Search

Your search keyword '"Wiggs, Janey L"' showing total 16 results
Start Over Author "Wiggs, Janey L" Language undetermined
16 results on '"Wiggs, Janey L"'

1. Additional file 2 of Exome-based investigation of the genetic basis of human pigmentary glaucoma

Author

van der Heide, Carly, Goar, Wes, Meyer, Kacie J., Alward, Wallace L. M., Boese, Erin A., Sears, Nathan C., Roos, Ben R., Kwon, Young H., DeLuca, Adam P., Siggs, Owen M., Gonzaga-Jauregui, Claudia, Sheffield, Val C., Wang, Kai, Stone, Edwin M., Mullins, Robert F., Anderson, Michael G., Fan, Bao Jian, Ritch, Robert, Craig, Jamie E., Wiggs, Janey L., Scheetz, Todd E., and Fingert, John H.

Abstract

Additional file 2: Supplementary Table 2. Secondary analysis: mutations detected in candidate genes. Single instances of loss-of-function mutations were detected in three of the candidate genes in the secondary analysis.

Published
2021
Full Text
View/download PDF

2. Additional file 1 of Exome-based investigation of the genetic basis of human pigmentary glaucoma

Author

van der Heide, Carly, Goar, Wes, Meyer, Kacie J., Alward, Wallace L. M., Boese, Erin A., Sears, Nathan C., Roos, Ben R., Kwon, Young H., DeLuca, Adam P., Siggs, Owen M., Gonzaga-Jauregui, Claudia, Sheffield, Val C., Wang, Kai, Stone, Edwin M., Mullins, Robert F., Anderson, Michael G., Fan, Bao Jian, Ritch, Robert, Craig, Jamie E., Wiggs, Janey L., Scheetz, Todd E., and Fingert, John H.

Abstract

Additional file 1: Supplementary Table 1. Secondary analysis of candidate genes. The symbols, names, and functions of genes included in the secondary analysis due to their role in melanin synthesis or melanosome structure.

Published
2021
Full Text
View/download PDF

3. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author

Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Hauser, Michael A, Allingham, R Rand, Aung, Tin, Van Der Heide, Carly J, Taylor, Kent D, Rotter, Jerome I, Wang, Shih-Hsiu J, Bonnemaijer, Pieter WM, Williams, Susan E, Abdullahi, Sadiq M, Abu-Amero, Khaled K, Anderson, Michael G, Akafo, Stephen, Alhassan, Mahmoud B, Asimadu, Ifeoma, Ayyagari, Radha, Bakayoko, Saydou, Nyamsi, Prisca Biangoup, Bowden, Donald W, Bromley, William C, Budenz, Donald L, Carmichael, Trevor R, Challa, Pratap, Chen, Yii-Der Ida, Chuka-Okosa, Chimdi M, Cooke Bailey, Jessica N, Costa, Vital Paulino, Cruz, Dianne A, DuBiner, Harvey, Ervin, John F, Feldman, Robert M, Flamme-Wiese, Miles, Gaasterland, Douglas E, Garnai, Sarah J, Girkin, Christopher A, Guirou, Nouhoum, Guo, Xiuqing, Haines, Jonathan L, Hammond, Christopher J, Herndon, Leon, Hoffmann, Thomas J, Hulette, Christine M, Hydara, Abba, Igo, Robert P, Jorgenson, Eric, Kabwe, Joyce, Kilangalanga, Ngoy Janvier, Kizor-Akaraiwe, Nkiru, Kuchtey, Rachel W, Lamari, Hasnaa, Li, Zheng, Liebmann, Jeffrey M, Liu, Yutao, Loos, Ruth JF, Melo, Monica B, Moroi, Sayoko E, Msosa, Joseph M, Mullins, Robert F, Nadkarni, Girish, Napo, Abdoulaye, Ng, Maggie CY, Nunes, Hugo Freire, Obeng-Nyarkoh, Ebenezer, Okeke, Anthony, Okeke, Suhanya, Olaniyi, Olusegun, Olawoye, Olusola, Oliveira, Mariana Borges, Pasquale, Louise R, Perez-Grossmann, Rodolfo A, Pericak-Vance, Margaret A, Qin, Xue, Ramsay, Michele, Resnikoff, Serge, Richards, Julia E, Schimiti, Rui Barroso, Sim, Kar Seng, Sponsel, William E, Svidnicki, Paulo Vinicius, Thiadens, Alberta AHJ, Uche, Nkechinyere J, van Duijn, Cornelia M, de Vasconcellos, José Paulo Cabral, Wiggs, Janey L, Zangwill, Linda M, Risch, Neil, Milea, Dan, Ashaye, Adeyinka, Klaver, Caroline CW, Weinreb, Robert N, Ashley Koch, Allison E, Fingert, John H, and Khor, Chiea Chuen

Subjects
Male, Aging, Genotype, Black People, Neurodegenerative, Medical and Health Sciences, Meta-Analysis as Topic, Risk Factors, Clinical Research, General & Internal Medicine, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Aetiology, Polymorphism, Eye Disease and Disorders of Vision, Aged, African Continental Ancestry Group, Amyloid beta-Peptides, Human Genome, Signal Transducing, Neurosciences, Adaptor Proteins, Glaucoma, Single Nucleotide, Middle Aged, Immunohistochemistry, Open-Angle, Case-Control Studies, Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Female, 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 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

Published
2019

4. Myocilin Mutations in Patients With Normal-Tension Glaucoma

Author

Alward, Wallace LM, van der Heide, Carly, Khanna, Cheryl L, Roos, Ben R, Sivaprasad, Sobha, Kam, Jason, Ritch, Robert, Lotery, Andrew, Igo, Robert P, Cooke Bailey, Jessica N, Stone, Edwin M, Scheetz, Todd E, Kwon, Young H, Pasquale, Louis R, Wiggs, Janey L, Fingert, John H, and NEIGHBORHOOD Consortium

Subjects
Male, genetic structures, NEIGHBORHOOD Consortium, Middle Aged, Ophthalmology & Optometry, eye diseases, Cytoskeletal Proteins, Opthalmology and Optometry, Case-Control Studies, Mutation, Humans, Female, sense organs, Low Tension Glaucoma, Eye Proteins, Intraocular Pressure, Glycoproteins, Aged
Abstract

Importance:Mutations in the myocilin (MYOC) gene are the most common molecularly defined cause of primary open-angle glaucoma that typically occurs in patients with high intraocular pressures (IOP). One MYOC mutation, p.Gln368Ter, has been associated with as many as 1.6% of primary open-angle glaucoma cases that had a mean maximum recorded IOP of 30 mm Hg. However, to our knowledge, the role of the p.Gln368Ter mutation in patients with normal-tension glaucoma (NTG) with an IOP of 21 mm Hg or lower has not been investigated. Objective:To evaluate the role of the p.Gln368Ter MYOC mutation in patients with NTG. Design, Setting, and Participants:In this case-control study of the prevalence of the p.Gln368Ter mutation in patients with NTG, cohort 1 was composed of 772 patients with NTG and 2152 controls from the United States (Iowa, Minnesota, and New York) and England and cohort 2 was composed of 561 patients with NTG and 2606 controls from the Massachusetts Eye and Ear Infirmary and the NEIGHBORHOOD consortium. Genotyping was conducted using real-time polymerase chain reaction that was confirmed with Sanger sequencing, the imputation of genome-wide association study data, or an analysis of whole-exome sequence data. Data analysis occurred between April 2007 and April 2018. Main Outcomes and Measures:Comparison of the frequency of the p.Gln368Ter MYOC mutation between NTG cases and controls with the Fisher exact test. Results:Of 6091 total participants, 3346 (54.9%) were women and 5799 (95.2%) were white. We detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) in cohort 1 (P = .03). In cohort 2, we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%; P = .15). When the cohorts were analyzed as a group, the p.Gln368Ter mutation was associated with NTG (odds ratio, 2.3; 95% CI, 0.98-5.3; P = .04). Conclusions and Relevance:In cohorts 1 and 2, the p.Gln368Ter mutation in MYOC was found in patients with IOPs that were 21 mm Hg or lower (NTG), although at a frequency that is lower than previously detected in patients with higher IOP. These data suggest that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater than 21 mm Hg.

Published
2019

5. 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
Male, GIGA Study Group, Aging, Thioredoxin Reductase 2, Vesicular Transport Proteins, Neurodegenerative, Paediatrics and Reproductive Medicine, Complementary and Alternative Medicine, 80 and over, Genetics, Humans, 2.1 Biological and endogenous factors, Eye Disease and Disorders of Vision, Aged, African Continental Ancestry Group, Genetics & Heredity, NEIGHBORHOOD Consortium, Human Genome, Neurosciences, Glaucoma, Eyes of Africa Genetics Consortium, Middle Aged, eye diseases, Open-Angle, Genetic Loci, Female, Genome-Wide Association Study
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

6. 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
Male, GIGA Study Group, Aging, Thioredoxin Reductase 2, Vesicular Transport Proteins, Black People, Neurodegenerative, Paediatrics and Reproductive Medicine, Complementary and Alternative Medicine, 80 and over, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Eye Disease and Disorders of Vision, Aged, Genetics & Heredity, NEIGHBORHOOD Consortium, Human Genome, Neurosciences, Glaucoma, Eyes of Africa Genetics Consortium, Middle Aged, Blacks, eye diseases, Open-Angle, Genetic Loci, Female, Genome-Wide Association Study
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

7. 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
Asian Continental Ancestry Group, Lumican, genetic structures, Corneal Dystrophies, Eye Diseases, Fibrillin-1, 1.1 Normal biological development and functioning, European Continental Ancestry Group, Quantitative Trait Loci, Gene Expression, Keratoconus, Eye, White People, Marfan Syndrome, Corneal Diseases, Cornea, Quantitative Trait, Transforming Growth Factor beta2, ADAMTS Proteins, Rare Diseases, Asian People, Underpinning research, Blue Mountains Eye Study—GWAS group, Myopia, Genetics, Humans, Polymorphism, Heritable, Eye Disease and Disorders of Vision, Loeys-Dietz Syndrome, Genome, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Human Genome, Glaucoma, Single Nucleotide, Mendelian Randomization Analysis, eye diseases, Hereditary, Open-Angle, Ehlers-Danlos Syndrome, Proteoglycans, sense organs, Decorin, Human, Genome-Wide Association Study
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

8. Genome-wide association study identifies WNT7B as a novel locus for central corneal thickness in Latinos

Author

Gao, Xiaoyi, Nannini, Drew R, Corrao, Kristen, Torres, Mina, Chen, Yii-Der I, Fan, Bao J, Wiggs, Janey L, International Glaucoma Genetics Consortium, Taylor, Kent D, Gauderman, W James, Rotter, Jerome I, and Varma, Rohit

Subjects
Adult, Male, Aging, Genotype, Corneal Pachymetry, International Glaucoma Genetics Consortium, Keratoconus, Eye, Medical and Health Sciences, Cornea, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Aetiology, Eye Disease and Disorders of Vision, Aged, Genetics & Heredity, Human Genome, Glaucoma, Single Nucleotide, Hispanic or Latino, Middle Aged, Biological Sciences, Los Angeles, Wnt Proteins, Open-Angle, Genetic Loci, Female, Genome-Wide Association Study
Abstract

The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT. In this study, we conducted a genome-wide association study (GWAS) in Latinos, a traditionally understudied population in genetic research, to further identify loci contributing to CCT. Study participants were genotyped using either the Illumina OmniExpress BeadChip (∼730K markers) or the Illumina Hispanic/SOL BeadChip (∼2.5 million markers). All study participants were 40 years of age and older. We assessed the association between individual single nucleotide polymorphisms (SNPs) and CCT using linear regression, adjusting for age, gender and principal components of genetic ancestry. To expand genomic coverage and to interrogate additional SNPs, we imputed SNPs from the 1000 Genomes Project reference panels. We identified a novel SNP, rs10453441 (P = 6.01E-09), in an intron of WNT7B that is associated with CCT. Furthermore, WNT7B is expressed in the human cornea. We also replicated 11 previously reported loci, including IBTK, RXRA-COL5A1, COL5A1, FOXO1, LRRK1 and ZNF469 (P

Published
2016

9. Erratum

Author

Liu, Yutao, Bailey, Jessica Cooke, Helwa, Inas, Dismuke, W Michael, Cai, Jingwen, Drewry, Michelle, Brilliant, Murray H, Budenz, Donald L, Christen, William G, Chasman, Daniel I, Fingert, John H, Gaasterland, Douglas, Gaasterland, Terry, Gordon, Mae O, Igo, Robert P, Kang, Jae H, Kass, Michael A, Kraft, Peter, Lee, Richard K, Lichter, Paul, Moroi, Sayoko E, Realini, Anthony, Richards, Julia E, Ritch, Robert, Schuman, Joel S, Scott, William K, Singh, Kuldev, Sit, Arthur J, Song, Yeunjoo E, Vollrath, Douglas, Weinreb, Robert, Medeiros, Felipe, Wollstein, Gadi, Zack, Donald J, Zhang, Kang, Pericak-Vance, Margaret A, Gonzalez, Pedro, Stamer, W Daniel, Kuchtey, John, Kuchtey, Rachel W, Allingham, R Rand, Hauser, Michael A, Pasquale, Louis R, Haines, Jonathan L, and Wiggs, Janey L

Subjects
Biological Sciences, Ophthalmology & Optometry, Medical and Health Sciences
Published
2016

10. Erratum

Author

Liu, Yutao, Bailey, Jessica Cooke, Helwa, Inas, Dismuke, W Michael, Cai, Jingwen, Drewry, Michelle, Brilliant, Murray H, Budenz, Donald L, Christen, William G, Chasman, Daniel I, Fingert, John H, Gaasterland, Douglas, Gaasterland, Terry, Gordon, Mae O, Igo, Robert P, Kang, Jae H, Kass, Michael A, Kraft, Peter, Lee, Richard K, Lichter, Paul, Moroi, Sayoko E, Realini, Anthony, Richards, Julia E, Ritch, Robert, Schuman, Joel S, Scott, William K, Singh, Kuldev, Sit, Arthur J, Song, Yeunjoo E, Vollrath, Douglas, Weinreb, Robert, Medeiros, Felipe, Wollstein, Gadi, Zack, Donald J, Zhang, Kang, Pericak-Vance, Margaret A, Gonzalez, Pedro, Stamer, W Daniel, Kuchtey, John, Kuchtey, Rachel W, Allingham, R Rand, Hauser, Michael A, Pasquale, Louis R, Haines, Jonathan L, and Wiggs, Janey L

Subjects
Male, Aging, Genotype, Neurodegenerative, Exosomes, Ophthalmology & Optometry, Polymerase Chain Reaction, Medical and Health Sciences, Aqueous Humor, Gene Frequency, Genetics, 80 and over, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Eye Disease and Disorders of Vision, Alleles, Intraocular Pressure, Aged, Human Genome, Neurosciences, Glaucoma, Middle Aged, Biological Sciences, MicroRNAs, Open-Angle, Gene Expression Regulation, RNA, Female, Biotechnology
Published
2016

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

12. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Author

Aung, Tin, Ozaki, Mineo, Mizoguchi, Takanori, Allingham, R Rand, Li, Zheng, Haripriya, Aravind, Nakano, Satoko, Uebe, Steffen, Harder, Jeffrey M, Chan, Anita S Y, Lee, Mei Chin, Burdon, Kathryn P, Astakhov, Yury S, Abu-Amero, Khaled K, Zenteno, Juan C, Nilgün, Yildirim, Zarnowski, Tomasz, Pakravan, Mohammad, Safieh, Leen Abu, Jia, Liyun, Wang, Ya Xing, Williams, Susan, Paoli, Daniela, Schlottmann, Patricio G, Huang, Lulin, Sim, Kar Seng, Foo, Jia Nee, Nakano, Masakazu, Ikeda, Yoko, Kumar, Rajesh S, Ueno, Morio, Manabe, Shin-ichi, Hayashi, Ken, Kazama, Shigeyasu, Ideta, Ryuichi, Mori, Yosai, Miyata, Kazunori, Sugiyama, Kazuhisa, Higashide, Tomomi, Chihara, Etsuo, Inoue, Kenji, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Aihara, Makoto, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Matsuda, Fumihiko, Yamashiro, Kenji, Gotoh, Norimoto, Miyake, Masahiro, Astakhov, Sergei Y, Osman, Essam A, Al-Obeidan, Saleh A, Owaidhah, Ohoud, Al-Jasim, Leyla, Al Shahwan, Sami, Fogarty, Rhys A, Leo, Paul, Yetkin, Yaz, Oguz, Çilingir, Kanavi, Mozhgan Rezaei, Beni, Afsaneh Nederi, Yazdani, Shahin, Akopov, Evgeny L, Toh, Kai-Yee, Howell, Gareth R, Orr, Andrew C, Goh, Yufen, Meah, Wee Yang, Peh, Su Qin, Kosior-Jarecka, Ewa, Lukasik, Urszula, Krumbiegel, Mandy, Vithana, Eranga N, Wong, Tien Yin, Liu, Yutao, Koch, Allison E Ashley, Challa, Pratap, Rautenbach, Robyn M, Mackey, David A, Hewitt, Alex W, Mitchell, Paul, Wang, Jie Jin, Ziskind, Ari, Carmichael, Trevor, Ramakrishnan, Rangappa, Narendran, Kalpana, Venkatesh, Rangaraj, Vijayan, Saravanan, Zhao, Peiquan, Chen, Xueyi, Guadarrama-Vallejo, Dalia, Cheng, Ching Yu, Perera, Shamira A, Husain, Rahat, Ho, Su-Ling, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Schloetzer-Schrehardt, Ursula, Hillmer, Axel M, Herms, Stefan, Moebus, Susanne, Nöthen, Markus M, Weisschuh, Nicole, Shetty, Rohit, Ghosh, Arkasubhra, Teo, Yik Ying, Brown, Matthew A, Lischinsky, Ignacio, Crowston, Jonathan G, Coote, Michael, Zhao, Bowen, Sang, Jinghong, Zhang, Nihong, You, Qisheng, Vysochinskaya, Vera, Founti, Panayiota, Chatzikyriakidou, Anthoula, Lambropoulos, Alexandros, Anastasopoulos, Eleftherios, Coleman, Anne L, Wilson, M Roy, Rhee, Douglas J, Kang, Jae Hee, May-Bolchakova, Inna, Heegaard, Steffen, Mori, Kazuhiko, Alward, Wallace L M, Jonas, Jost B, Xu, Liang, Liebmann, Jeffrey M, Chowbay, Balram, Schaeffeler, Elke, Schwab, Matthias, Lerner, Fabian, Wang, Ningli, Yang, Zhenglin, Frezzotti, Paolo, Kinoshita, Shigeru, Fingert, John H, Inatani, Masaru, Tashiro, Kei, Reis, André, Edward, Deepak P, Pasquale, Louis R, Kubota, Toshiaki, Wiggs, Janey L, Pasutto, Francesca, Topouzis, Fotis, Dubina, Michael, Craig, Jamie E, Yoshimura, Nagahisa, Sundaresan, Periasamy, John, Simon W M, Ritch, Robert, Hauser, Michael A, Khor, Chiea-Chuen, Rochtchina, Elena, Viswanathan, Ananth C, Wong, Tien Y, Xie, Jing, Sim, Xueling, Inouye, Michael, Holliday, Elizabeth G, Attia, John, Scott, Rodney J, Baird, Paul N, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
Asian Continental Ancestry Group, Pseudoexfoliation syndrome, Medizin, Locus (genetics), Genome-wide association study, Biology, Inbred C57BL, Exfoliation Syndrome, Polymorphism, Single Nucleotide, Article, Mice, Animals, Calcium Channels, Case-Control Studies, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle, HEK293 Cells, HeLa Cells, Humans, Japan, MCF-7 Cells, Mice, Inbred C57BL, Tumor Cells, Cultured, Genetics, Asian People, medicine, SNP, Allele, Polymorphism, Cultured, Case-control study, Glaucoma, Odds ratio, Single Nucleotide, medicine.disease, eye diseases, Tumor Cells, Open-Angle, Etiology
Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Published
2014

13. 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
Lumican, genetic structures, Fibrillin-1, Quantitative Trait Loci, Gene Expression, Keratoconus, Polymorphism, Single Nucleotide, White People, Corneal Diseases, Marfan Syndrome, Cornea, Transforming Growth Factor beta2, ADAMTS Proteins, Quantitative Trait, Heritable, Asian People, Myopia, Humans, Corneal Dystrophies, Hereditary, Loeys-Dietz Syndrome, Genome, Human, Eye Diseases, Hereditary, Mendelian Randomization Analysis, eye diseases, 3. Good health, Ehlers-Danlos Syndrome, Proteoglycans, sense organs, Decorin, Glaucoma, Open-Angle, Genome-Wide Association Study
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.

14. Investigation of founder effects for the Thr377Met Myocilin mutation in glaucoma families from differing ethnic backgrounds

Author

Hewitt, Alex W., Samples, John R., Rand Allingham, R., Irma Järvelä, George Kitsos, Krishnadas, Subbiah R., Richards, Julia E., Lichter, Paul R., Petersen, Michael B., Periasamy Sundaresan, Wiggs, Janey L., Mackey, David A., and Wirtz, Mary K.

Subjects
Adult, Threonine, genetic structures, Australia, Middle Aged, Polymorphism, Single Nucleotide, eye diseases, Founder Effect, Linkage Disequilibrium, United States, Europe, Cytoskeletal Proteins, Methionine, Haplotypes, Mutation, Humans, Eye Proteins, Glaucoma, Open-Angle, Research Article, Glycoproteins, Microsatellite Repeats
Abstract

Purpose The aim of this study was to determine if there is a common founder for the Thr377Met myocilin mutation in primary open angle glaucoma (POAG) families with various ethnic backgrounds. Methods Genomic DNA of 24 POAG-affected individuals from nine pedigrees with the Thr377Met mutation and 104 unaffected family members was genotyped with six microsatellite markers and four single nucleotide polymorphisms. The families were from Greece, India, Finland, the USA, and Australia. To assess the degree of linkage disequilibrium across MYOC in the general population we also investigated data generated from the HapMap consortium. Results Three distinct haplotypes associated with the Thr377Met myocilin mutation were identified. The families from the USA and Greece, as well as the three Australian families originating from Greece and the former Yugoslavian Republic of Macedonia had one common haplotype. Interestingly, however, HapMap data suggest that linkage disequilibrium across MYOC was not strong. Conclusions The Thr377Met myocilin mutation has arisen at least three separate times. Evidence for genetic founder effects in this prevalent age-related, yet heterogeneous, disease has important implications for future gene identification strategies.

15. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author

Gharahkhani, Puya, Jorgenson, Eric, Hysi, Pirro, Khawaja, Anthony P, Pendergrass, Sarah, Han, Xikun, Ong, Jue Sheng, Hewitt, Alex W, Segrè, Ayellet V, Rouhana, John M, Hamel, Andrew R, Igo, Robert P, Choquet, Helene, Qassim, Ayub, Josyula, Navya S, Cooke Bailey, Jessica N, Bonnemaijer, Pieter WM, Iglesias, Adriana, Siggs, Owen M, Young, Terri L, Vitart, Veronique, Thiadens, Alberta AHJ, Karjalainen, Juha, Uebe, Steffen, Melles, Ronald B, Nair, K Saidas, Luben, Robert, Simcoe, Mark, Amersinghe, Nishani, Cree, Angela J, Hohn, Rene, Poplawski, Alicia, Chen, Li Jia, Rong, Shi-Song, Aung, Tin, Vithana, Eranga Nishanthie, NEIGHBORHOOD Consortium, ANZRAG Consortium, Biobank Japan Project, FinnGen Study, UK Biobank Eye And Vision Consortium, GIGA Study Group, 23 And Me Research Team, Tamiya, Gen, Shiga, Yukihiro, Yamamoto, Masayuki, Nakazawa, Toru, Currant, Hannah, Birney, Ewan, Wang, Xin, Auton, Adam, Lupton, Michelle K, Martin, Nicholas G, Ashaye, Adeyinka, Olawoye, Olusola, Williams, Susan E, Akafo, Stephen, Ramsay, Michele, Hashimoto, Kazuki, Kamatani, Yoichiro, Akiyama, Masato, Momozawa, Yukihide, Foster, Paul J, Khaw, Peng T, Morgan, James E, Strouthidis, Nicholas G, Kraft, Peter, Kang, Jae H, Pang, Chi Pui, Pasutto, Francesca, Mitchell, Paul, Lotery, Andrew J, Palotie, Aarno, Van Duijn, Cornelia, Haines, Jonathan L, Hammond, Chris, Pasquale, Louis R, Klaver, Caroline CW, Hauser, Michael, Khor, Chiea Chuen, Mackey, David A, Kubo, Michiaki, Cheng, Ching-Yu, Craig, Jamie E, MacGregor, Stuart, and Wiggs, Janey L

Subjects
genetic structures, Asian People, Genotype, Genetic Loci, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, eye diseases, Glaucoma, Open-Angle, White People, 3. Good health, Genome-Wide Association Study
Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

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

Author

Nicholas G. Martin, René Höhn, Paul Mitchell, Gavin Band, Pamela Whittaker, Michelle Ricketts, Pirro G. Hysi, Jenefer M. Blackwell, Grant W. Montgomery, Elena Rochtchina, Manfred E. Beutel, Richard A. Mills, Anna Rautanen, Alagurevathi Jayakumar, Colin Freeman, Stephen Sawcer, Stuart MacGregor, Irene Schmidtmann, Cornelia M. van Duijn, Nicholas W. Wood, Sayoko E. Moroi, Jonathan L. Haines, Aniket Mishra, Ananth C. Viswanathan, Jie Jin Wang, Donald L. Budenz, Seyhan Yazar, Janey L. Wiggs, Garrett Hellenthal, Kathryn P. Burdon, Jerome I. Rotter, Jamie E Craig, Puya Gharahkhani, Juan P. Casas, R. Rand Allingham, Jost B. Jonas, Ozren Polasek, Julia E. Richards, Sarah Edkins, Rodney J. Scott, Abhishek Nag, Tanja Zeller, Rhian Gwilliam, Chris C. A. Spencer, David S. Friedman, Adriana I Iglesias, Radhi Ravindrarajah, Kent D. Taylor, Caroline Hayward, Eleni Giannoulatou, David A. Mackey, Michael A. Hauser, Paul J. Foster, Emma Gray, Audrey Duncanson, Yih Chung Tham, Murray H. Brilliant, Ching-Yu Cheng, William K. Scott, Robert N. Weinreb, Hugh S. Markus, Xueling Sim, David S. Siscovick, Matti Pirinen, John H. Fingert, Yelena Bykhovskaya, Louis R. Pasquale, Peter Donnelly, Donald J. Zack, Kuldev Singh, Cordelia Langford, Zhan Su, Céline Bellenguez, Joel S. Schuman, Peter Kraft, Christopher G. Mathew, Hannah Blackburn, Sara Widaa, Yuan Shi, Gabriel Cuellar-Partida, André G. Uitterlinden, Naomi Hammond, Panos Deloukas, Richard K. Lee, Robert Plomin, Jessica N. Cooke Bailey, Jae H. Kang, John Attia, Yutao Liu, Simon C. Potter, Jennifer Liddle, Matthew Gillman, Alex W. Hewitt, Margaret A. Pericak-Vance, James F. Wilson, Tien Yin Wong, Elvira Bramon, Janusz Jankowski, Henriët Springelkamp, Sarah E. Hunt, Anthony P Khawaja, Veronique Vitart, Xiaohui Li, Pieter W.M. Bonnemaijer, Damjan Vukcevic, Paul R. Lichter, Aiden Corvin, Sionne E. M. Lucas, Matthew Waller, Caroline C W Klaver, Douglas E. Gaasterland, Terry Gaasterland, Norbert Pfeiffer, Douglas Vollrath, Anthony Realini, Eranga N. Vithana, Gadi Wollstein, Thibaud Boutin, Owen T. McCann, Paul A. Weston, Lisa S. Kearns, Inês Barroso, Richard G. Pearson, Christopher J Hammond, Colin N. A. Palmer, Michael Inouye, Chiea Chuen Khor, Stephanie Loomis, Sandra E Staffieri, Yaron S. Rabinowitz, Richard C. Trembath, Tin Aung, William G. Christen, Paul N. Baird, Jing Xie, Elisabeth M. van Leeuwen, Serge Dronov, Arthur J. Sit, Colin E. Willoughby, Kang Zhang, Matthew A. Brown, Suzannah Bumpstead, Amy Strange, Elizabeth G. Holliday, Clinical Genetics, Epidemiology, Ophthalmology, Internal Medicine, Experimental Immunology, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iglesias, Adriana I [0000-0001-5532-764X], Gharahkhani, Puya [0000-0002-4203-5952], Bailey, Jessica N Cooke [0000-0002-4001-8702], Li, Xiaohui [0000-0002-5037-3572], Khawaja, Anthony P [0000-0001-6802-8585], Haines, Jonathan L [0000-0002-4351-4728], Hayward, Caroline [0000-0002-9405-9550], Bonnemaijer, Pieter [0000-0001-5154-6765], Staffieri, Sandra E [0000-0003-3131-9359], Jonas, Jost B [0000-0003-2972-5227], Kang, Jae H [0000-0003-4812-0557], Wilson, James F [0000-0001-5751-9178], Foster, Paul J [0000-0002-4755-177X], Hysi, Pirro G [0000-0001-5752-2510], Hewitt, Alex W [0000-0002-5123-5999], Khor, Chiea Chuen [0000-0002-1128-4729], Pasquale, Louis R [0000-0002-5835-3496], Montgomery, Grant W [0000-0002-4140-8139], Klaver, Caroline CW [0000-0002-2355-5258], Hammond, Christopher J [0000-0002-3227-2620], Wiggs, Janey L [0000-0003-1890-3278], Burdon, Kathryn P [0000-0001-8217-1249], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Lumican, Candidate gene, genetic structures, Fibrillin-1, Gene Expression, General Physics and Astronomy, Glaucoma, Genome-wide association study, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, 0302 clinical medicine, Myopia, lcsh:Science, Corneal Dystrophies, Hereditary, Genetics, Multidisciplinary, Eye Diseases, Hereditary, Mendelian Randomization Analysis, 3. Good health, medicine.anatomical_structure, Proteoglycans, Decorin, Glaucoma, Open-Angle, Keratoconus, Science, Quantitative Trait Loci, 610 Medicine & health, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Transforming Growth Factor beta2, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Quantitative Trait, Heritable, Asian People, medicine, Humans, CHROMATIN STATES, GENE-EXPRESSION, RISK-FACTOR, MUTATIONS, LUMICAN, MOUSE, KERATOCONUS, DECORIN, POLYMORPHISMS, HERITABILITY, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Loeys-Dietz Syndrome, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genome, Human, General Chemistry, medicine.disease, eye diseases, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, lcsh:Q, Ehlers-Danlos Syndrome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, Genome-Wide Association Study
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
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results