lichter, Paul R, Mackey, David A, McGuffin, Peter, Mitchell, Paul, Moroi, Sayoko E, Perera, Shamira A, Pepper, Keating W, Qi, Qibin, Realini, Tony, Richards, Julia E, Ridker, Paul M, Rimm, Eric, Ritch, Robert, Ritchie, Marylyn, Schuman, Joel S, Scott, William K, Singh, Kuldev, Sit, Arthur J, Song, Yeunjoo E, Tamimi, Rulla M, Topouzis, Fotis, Viswanathan, Ananth C, Verma, Shefali Setia, Vollrath, Douglas, Wang, Jie Jin, Weisschuh, Nicole, Wissinger, Bernd, Wollstein, Gadi, Wong, Tien Y, Yaspan, Brian L, Zack, Donald J, Zhang, Kang, Study, EPIC-Norfolk Eye, Weinreb, Robert N, Pericak-Vance, Margaret A, Small, Kerrin, Hammond, Christopher J, Aung, Tin, Liu, Yutao, Vithana, Eranga N, MacGregor, Stuart, Craig, Jamie E, Kraft, Peter, Howell, Gareth, Hauser, Michael A, Pasquale, Louis R, Haines, Jonathan L, and Wiggs, Janey L

Subjects
Biological Sciences, Genetics, Eye Disease and Disorders of Vision, Neurodegenerative, Neurosciences, Human Genome, Aging, Eye, Ataxin-2, Forkhead Transcription Factors, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle, Humans, Polymorphism, Single Nucleotide, Thioredoxin Reductase 2, ANZRAG Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Published
2016

17. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

de Vries, Paul S, Chasman, Daniel I, Sabater-Lleal, Maria, Chen, Ming-Huei, Huffman, Jennifer E, Steri, Maristella, Tang, Weihong, Teumer, Alexander, Marioni, Riccardo E, Grossmann, Vera, Hottenga, Jouke J, Trompet, Stella, Müller-Nurasyid, Martina, Zhao, Jing Hua, Brody, Jennifer A, Kleber, Marcus E, Guo, Xiuqing, Wang, Jie Jin, Auer, Paul L, Attia, John R, Yanek, Lisa R, Ahluwalia, Tarunveer S, Lahti, Jari, Venturini, Cristina, Tanaka, Toshiko, Bielak, Lawrence F, Joshi, Peter K, Rocanin-Arjo, Ares, Kolcic, Ivana, Navarro, Pau, Rose, Lynda M, Oldmeadow, Christopher, Riess, Helene, Mazur, Johanna, Basu, Saonli, Goel, Anuj, Yang, Qiong, Ghanbari, Mohsen, Willemsen, Gonneke, Rumley, Ann, Fiorillo, Edoardo, de Craen, Anton JM, Grotevendt, Anne, Scott, Robert, Taylor, Kent D, Delgado, Graciela E, Yao, Jie, Kifley, Annette, Kooperberg, Charles, Qayyum, Rehan, Lopez, Lorna M, Berentzen, Tina L, Räikkönen, Katri, Mangino, Massimo, Bandinelli, Stefania, Peyser, Patricia A, Wild, Sarah, Trégouët, David-Alexandre, Wright, Alan F, Marten, Jonathan, Zemunik, Tatijana, Morrison, Alanna C, Sennblad, Bengt, Tofler, Geoffrey, de Maat, Moniek PM, de Geus, Eco JC, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Binder, Harald, Völker, Uwe, Waldenberger, Melanie, Khaw, Kay-Tee, Mcknight, Barbara, Huang, Jie, Jenny, Nancy S, Holliday, Elizabeth G, Qi, Lihong, Mcevoy, Mark G, Becker, Diane M, Starr, John M, Sarin, Antti-Pekka, Hysi, Pirro G, Hernandez, Dena G, Jhun, Min A, Campbell, Harry, Hamsten, Anders, Rivadeneira, Fernando, Mcardle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Koenig, Wolfgang, Psaty, Bruce M, Haritunians, Talin, Liu, Jingmin, Palotie, Aarno, Uitterlinden, André G, Stott, David J, Hofman, Albert, and Franco, Oscar H

Subjects
Biological Sciences, Genetics, Human Genome, Adult, Aged, Aged, 80 and over, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Published
2016

18. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, Sarah, Marenholz, Ingo, Esparza-Gordillo, Jorge, Arnau-Soler, Aleix, Pairo-Castineira, Erola, Rüschendorf, Franz, Ahluwalia, Tarunveer S., Almqvist, Catarina, Arnold, Andreas, Baurecht, Hansjörg, Bisgaard, Hans, Bønnelykke, Klaus, Brown, Sara J., Bustamante, Mariona, Curtin, John A., Custovic, Adnan, Dharmage, Shyamali C., Esplugues, Ana, Falchi, Mario, Fernandez-Orth, Dietmar, Ferreira, Manuel A. R., Franke, Andre, Gerdes, Sascha, Gieger, Christian, Hakonarson, Hakon, Holt, Patrick G., Homuth, Georg, Hubner, Norbert, Hysi, Pirro G., Jarvelin, Marjo-Riitta, Karlsson, Robert, Koppelman, Gerard H., Lau, Susanne, Lutz, Manuel, Magnusson, Patrik K. E., Marks, Guy B., Müller-Nurasyid, Martina, Nöthen, Markus M., Paternoster, Lavinia, Pennell, Craig E., Peters, Annette, Rawlik, Konrad, Robertson, Colin F., Rodriguez, Elke, Sebert, Sylvain, Simpson, Angela, Sleiman, Patrick M. A., Standl, Marie, Stölzl, Dora, Strauch, Konstantin, Szwajda, Agnieszka, Tenesa, Albert, Thompson, Philip J., Ullemar, Vilhelmina, Visconti, Alessia, Vonk, Judith M., Wang, Carol A., Weidinger, Stephan, Wielscher, Matthias, Worth, Catherine L., Xu, Chen-Jian, and Lee, Young-Ae

Published
2021
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20. Meta‐analysis of Genome‐Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author

Springelkamp, Henriët, Mishra, Aniket, Hysi, Pirro G, Gharahkhani, Puya, Höhn, René, Khor, Chiea‐Chuen, Bailey, Jessica N Cooke, Luo, Xiaoyan, Ramdas, Wishal D, Vithana, Eranga, Koh, Victor, Yazar, Seyhan, Xu, Liang, Forward, Hannah, Kearns, Lisa S, Amin, Najaf, Iglesias, Adriana I, Sim, Kar‐Seng, Leeuwen, Elisabeth M, Demirkan, Ayse, der Lee, Sven, Loon, Seng‐Chee, Rivadeneira, Fernando, Nag, Abhishek, Sanfilippo, Paul G, Schillert, Arne, de Jong, Paulus TVM, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Consortium, NEIGHBORHOOD, Zhou, Tiger, Burdon, Kathryn P, Spector, Timothy D, Lackner, Karl J, Saw, Seang‐Mei, Vingerling, Johannes R, Teo, Yik‐Ying, Pasquale, Louis R, Wolfs, Roger CW, Lemij, Hans G, Tai, E‐Shyong, Jonas, Jost B, Cheng, Ching‐Yu, Aung, Tin, Jansonius, Nomdo M, Klaver, Caroline CW, Craig, Jamie E, Young, Terri L, Haines, Jonathan L, MacGregor, Stuart, Mackey, David A, Pfeiffer, Norbert, Wong, Tien‐Yin, Wiggs, Janey L, Hewitt, Alex W, Duijn, Cornelia M, and Hammond, Christopher J

Subjects
Aging, Human Genome, Eye Disease and Disorders of Vision, Genetics, Neurosciences, Neurodegenerative, Eye, Asian People, Genome-Wide Association Study, Glaucoma, Humans, Optic Disk, Optic Nerve Diseases, Quantitative Trait Loci, White People, NEIGHBORHOOD Consortium, GWAS, cup area, disc area, glaucoma, Public Health and Health Services, Epidemiology
Abstract

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.

Published
2015

21. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.

Author

Springelkamp, Henriët, Höhn, René, Mishra, Aniket, Hysi, Pirro G, Khor, Chiea-Chuen, Loomis, Stephanie J, Bailey, Jessica N Cooke, Gibson, Jane, Thorleifsson, Gudmar, Janssen, Sarah F, Luo, Xiaoyan, Ramdas, Wishal D, Vithana, Eranga, Nongpiur, Monisha E, Montgomery, Grant W, Xu, Liang, Mountain, Jenny E, Gharahkhani, Puya, Lu, Yi, Amin, Najaf, Karssen, Lennart C, Sim, Kar-Seng, van Leeuwen, Elisabeth M, Iglesias, Adriana I, Verhoeven, Virginie JM, Hauser, Michael A, Loon, Seng-Chee, Despriet, Dominiek DG, Nag, Abhishek, Venturini, Cristina, Sanfilippo, Paul G, Schillert, Arne, Kang, Jae H, Landers, John, Jonasson, Fridbert, Cree, Angela J, van Koolwijk, Leonieke ME, Rivadeneira, Fernando, Souzeau, Emmanuelle, Jonsson, Vesteinn, Menon, Geeta, Blue Mountains Eye Study—GWAS group, Weinreb, Robert N, de Jong, Paulus TVM, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Ennis, Sarah, Thorsteinsdottir, Unnur, Burdon, Kathryn P, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Spector, Timothy D, Mirshahi, Alireza, Saw, Seang-Mei, Vingerling, Johannes R, Teo, Yik-Ying, Haines, Jonathan L, Wolfs, Roger CW, Lemij, Hans G, Tai, E-Shyong, Jansonius, Nomdo M, Jonas, Jost B, Cheng, Ching-Yu, Aung, Tin, Viswanathan, Ananth C, Klaver, Caroline CW, Craig, Jamie E, Macgregor, Stuart, Mackey, David A, Lotery, Andrew J, Stefansson, Kari, Bergen, Arthur AB, Young, Terri L, Wiggs, Janey L, Pfeiffer, Norbert, Wong, Tien-Yin, Pasquale, Louis R, Hewitt, Alex W, van Duijn, Cornelia M, and Hammond, Christopher J

Subjects
Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Optic Nerve, Optic Disk, Humans, Glaucoma, Case-Control Studies, Gene Expression Profiling, Gene Frequency, Genotype, Phenotype, Polymorphism, Single Nucleotide, Asian Continental Ancestry Group, European Continental Ancestry Group, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Human Genome, Genetics, Neurodegenerative, Eye Disease and Disorders of Vision, Neurosciences, 2.1 Biological and endogenous factors, Eye
Abstract

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Published
2014

22. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author

Loth, Daan W, Artigas, María Soler, Gharib, Sina A, Wain, Louise V, Franceschini, Nora, Koch, Beate, Pottinger, Tess D, Smith, Albert Vernon, Duan, Qing, Oldmeadow, Chris, Lee, Mi Kyeong, Strachan, David P, James, Alan L, Huffman, Jennifer E, Vitart, Veronique, Ramasamy, Adaikalavan, Wareham, Nicholas J, Kaprio, Jaakko, Wang, Xin-Qun, Trochet, Holly, Kähönen, Mika, Flexeder, Claudia, Albrecht, Eva, Lopez, Lorna M, de Jong, Kim, Thyagarajan, Bharat, Alves, Alexessander Couto, Enroth, Stefan, Omenaas, Ernst, Joshi, Peter K, Fall, Tove, Viñuela, Ana, Launer, Lenore J, Loehr, Laura R, Fornage, Myriam, Li, Guo, Wilk, Jemma B, Tang, Wenbo, Manichaikul, Ani, Lahousse, Lies, Harris, Tamara B, North, Kari E, Rudnicka, Alicja R, Hui, Jennie, Gu, Xiangjun, Lumley, Thomas, Wright, Alan F, Hastie, Nicholas D, Campbell, Susan, Kumar, Rajesh, Pin, Isabelle, Scott, Robert A, Pietiläinen, Kirsi H, Surakka, Ida, Liu, Yongmei, Holliday, Elizabeth G, Schulz, Holger, Heinrich, Joachim, Davies, Gail, Vonk, Judith M, Wojczynski, Mary, Pouta, Anneli, Johansson, Åsa, Wild, Sarah H, Ingelsson, Erik, Rivadeneira, Fernando, Völzke, Henry, Hysi, Pirro G, Eiriksdottir, Gudny, Morrison, Alanna C, Rotter, Jerome I, Gao, Wei, Postma, Dirkje S, White, Wendy B, Rich, Stephen S, Hofman, Albert, Aspelund, Thor, Couper, David, Smith, Lewis J, Psaty, Bruce M, Lohman, Kurt, Burchard, Esteban G, Uitterlinden, André G, Garcia, Melissa, Joubert, Bonnie R, McArdle, Wendy L, Musk, A Bill, Hansel, Nadia, Heckbert, Susan R, Zgaga, Lina, van Meurs, Joyce BJ, Navarro, Pau, Rudan, Igor, Oh, Yeon-Mok, Redline, Susan, Jarvis, Deborah L, Zhao, Jing Hua, Rantanen, Taina, O'Connor, George T, and Ripatti, Samuli

Subjects
Biological Sciences, Genetics, Human Genome, Rare Diseases, Lung, Cancer, Lung Cancer, Respiratory, Cohort Studies, Databases, Genetic, Follow-Up Studies, Forced Expiratory Volume, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung Diseases, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Respiratory Function Tests, Spirometry, Vital Capacity, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

Published
2014

23. Low copy number of the salivary amylase gene predisposes to obesity

Author

Falchi, Mario, El-Sayed Moustafa, Julia Sarah, Takousis, Petros, Pesce, Francesco, Bonnefond, Amélie, Andersson-Assarsson, Johanna C, Sudmant, Peter H, Dorajoo, Rajkumar, Al-Shafai, Mashael Nedham, Bottolo, Leonardo, Ozdemir, Erdal, So, Hon-Cheong, Davies, Robert W, Patrice, Alexandre, Dent, Robert, Mangino, Massimo, Hysi, Pirro G, Dechaume, Aurélie, Huyvaert, Marlène, Skinner, Jane, Pigeyre, Marie, Caiazzo, Robert, Raverdy, Violeta, Vaillant, Emmanuel, Field, Sarah, Balkau, Beverley, Marre, Michel, Visvikis-Siest, Sophie, Weill, Jacques, Poulain-Godefroy, Odile, Jacobson, Peter, Sjostrom, Lars, Hammond, Christopher J, Deloukas, Panos, Sham, Pak Chung, McPherson, Ruth, Lee, Jeannette, Tai, E Shyong, Sladek, Robert, Carlsson, Lena MS, Walley, Andrew, Eichler, Evan E, Pattou, Francois, Spector, Timothy D, and Froguel, Philippe

Subjects
Biological Sciences, Genetics, Cancer, Body Mass Index, Carbohydrate Metabolism, Gene Dosage, Genetic Predisposition to Disease, Genomics, Humans, Microarray Analysis, Obesity, Odds Ratio, Salivary alpha-Amylases, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

Published
2014

24. Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.

Author

Simpson, Claire L, Wojciechowski, Robert, Oexle, Konrad, Murgia, Federico, Portas, Laura, Li, Xiaohui, Verhoeven, Virginie JM, Vitart, Veronique, Schache, Maria, Hosseini, S Mohsen, Hysi, Pirro G, Raffel, Leslie J, Cotch, Mary Frances, Chew, Emily, Klein, Barbara EK, Klein, Ronald, Wong, Tien Yin, van Duijn, Cornelia M, Mitchell, Paul, Saw, Seang Mei, Fossarello, Maurizio, Wang, Jie Jin, DCCT/EDIC Research Group, Polašek, Ozren, Campbell, Harry, Rudan, Igor, Oostra, Ben A, Uitterlinden, André G, Hofman, Albert, Rivadeneira, Fernando, Amin, Najaf, Karssen, Lennart C, Vingerling, Johannes R, Döring, Angela, Bettecken, Thomas, Bencic, Goran, Gieger, Christian, Wichmann, H-Erich, Wilson, James F, Venturini, Cristina, Fleck, Brian, Cumberland, Phillippa M, Rahi, Jugnoo S, Hammond, Chris J, Hayward, Caroline, Wright, Alan F, Paterson, Andrew D, Baird, Paul N, Klaver, Caroline CW, Rotter, Jerome I, Pirastu, Mario, Meitinger, Thomas, Bailey-Wilson, Joan E, and Stambolian, Dwight

Subjects
DCCT/EDIC Research Group, Eye, Humans, Hyperopia, Myopia, Genetic Predisposition to Disease, Genetic Markers, Age of Onset, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, Aged, 80 and over, Middle Aged, European Continental Ancestry Group, Female, Male, Genetic Association Studies, and over, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Published
2014

25. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Author

Cheng, Ching-Yu, Schache, Maria, Ikram, M Kamran, Young, Terri L, Guggenheim, Jeremy A, Vitart, Veronique, MacGregor, Stuart, Verhoeven, Virginie JM, Barathi, Veluchamy A, Liao, Jiemin, Hysi, Pirro G, Bailey-Wilson, Joan E, St. Pourcain, Beate, Kemp, John P, McMahon, George, Timpson, Nicholas J, Evans, David M, Montgomery, Grant W, Mishra, Aniket, Wang, Ya Xing, Wang, Jie Jin, Rochtchina, Elena, Polasek, Ozren, Wright, Alan F, Amin, Najaf, van Leeuwen, Elisabeth M, Wilson, James F, Pennell, Craig E, van Duijn, Cornelia M, de Jong, Paulus TVM, Vingerling, Johannes R, Zhou, Xin, Chen, Peng, Li, Ruoying, Tay, Wan-Ting, Zheng, Yingfeng, Chew, Merwyn, Error and Myopia, Consortium for Refractive, Cohort, 1958 British Birth, Rahi, Jugnoo S, cohort, Aichi, Yoshimura, Nagahisa, Yamashiro, Kenji, Miyake, Masahiro, ALIENOR, Delcourt, Cécile, Maubaret, Cecilia, ALSPAC, Williams, Cathy, Northstone, Kate, Ring, Susan M, Davey-Smith, George, ANZRAG, Craig, Jamie E, Burdon, Kathryn P, Fogarty, Rhys D, AREDS1a, Iyengar, Sudha K, Igo, Robert P, Chew, Emily, Janmahasathian, Sarayut, AREDS1b, AREDS1c, Stambolian, Dwight, Wilson, Joan E Bailey, BATS, Lu, Yi, Study, Beijing Eye, Jonas, Jost B, Xu, Liang, Saw, Seang-Mei, BMES, Baird, Paul N, Mitchell, Paul, CIEMS, Nangia, Vinay, CROATIA-Korčula, Hayward, Caroline, CROATIA-Split, Campbell, Harry, CROATIA-Vis, Rudan, Igor, Vatavuk, Zoran, DCCT, Paterson, Andrew D, Hosseini, S Mohsen, GWAS, FECD Fuchs Dystrophy, Fondran, Jeremy R, Study, Myopia, Feng, Sheng, and Study, Erasmus Rucphen Family

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Allied Health and Rehabilitation Science, Health Sciences, Ophthalmology and Optometry, Human Genome, Eye Disease and Disorders of Vision, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Eye, Adolescent, Adult, Aged, Asian People, Axial Length, Eye, Eye Proteins, Female, Gene Expression, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Refractive Errors, Signal Transduction, White People, Consortium for Refractive Error and Myopia, Fuchs' Genetics Multi-Center Study Group, Wellcome Trust Case Control Consortium 2, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, and Complications Research Group, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Published
2013

27. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Author

Yonova-Doing, Ekaterina, Zhao, Wanting, Igo, Jr, Robert P., Wang, Chaolong, Sundaresan, Periasamy, Lee, Kristine E., Jun, Gyungah R., Alves, Alexessander Couto, Chai, Xiaoran, Chan, Anita S. Y., Lee, Mei Chin, Fong, Allan, Tan, Ava G., Khor, Chiea Chuen, Chew, Emily Y., Hysi, Pirro G., Fan, Qiao, Chua, Jacqueline, Chung, Jaeyoon, Liao, Jiemin, Colijn, Johanna M., Burdon, Kathryn P., Fritsche, Lars G., Swift, Maria K., Hilmy, Maryam H., Chee, Miao Ling, Tedja, Milly, Bonnemaijer, Pieter W. M., Gupta, Preeti, Tan, Queenie S., Li, Zheng, Vithana, Eranga N., Ravindran, Ravilla D., Chee, Soon-Phaik, Shi, Yuan, Liu, Wenting, Su, Xinyi, Sim, Xueling, Shen, Yang, Wang, Ya Xing, Li, Hengtong, Tham, Yih-Chung, Teo, Yik Ying, Aung, Tin, Small, Kerrin S., Mitchell, Paul, Jonas, Jost B., Wong, Tien Yin, Fletcher, Astrid E., Klaver, Caroline C. W., Klein, Barbara E. K., Wang, Jie Jin, Iyengar, Sudha K., Hammond, Christopher J., and Cheng, Ching-Yu

Published
2020
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29. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size

Author

Macgregor, Stuart, Hewitt, Alex W, Hysi, Pirro G, Ruddle, Jonathan B, Medland, Sarah E, Henders, Anjali K, Gordon, Scott D, Andrew, Toby, McEvoy, Brian, Sanfilippo, Paul G, Carbonaro, Francis, Tah, Vikas, Li, Yi Ju, Bennett, Sonya L, Craig, Jamie E, Montgomery, Grant W, Tran-Viet, Khanh-Nhat, Brown, Nadean L, Spector, Timothy D, Martin, Nicholas G, Young, Terri L, Hammond, Christopher J, and Mackey, David A

Subjects
Eye Disease and Disorders of Vision, Neurosciences, Human Genome, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Aetiology, Eye, Adolescent, Adult, Aged, Aged, 80 and over, Australia, Basic Helix-Loop-Helix Transcription Factors, Blindness, Child, Child, Preschool, Genome-Wide Association Study, Humans, Membrane Proteins, Middle Aged, Optic Disk, Optic Nerve, Polymorphism, Single Nucleotide, Twins, United Kingdom, Young Adult, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P=6.2x10(-10), near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-7), in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P=0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.

Published
2010

30. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author

Tedja, Milly S., Wojciechowski, Robert, Hysi, Pirro G., Eriksson, Nicholas, Furlotte, Nicholas A., Verhoeven, Virginie J. M., Iglesias, Adriana I., Meester-Smoor, Magda A., Tompson, Stuart W., Fan, Qiao, Khawaja, Anthony P., Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B., Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Paterson, Andrew D., Hosseini, S. Mohsen, Shah, Rupal L., Williams, Cathy, Teo, Yik Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E., Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F., The CREAM Consortium, 23andMe Research Team, UK Biobank Eye and Vision Consortium, Joshi, Peter K., Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N., Zeller, Tanja, van der Spek, Peter J., Haak, Roxanna, Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M., Iyengar, Sudha K., Lass, Jonathan H., Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, André G., Vingerling, Johannes R., Lehtimäki, Terho, Raitakari, Olli T., Biino, Ginevra, Concas, Maria Pina, Schwantes-An, Tae-Hwi, Igo, Jr, Robert P., Cuellar-Partida, Gabriel, Martin, Nicholas G., Craig, Jamie E., Gharahkhani, Puya, Williams, Katie M., Nag, Abhishek, Rahi, Jugnoo S., Cumberland, Phillippa M., Delcourt, Cécile, Bellenguez, Céline, Ried, Janina S., Bergen, Arthur A., Meitinger, Thomas, Gieger, Christian, Wong, Tien Yin, Hewitt, Alex W., Mackey, David A., Simpson, Claire L., Pfeiffer, Norbert, Pärssinen, Olavi, Baird, Paul N., Vitart, Veronique, Amin, Najaf, van Duijn, Cornelia M., Bailey-Wilson, Joan E., Young, Terri L., Saw, Seang-Mei, Stambolian, Dwight, MacGregor, Stuart, Guggenheim, Jeremy A., Tung, Joyce Y., Hammond, Christopher J., and Klaver, Caroline C. W.

Published
2018
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31. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma

Author

Khawaja, Anthony P., Cooke Bailey, Jessica N., Wareham, Nicholas J., Scott, Robert A., Simcoe, Mark, Igo, Jr, Robert P., Song, Yeunjoo E., Wojciechowski, Robert, Cheng, Ching-Yu, Khaw, Peng T., Pasquale, Louis R., Haines, Jonathan L., Foster, Paul J., Wiggs, Janey L., Hammond, Chris J., Hysi, Pirro G., UK Biobank Eye and Vision Consortium, and NEIGHBORHOOD Consortium

Published
2018
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32. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author

Hysi, Pirro G., Valdes, Ana M., Liu, Fan, Furlotte, Nicholas A., Evans, David M., Bataille, Veronique, Visconti, Alessia, Hemani, Gibran, McMahon, George, Ring, Susan M., Smith, George Davey, Duffy, David L., Zhu, Gu, Gordon, Scott D., Medland, Sarah E., Lin, Bochao D., Willemsen, Gonneke, Jan Hottenga, Jouke, Vuckovic, Dragana, Girotto, Giorgia, Gandin, Ilaria, Sala, Cinzia, Concas, Maria Pina, Brumat, Marco, Gasparini, Paolo, Toniolo, Daniela, Cocca, Massimiliano, Robino, Antonietta, Yazar, Seyhan, Hewitt, Alex W., Chen, Yan, Zeng, Changqing, Uitterlinden, Andre G., Ikram, M. Arfan, Hamer, Merel A., van Duijn, Cornelia M., Nijsten, Tamar, Mackey, David A., Falchi, Mario, Boomsma, Dorret I., Martin, Nicholas G., The International Visible Trait Genetics Consortium, Hinds, David A., Kayser, Manfred, and Spector, Timothy D.

Published
2018
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35. Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

Author

Liu, Fan, Visser, Mijke, Duffy, David L., Hysi, Pirro G., Jacobs, Leonie C., Lao, Oscar, Zhong, Kaiyin, Walsh, Susan, Chaitanya, Lakshmi, Wollstein, Andreas, Zhu, Gu, Montgomery, Grant W., Henders, Anjali K., Mangino, Massimo, Glass, Daniel, Bataille, Veronique, Sturm, Richard A., Rivadeneira, Fernando, Hofman, Albert, van IJcken, Wilfred F. J., Uitterlinden, André G., Palstra, Robert-Jan T. S., Spector, Timothy D., Martin, Nicholas G., Nijsten, Tamar E. C., and Kayser, Manfred

Published
2015
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36. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Author

Li, Qing, Wojciechowski, Robert, Simpson, Claire L., Hysi, Pirro G., Verhoeven, Virginie J. M., Ikram, Mohammad Kamran, Höhn, René, Vitart, Veronique, Hewitt, Alex W., Oexle, Konrad, Mäkelä, Kari-Matti, MacGregor, Stuart, Pirastu, Mario, Fan, Qiao, Cheng, Ching-Yu, St Pourcain, Beaté, McMahon, George, Kemp, John P., Northstone, Kate, Rahi, Jugnoo S., Cumberland, Phillippa M., Martin, Nicholas G., Sanfilippo, Paul G., Lu, Yi, Wang, Ya Xing, Hayward, Caroline, Polašek, Ozren, Campbell, Harry, Bencic, Goran, Wright, Alan F., Wedenoja, Juho, Zeller, Tanja, Schillert, Arne, Mirshahi, Alireza, Lackner, Karl, Yip, Shea Ping, Yap, Maurice K. H., Ried, Janina S., Gieger, Christian, Murgia, Federico, Wilson, James F., Fleck, Brian, Yazar, Seyhan, Vingerling, Johannes R., Hofman, Albert, Uitterlinden, André, Rivadeneira, Fernando, Amin, Najaf, Karssen, Lennart, Oostra, Ben A., Zhou, Xin, Teo, Yik-Ying, Tai, E. Shyong, Vithana, Eranga, Barathi, Veluchamy, Zheng, Yingfeng, Siantar, Rosalynn Grace, Neelam, Kumari, Shin, Youchan, Lam, Janice, Yonova-Doing, Ekaterina, Venturini, Cristina, Hosseini, S. Mohsen, Wong, Hoi-Suen, Lehtimäki, Terho, Kähönen, Mika, Raitakari, Olli, Timpson, Nicholas J., Evans, David M., Khor, Chiea-Chuen, Aung, Tin, Young, Terri L., Mitchell, Paul, Klein, Barbara, van Duijn, Cornelia M., Meitinger, Thomas, Jonas, Jost B., Baird, Paul N., Mackey, David A., Wong, Tien Yin, Saw, Seang-Mei, Pärssinen, Olavi, Stambolian, Dwight, Hammond, Christopher J., Klaver, Caroline C. W., Williams, Cathy, Paterson, Andrew D., Bailey-Wilson, Joan E., Guggenheim, Jeremy A., and The CREAM Consortium

Published
2015
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37. Publisher Correction: Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author

Hysi, Pirro G., Valdes, Ana M., Liu, Fan, Furlotte, Nicholas A., Evans, David M., Bataille, Veronique, Visconti, Alessia, Hemani, Gibran, McMahon, George, Ring, Susan M., Smith, George Davey, Duffy, David L., Zhu, Gu, Gordon, Scott D., Medland, Sarah E., Lin, Bochao D., Willemsen, Gonneke, Jan Hottenga, Jouke, Vuckovic, Dragana, Girotto, Giorgia, Gandin, Ilaria, Sala, Cinzia, Concas, Maria Pina, Brumat, Marco, Gasparini, Paolo, Toniolo, Daniela, Cocca, Massimiliano, Robino, Antonietta, Yazar, Seyhan, Hewitt, Alex W., Chen, Yan, Zeng, Changqing, Uitterlinden, Andre G., Ikram, M. Arfan, Hamer, Merel A., van Duijn, Cornelia M., Nijsten, Tamar, Mackey, David A., Falchi, Mario, Boomsma, Dorret I., Martin, Nicholas G., The International Visible Trait Genetics Consortium, Hinds, David A., Kayser, Manfred, and Spector, Timothy D.

Published
2019
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39. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), and Lee, Y.-A. (Young-Ae)

Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Published
2021

40. Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium

Author

Verhoeven, Virginie J. M., Hysi, Pirro G., Saw, Seang-Mei, Vitart, Veronique, Mirshahi, Alireza, Guggenheim, Jeremy A., Cotch, Mary Frances, Yamashiro, Kenji, Baird, Paul N., Mackey, David A., Wojciechowski, Robert, Ikram, M. Kamran, Hewitt, Alex W., Duggal, Priya, Janmahasatian, Sarayut, Khor, Chiea-Chuen, Fan, Qiao, Zhou, Xin, Young, Terri L., Tai, E-Shyong, Goh, Liang-Kee, Li, Yi-Ju, Aung, Tin, Vithana, Eranga, Teo, Yik-Ying, Tay, Wanting, Sim, Xueling, Rudan, Igor, Hayward, Caroline, Wright, Alan F., Polasek, Ozren, Campbell, Harry, Wilson, James F., Fleck, Brian W., Nakata, Isao, Yoshimura, Nagahisa, Yamada, Ryo, Matsuda, Fumihiko, Ohno-Matsui, Kyoko, Nag, Abhishek, McMahon, George, Pourcain, Beate St., Lu, Yi, Rahi, Jugnoo S., Cumberland, Phillippa M., Bhattacharya, Shomi, Simpson, Claire L., Atwood, Larry D., Li, Xiaohui, Raffel, Leslie J., Murgia, Federico, Portas, Laura, Despriet, Dominiek D. G., van Koolwijk, Leonieke M. E., Wolfram, Christian, Lackner, Karl J., Tönjes, Anke, Mägi, Reedik, Lehtimäki, Terho, Kähönen, Mika, Esko, Tõnu, Metspalu, Andres, Rantanen, Taina, Pärssinen, Olavi, Klein, Barbara E., Meitinger, Thomas, Spector, Timothy D., Oostra, Ben A., Smith, Albert V., de Jong, Paulus T. V. M., Hofman, Albert, Amin, Najaf, Karssen, Lennart C., Rivadeneira, Fernando, Vingerling, Johannes R., Eiríksdóttir, Guðný, Gudnason, Vilmundur, Döring, Angela, Bettecken, Thomas, Uitterlinden, André G., Williams, Cathy, Zeller, Tanja, Castagné, Raphaële, Oexle, Konrad, van Duijn, Cornelia M., Iyengar, Sudha K., Mitchell, Paul, Wang, Jie Jin, Höhn, René, Pfeiffer, Norbert, Bailey-Wilson, Joan E., Stambolian, Dwight, Wong, Tien-Yin, Hammond, Christopher J., and Klaver, Caroline C. W.

Published
2012
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41. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

Author

Grosche, S. (Sarah), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Arnau-Soler, A. (Aleix), Pairo-Castineira, E. (Erola), Rueschendorf, F. (Franz), Ahluwalia, T. S. (Tarunveer S.), Almqvist, C. (Catarina), Arnold, A. (Andreas), Baurecht, H. (Hansjoerg), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Brown, S. J. (Sara J.), Bustamante, M. (Mariona), Curtin, J. A. (John A.), Custovic, A. (Adnan), Dharmage, S. C. (Shyamali C.), Esplugues, A. (Ana), Falchi, M. (Mario), Fernandez-Orth, D. (Dietmar), Ferreira, M. A. (Manuel A. R.), Franke, A. (Andre), Gerdes, S. (Sascha), Gieger, C. (Christian), Hakonarson, H. (Hakon), Holt, P. G. (Patrick G.), Homuth, G. (Georg), Hubner, N. (Norbert), Hysi, P. G. (Pirro G.), Järvelin, M.-R. (Marjo-Riitta), Karlsson, R. (Robert), Koppelman, G. H. (Gerard H.), Lau, S. (Susanne), Lutz, M. (Manuel), Magnusson, P. K. (Patrik K. E.), Marks, G. B. (Guy B.), Mueller-Nurasyid, M. (Martina), Noethen, M. M. (Markus M.), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Peters, A. (Annette), Rawlik, K. (Konrad), Robertson, C. F. (Colin F.), Rodriguez, E. (Elke), Sebert, S. (Sylvain), Simpson, A. (Angela), Sleiman, P. M. (Patrick M. A.), Standl, M. (Marie), Stoelzl, D. (Dora), Strauch, K. (Konstantin), Szwajda, A. (Agnieszka), Tenesa, A. (Albert), Thompson, P. J. (Philip J.), Ullemar, V. (Vilhelmina), Visconti, A. (Alessia), Vonk, J. M. (Judith M.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Wielscher, M. (Matthias), Worth, C. L. (Catherine L.), Xu, C.-J. (Chen-Jian), Lee, Y.-A. (Young-Ae), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Sodium-Hydrogen Exchangers, Genotype, Eczema, Gene Expression, Genetic predisposition to disease, Dual Specificity Phosphatase 1, Rare variants, Matrix Attachment Region Binding Proteins, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, Cytokine Receptor Common beta Subunit, Skin diseases, Rare Diseases, Cardiovascular and Metabolic Diseases, Humans, Receptor, Notch4, Genome-Wide Association Study, Atopic dermatitis
Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema., Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Published
2020

42. One-year surgical outcomes of the PreserFlo MicroShunt in glaucoma: a multicentre analysis

Author

Tanner, Alexander, Haddad, Fadi, Fajardo-Sanchez, Julia, Nguyen, Ethan, Thong, Kai Xin, Ah-Moye, Sarah, Perl, Nicole, Abu-Bakra, Mohammed, Kulkarni, Avinash, Trikha, Sameer, Lascaratos, Gerassimos, Parnell, Miles, Kailani, Obeda, King, Anthony J, Agrawal, Pavi, Stead, Richard, Giannouladis, Konstantinos, Rodrigues, Ian, Goyal, Saurabh, Hysi, Pirro G, Lim, Sheng, and Yu-Wai-Man, Cynthia

Abstract

Background/aimsTo evaluate the efficacy and safety of the PreserFlo MicroShunt glaucoma device in a multicentre cohort study.MethodsAll consecutive patients who received the microshunt with mitomycin-C (MMC) 0.4 mg/mL from May 2019 to September 2020 in three UK tertiary centres. Primary outcome at 1 year was a complete success, with failure defined as intraocular pressure (IOP) >21 mmHg or <20% reduction, IOP≤5 mmHg with any decreased vision on two consecutive visits, reoperation or loss of light perception vision. Secondary outcomes were IOP, best-corrected visual acuity, medications, complications, interventions and reoperations. We also performed subgroup analyses for severe glaucoma and assessed risk factors for failure.Results104 eyes had 1-year follow-up. Complete and qualified success at 1 year were achieved in 51.9% (N=54) and 16.4% (N=17), respectively, and failure occurred in 31.7% (N=33). There was a significant reduction in IOP (mmHg) from preoperatively (23.4±0.8, N=104) to 12 months (14.7±0.6, N=104) (p<0.0001). Antiglaucoma medications also decreased from preoperatively (3.4±0.1, N=104) to 12 months (0.7±0.1, N=104) (p<0.0001). Multivariate analyses showed an association between higher mean deviation and failure (HR 1.055, 95% CI 1.0075 to 1.11, p=0.0227). Complications were hypotony (19.2%; N=20), choroidal detachments (10.6%; N=11), hyphaema (5.8%; N=6) and bleb leak (5.8%; N=6). Needling and 5-fluorouracil injections were performed in 12.5% (N=13) and 33.7% (N=35), respectively, and 11.5% (N=12) required revision surgery.ConclusionThe PreserFlo MicroShunt with MMC 0.4 mg/mL showed an overall success rate of 68.3% at 1 year, and led to significant IOP and medication reduction with a low rate of adverse effects.

Published
2023
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43. Publisher Correction: Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability (Nature Genetics, (2018), 50, 5, (652-656), 10.1038/s41588-018-0100-5)

Author

Hysi P. G., Valdes A. M., Liu F., Furlotte N. A., Evans D. M., Bataille V., Visconti A., Hemani G., McMahon G., Ring S. M., Smith G. D., Duffy D. L., Zhu G., Gordon S. D., Medland S. E., Lin B. D., Willemsen G., Jan Hottenga J., Vuckovic D., Girotto G., Gandin I., Sala C., Concas M. P., Brumat M., Gasparini P., Toniolo D., Cocca M., Robino A., Yazar S., Hewitt A. W., Chen Y., Zeng C., Uitterlinden A. G., Ikram M. A., Hamer M. A., van Duijn C. M., Nijsten T., Mackey D. A., Falchi M., Boomsma D. I., Martin N. G., Hinds D. A., Kayser M., Spector T. D., Hysi, P. G., Valdes, A. M., Liu, F., Furlotte, N. A., Evans, D. M., Bataille, V., Visconti, A., Hemani, G., Mcmahon, G., Ring, S. M., Smith, G. D., Duffy, D. L., Zhu, G., Gordon, S. D., Medland, S. E., Lin, B. D., Willemsen, G., Jan Hottenga, J., Vuckovic, D., Girotto, G., Gandin, I., Sala, C., Concas, M. P., Brumat, M., Gasparini, P., Toniolo, D., Cocca, M., Robino, A., Yazar, S., Hewitt, A. W., Chen, Y., Zeng, C., Uitterlinden, A. G., Ikram, M. A., Hamer, M. A., van Duijn, C. M., Nijsten, T., Mackey, D. A., Falchi, M., Boomsma, D. I., Martin, N. G., Hinds, D. A., Kayser, M., and Spector, T. D.

Subjects
Publisher correction
Abstract

N/A

Published
2019

45. Association Between Myopic Refractive Error and Primary Open-Angle Glaucoma: A 2-Sample Mendelian Randomization Study

Author

Choquet, Hélène, Khawaja, Anthony P., Jiang, Chen, Yin, Jie, Melles, Ronald B., Glymour, M. Maria, Hysi, Pirro G., and Jorgenson, Eric

Abstract

IMPORTANCE: Refractive error (RE) is the most common form of visual impairment, and myopic RE is associated with an increased risk of primary open-angle glaucoma (POAG). Whether this association represents a causal role of RE in the etiology of POAG remains unknown. OBJECTIVE: To evaluate shared genetic influences and investigate the association of myopic RE with the risk for POAG. DESIGN, SETTING, AND PARTICIPANTS: Observational analyses were used to evaluate the association between mean spherical equivalent (MSE) RE (continuous trait) or myopia (binary trait) and POAG risk in individuals from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. To quantify genetic overlap, genome-wide genetic correlation analyses were performed using genome-wide association studies (GWAS) of MSE RE or myopia and POAG from GERA. Potential causal effects were assessed between MSE RE and POAG using 2-sample Mendelian randomization. Genetic variants associated with MSE RE were derived using GWAS summary statistics from a GWAS of RE conducted in 102 117 UK Biobank participants. For POAG, we used GWAS summary statistics from our previous GWAS (3836 POAG cases and 48 065 controls from GERA). Data analyses occurred between July 2020 and October 2021. MAIN OUTCOMES AND MEASURE: Our main outcome was POAG risk as odds ratio (OR) caused by per-unit difference in MSE RE (in diopters). RESULTS: Our observational analyses included data for 54 755 non-Hispanic White individuals (31 926 [58%] females and 22 829 [42%] males). Among 4047 individuals with POAG, mean (SD) age was 73.64 (9.20) years; mean (SD) age of the 50 708 controls was 65.38 (12.24) years. Individuals with POAG had a lower refractive MSE and were more likely to have myopia or high myopia compared with the control participants (40.2% vs 34.1%, P = 1.31 × 10−11 for myopia; 8.5% vs 6.8%, P = .004 for high myopia). Our genetic correlation analyses demonstrated that POAG was genetically correlated with MSE RE (rg, −0.24; SE, 0.06; P = 3.90 × 10−5), myopia (rg, 0.21; SE, 0.07; P = .004), and high myopia (rg, 0.23; SE, 0.09; P = .01). Genetically assessed refractive MSE was negatively associated with POAG risk (inverse-variance weighted model: OR per diopter more hyperopic MSE = 0.94; 95% CI, 0.89-0.99; P = .01). CONCLUSIONS AND RELEVANCE: These findings demonstrate a shared genetic basis and an association between myopic RE and POAG risk. This may support population POAG risk stratification and screening strategies, based on RE information.

Published
2022
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47. Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero

Author

Warrington, N. M., Shevroja, E., Hemani, G., Hysi, P. G., Jiang, Y., Auton, A., Boer, C. G., Mangino, M., Wang, C. A., Kemp, J. P., McMahon, G., Medina-Gomez, C., Hickey, M., Trajanoska, K., Wolke, Dieter, Ikram, M. Arfan, Montgomery, Grant W., Felix, Janine F., Wright, Margaret J., Mackey, David A., Jaddoe, Vincent W., Martin, Nicholas G., Tung, Joyce Y., Smith, George Davey, Pennell, Craig E., Spector, Tim D., Meurs, Joyce van, Rivadeneira, Fernando, Medland, Sarah E., Evans, David M., and HASH(0x5651c98ee3f8)

Abstract

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a noninvasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N=15,661, with replication N=75,821), we identified eleven loci (nine novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (β=0.06; P=0.02) between 2D:4D ratio and sensitivity to testosterone (length of the CAG microsatellite repeat in the androgen receptor gene) in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

Published
2018

48. A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population

Author

Bonfiglio, F, Hysi, P G, Ek, Weronica, Karhunen, V, Rivera, N V, Männikkö, M, Nordenstedt, H, Zucchelli, M, Bresso, F, Williams, F, Tornblom, H, Magnusson, P K, Pedersen, N L, Ronkainen, J, Schmidt, P T, D'Amato, M, Bonfiglio, F, Hysi, P G, Ek, Weronica, Karhunen, V, Rivera, N V, Männikkö, M, Nordenstedt, H, Zucchelli, M, Bresso, F, Williams, F, Tornblom, H, Magnusson, P K, Pedersen, N L, Ronkainen, J, Schmidt, P T, and D'Amato, M

Abstract

BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes. METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap). KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10(-5) ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

Published
2017
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49. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Hysi, Pirro G., Choquet, Hélène, Khawaja, Anthony P., Wojciechowski, Robert, Tedja, Milly S., Yin, Jie, Simcoe, Mark J., Patasova, Karina, Mahroo, Omar A., Thai, Khanh K., Cumberland, Phillippa M., Melles, Ronald B., Verhoeven, Virginie J. M., Vitart, Veronique, Segre, Ayellet, Stone, Richard A., Wareham, Nick, Hewitt, Alex W., Mackey, David A., Klaver, Caroline C. W., MacGregor, Stuart, Khaw, Peng T., Foster, Paul J., Guggenheim, Jeremy A., Rahi, Jugnoo S., Jorgenson, Eric, and Hammond, Christopher J.

Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Published
2020
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50. Genetic Heritability of Pigmentary Glaucoma and Associations With Other Eye Phenotypes

Author

Simcoe, Mark J., Weisschuh, Nicole, Wissinger, Bernd, Hysi, Pirro G., and Hammond, Christopher J.

Abstract

IMPORTANCE: Mechanisms behind pigmentary glaucoma, a form of early-onset glaucoma that may potentially lead to severe visual impairment or blindness, are poorly understood. OBJECTIVE: To calculate the single-nucleotide polymorphism (SNP) heritability of pigmentary glaucoma and identify genetic associations with the disease. DESIGN, SETTING AND PARTICIPANTS: This genome-wide association study included affected individuals from Germany and control participants from the United Kingdom. Genome-wide information was obtained for patients with pigmentary glaucoma and control participants free of glaucoma by using the Illumina Human Omni Express Exome 8v1-2 chip and genomic imputation. The SNP heritability of pigmentary glaucoma was estimated through a restricted maximum likelihood analysis. Associations between the genetic variants and pigmentary glaucoma obtained from age, sex, and principal component–adjusted logistic regression models were compared with those of SNPs previously associated with other eye phenotypes using Pearson product-moment correlations. Data were collected from November 2008 to January 2018, and analysis was completed between April 2018 and August 2019. MAIN OUTCOMES AND MEASURES: An estimate of SNP-explained heritability for pigmentary glaucoma; correlations of effect sizes between pigmentary glaucoma and iris pigmentation and myopia; and correlations of effect sizes between pigmentary glaucoma and other eye phenotypes. RESULTS: A total of 227 affected individuals (mean [SD] age, 58.7 [13.3] years) and 291 control participants (mean [SD] age, 80.2 [4.9] years) were included; all were of European ancestry. The SNP heritability of pigmentary glaucoma was 0.45 (SE, 0.22; P = 6.15 × 10−10). Twelve SNPs previously reported with genome-wide significant associations with eye pigmentation were associated with pigmentary glaucoma’s SNP heritability (4.9% SNP heritability; 0.022; P = 6.0 × 10−4). Pigmentary glaucoma SNP effect sizes were correlated moderately for myopia (r, 0.42 [95% CI, 0.14-0.63]; P = 4.3 × 10−3) and more strongly with those for iris pigmentation (r = −0.69 [95% CI, −0.91 to −0.20]; P = .01), although this was nonsignificant per a strict adjusted significance threshold (P &lt; .01). CONCLUSIONS AND RELEVANCE: These findings support the conclusion that pigmentary glaucoma may have a genetic basis and be highly heritable. Variants associated with lighter eye color and myopia appear to be associated with increased risk of pigmentary glaucoma, but no shared genetic basis with primary open-angle glaucoma (or its quantitative endophenotype of cup-disc ratio) was observed.

Published
2020
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