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1. SCIP: software for efficient clinical interpretation of copy number variants detected by whole-genome sequencing

Author: Ding, Qiliang, Somerville, Cherith, Manshaei, Roozbeh, Trost, Brett, Reuter, Miriam S., Kalbfleisch, Kelsey, Stanley, Kaitlin, Okello, John B. A., Hosseini, S. Mohsen, Liston, Eriskay, Curtis, Meredith, Zarrei, Mehdi, Higginbotham, Edward J., Chan, Ada J. S., Engchuan, Worrawat, Thiruvahindrapuram, Bhooma, Scherer, Stephen W., Kim, Raymond H., and Jobling, Rebekah K.
Published: 2023
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2. Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Author: Pollack, Samuela, Igo, Robert P, Jensen, Richard A, Christiansen, Mark, Li, Xiaohui, Cheng, Ching-Yu, Ng, Maggie CY, Smith, Albert V, Rossin, Elizabeth J, Segrè, Ayellet V, Davoudi, Samaneh, Tan, Gavin S, Chen, Yii-Der Ida, Kuo, Jane Z, Dimitrov, Latchezar M, Stanwyck, Lynn K, Meng, Weihua, Hosseini, S Mohsen, Imamura, Minako, Nousome, Darryl, Kim, Jihye, Hai, Yang, Jia, Yucheng, Ahn, Jeeyun, Leong, Aaron, Shah, Kaanan, Park, Kyu Hyung, Guo, Xiuqing, Ipp, Eli, Taylor, Kent D, Adler, Sharon G, Sedor, John R, Freedman, Barry I, Group, DCCT EDIC Research Group Family Investigation of Nephropathy and Diabetes-Eye Research, Lee, I-Te, Sheu, Wayne H-H, Kubo, Michiaki, Takahashi, Atsushi, Hadjadj, Samy, Marre, Michel, Tregouet, David-Alexandre, Mckean-Cowdin, Roberta, Varma, Rohit, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Lyssenko, Valeriya, Agardh, Elisabet, Morris, Andrew, Doney, Alex SF, Colhoun, Helen M, Toppila, Iiro, Sandholm, Niina, Groop, Per-Henrik, Maeda, Shiro, Hanis, Craig L, Penman, Alan, Chen, Ching J, Hancock, Heather, Mitchell, Paul, Craig, Jamie E, Chew, Emily Y, Paterson, Andrew D, Grassi, Michael A, Palmer, Colin, Bowden, Donald W, Yaspan, Brian L, Siscovick, David, Cotch, Mary Frances, Wang, Jie Jin, Burdon, Kathryn P, Wong, Tien Y, Klein, Barbara EK, Klein, Ronald, Rotter, Jerome I, Iyengar, Sudha K, Price, Alkes, and Sobrin, Lucia
Subjects: Biomedical and Clinical Sciences, Genetics, Eye Disease and Disorders of Vision, Diabetes, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Good Health and Well Being, Blood Glucose, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycated Hemoglobin, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Protein Binding, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract: To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value
Published: 2019

3. GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Author: Manshaei, Roozbeh, DeLong, Sean, Andric, Veronica, Joshi, Esha, Okello, John B. A., Dhir, Priya, Somerville, Cherith, Farncombe, Kirsten M., Kalbfleisch, Kelsey, Jobling, Rebekah K., Scherer, Stephen W., Kim, Raymond H., and Hosseini, S. Mohsen
Published: 2022
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4. The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

Author: Reuter, Miriam S., Chaturvedi, Rajiv R., Liston, Eriskay, Manshaei, Roozbeh, Aul, Ritu B., Bowdin, Sarah, Cohn, Iris, Curtis, Meredith, Dhir, Priya, Hayeems, Robin Z., Hosseini, S. Mohsen, Khan, Reem, Ly, Linh G., Marshall, Christian R., Mertens, Luc, Okello, John B. A., Pereira, Sergio L., Raajkumar, Akshaya, Seed, Mike, Thiruvahindrapuram, Bhooma, Scherer, Stephen W., Kim, Raymond H., and Jobling, Rebekah K.
Published: 2020
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5. 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

6. 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

7. Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot

Author: Reuter, Miriam S., Jobling, Rebekah, Chaturvedi, Rajiv R., Manshaei, Roozbeh, Costain, Gregory, Heung, Tracy, Curtis, Meredith, Hosseini, S. Mohsen, Liston, Eriskay, Lowther, Chelsea, Oechslin, Erwin, Sticht, Heinrich, Thiruvahindrapuram, Bhooma, Mil, Spencer van, Wald, Rachel M., Walker, Susan, Marshall, Christian R., Silversides, Candice K., Scherer, Stephen W., Kim, Raymond H., and Bassett, Anne S.
Published: 2019
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8. Reappraisal of Reported Genes for Sudden Arrhythmic Death: An Evidence-Based Evaluation of Gene Validity for Brugada Syndrome

Author: Hosseini, S. Mohsen, Kim, Raymond, Udupa, Sharmila, Costain, Gregory, Jobling, Rebekah, Liston, Eriskay, Jamal, Seema M., Szybowska, Marta, Morel, Chantal F., Bowdin, Sarah, Garcia, John, Care, Melanie, Sturm, Amy C., Novelli, Valeria, Ackerman, Michael J., Ware, James S., Hershberger, Ray E., Wilde, Arthur A. M., and Gollob, Michael H.
Published: 2018
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9. The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Author: Reuter, Miriam S., Walker, Susan, Thiruvahindrapuram, Bhooma, Whitney, Joe, Cohn, Iris, Sondheimer, Neal, Yuen, Ryan K.C., Trost, Brett, Paton, Tara A., Pereira, Sergio L., Herbrick, Jo-Anne, Wintle, Richard F., Merico, Daniele, Howe, Jennifer, MacDonald, Jeffrey R., Lu, Chao, Nalpathamkalam, Thomas, Sung, Wilson W.L., Wang, Zhuozhi, Patel, Rohan V., Pellecchia, Giovanna, Wei, John, Strug, Lisa J., Bell, Sherilyn, Kellam, Barbara, Mahtani, Melanie M., Bassett, Anne S., Bombard, Yvonne, Weksberg, Rosanna, Shuman, Cheryl, Cohn, Ronald D., Stavropoulos, Dimitri J., Bowdin, Sarah, Hildebrandt, Matthew R., Wei, Wei, Romm, Asli, Pasceri, Peter, Ellis, James, Ray, Peter, Meyn, M. Stephen, Monfared, Nasim, Hosseini, S. Mohsen, Joseph-George, Ann M., Keeley, Fred W., Cook, Ryan A., Fiume, Marc, Lee, Hin C., Marshall, Christian R., Davies, Jill, Hazell, Allison, Buchanan, Janet A., Szego, Michael J., and Scherer, Stephen W.
Subjects: Health policy -- Analysis, DNA sequencing -- Analysis, Pharmacogenomics -- Analysis, Health
Abstract: BACKGROUND: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. METHODS: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant. RESULTS: Whole genome sequencing of the first 56 participants identified 207662 805 sequence variants and 27494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants--associated with cancer, cardiac or neurodegenerative phenotypes--remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual. INTERPRETATION: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care., Rapid technological advances are enabling a view of human genetic variation in ever-increasing detail and at plummeting costs. (1) Until recently, analysis has been targeted largely to defined genes, but [...]
Published: 2018
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10. SCIP: software for efficient clinical interpretation of copy number variants detected by whole-genome sequencing

Author: Ding, Qiliang, primary, Somerville, Cherith, additional, Manshaei, Roozbeh, additional, Trost, Brett, additional, Reuter, Miriam S., additional, Kalbfleisch, Kelsey, additional, Stanley, Kaitlin, additional, Okello, John B. A., additional, Hosseini, S. Mohsen, additional, Liston, Eriskay, additional, Curtis, Meredith, additional, Zarrei, Mehdi, additional, Higginbotham, Edward J., additional, Chan, Ada J. S., additional, Engchuan, Worrawat, additional, Thiruvahindrapuram, Bhooma, additional, Scherer, Stephen W., additional, Kim, Raymond H., additional, and Jobling, Rebekah K., additional
Published: 2022
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11. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome

Author: Hosseini, S. Mohsen, Kim, Raymond, Udupa, Sharmila, Costain, Gregory, Jobling, Rebekah, Liston, Eriskay, Jamal, Seema M., Szybowska, Marta, Morel, Chantal F., Bowdin, Sarah, Garcia, John, Care, Melanie, Sturm, Amy C., Novelli, Valeria, Ackerman, Michael J., Ware, James S., Hershberger, Ray E., Wilde, Arthur A.M., and Gollob, Michael H.
Published: 2018
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12. The association of previously reported polymorphisms for microvascular complications in a meta-analysis of diabetic retinopathy

Author: Hosseini, S. Mohsen, Boright, Andrew P., Sun, Lei, Canty, Angelo J., Bull, Shelley B., Klein, Barbara E. K., Klein, Ronald, Paterson, Andrew D., and The DCCT/EDIC Research Group
Published: 2015
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13. 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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14. Additional file 1 of GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Author: Manshaei, Roozbeh, DeLong, Sean, Andric, Veronica, Joshi, Esha, Okello, John B. A., Dhir, Priya, Somerville, Cherith, Farncombe, Kirsten M., Kalbfleisch, Kelsey, Jobling, Rebekah K., Scherer, Stephen W., Kim, Raymond H., and Hosseini, S. Mohsen
Abstract: Additional file 1: Materials file. Table S2. GeneTerpret modules and respective databases with links to the used data. Table S3. The required VCF file annotation, headers and descriptions. Table S4. The standard format for the PED file. Table S5. Variant Interpretation Program (VIP) logic (pseudocode) for variant classification following ACMG criteria. Table S6. Bins Used for Ranking GeneTerpret Output. Table S7. Comparison of GeneTerpret output and previous manual interpretation of 10 trios. Table S8. Comparison of GeneTerpret output and previous manual interpretation of a cohort with 20 TOF patients. Findings from manual interpretation have been reported for five individuals in this cohort.
Published: 2022
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15. Additional file 4 of GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Author: Manshaei, Roozbeh, DeLong, Sean, Andric, Veronica, Joshi, Esha, Okello, John B. A., Dhir, Priya, Somerville, Cherith, Farncombe, Kirsten M., Kalbfleisch, Kelsey, Jobling, Rebekah K., Scherer, Stephen W., Kim, Raymond H., and Hosseini, S. Mohsen
Subjects: InformationSystems_INFORMATIONINTERFACESANDPRESENTATION(e.g.,HCI)
Abstract: Additional file 4: Figure S1. A snapshot of the GeneTerpret graphical user interface (GeneTerpret GUI). A general interpretation routine is depicted as an example. The user selects the needed modules from the top right panel; then drags and drops them one by one in the left workspace panel. Furthermore, the tissue or phenotype/disease of interest can be directly entered by the user as an input in the bottom right panel and the generated module could be dragged and dropped in the left workspace panel. The users can upload their annotated VCF file, gene list(s), family information (PED file) and phenotypes/diseases list as further input for GeneTerpret by tapping on the upload tab in the bottom right panel and drag and drop the assigned generated module for the uploaded file in the workspace panel in the left side.
Published: 2022
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16. Additional file 6 of GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Author: Manshaei, Roozbeh, DeLong, Sean, Andric, Veronica, Joshi, Esha, Okello, John B. A., Dhir, Priya, Somerville, Cherith, Farncombe, Kirsten M., Kalbfleisch, Kelsey, Jobling, Rebekah K., Scherer, Stephen W., Kim, Raymond H., and Hosseini, S. Mohsen
Subjects: ComputingMethodologies_PATTERNRECOGNITION
Abstract: Additional file 6: Figure S3. Variant Interpretation Program (VIP) internal structure. External databases used for VIP are fetched and processed, with the output being stored in a MongoDB collection. In VIP, each database collection is associated with a specific ACMG classification, but not all classifications use these collections. Each row of the input VCF file is inputted to all classifications, flagging them as 1 or 0. Then, using the logic outlined in Supplementary Table S3, the individual classifications are combined to provide the pathogenicity classification for each variant.
Published: 2022
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17. Additional file 5 of GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Author: Manshaei, Roozbeh, DeLong, Sean, Andric, Veronica, Joshi, Esha, Okello, John B. A., Dhir, Priya, Somerville, Cherith, Farncombe, Kirsten M., Kalbfleisch, Kelsey, Jobling, Rebekah K., Scherer, Stephen W., Kim, Raymond H., and Hosseini, S. Mohsen
Abstract: Additional file 5: Figure S2. Gene Validity Module architecture. External databases are first fetched and filtered based on certain criteria, and the results are entered into MongoDB collections. ExPhenosion, CanGene, and KING modules take in user input and the MongoDB collections to perform their functions.
Published: 2022
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18. Additional file 7 of GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Author: Manshaei, Roozbeh, DeLong, Sean, Andric, Veronica, Joshi, Esha, Okello, John B. A., Dhir, Priya, Somerville, Cherith, Farncombe, Kirsten M., Kalbfleisch, Kelsey, Jobling, Rebekah K., Scherer, Stephen W., Kim, Raymond H., and Hosseini, S. Mohsen
Abstract: Additional file 7: Figure S4. Overview of the causality module output; (A) the interactive visualization of variant distribution in the validity-pathogenicity space allows users to explore the desired variants. Dark green, light green, yellow, orange, and red colours represent the pathogenicity of variants in a 5-tier system: benign, likely benign, uncertain significance, likely pathogenic, and pathogenic variants. (B) Lasso filter allows the analyst to select the desired variants and filter them to a downloadable VCF file.
Published: 2022
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19. GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence

Author: Eny, Karen M., Lutgers, Helen L., Maynard, John, Klein, Barbara E. K., Lee, Kristine E., Atzmon, Gil, Monnier, Vincent M., van Vliet-Ostaptchouk, Jana V., Graaff, Reindert, van der Harst, Pim, Snieder, Harold, van der Klauw, Melanie M., Sell, David R., Hosseini, S. Mohsen, Cleary, Patricia A., Braffett, Barbara H., Orchard, Trevor J., Lyons, Timothy J., Howard, Kerri, Klein, Ronald, Crandall, Jill P., Barzilai, Nir, Milman, Sofiya, Ben-Avraham, Danny, Wolffenbuttel, Bruce H. R., Paterson, Andrew D., LifeLines Cohort Study Group, and DCCT/EDIC Research Group
Published: 2014
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20. CRYBA4, a novel human cataract gene, is also involved in microphthalmia

Author: Billingsley, Gail, Santhiya, Sathiyavedu T., Paterson, Andrew D., Ogata, Koji, Wodak, Shoshana, Hosseini, S. Mohsen, Manisastry, Shyam Manohar, Vijayalakshmi, Perumalsamy, Gopinath, Pudhiya Mundyat, Graw, Jochen, and Heon, Elise
Subjects: Microphthalmos -- Genetic aspects, Microphthalmos -- Research, Gene mutations -- Research, Cataract -- Genetic aspects, Cataract -- Research, Biological sciences
Abstract: A novel cataract gene CRYBA4 is identified by genetic analysis of a family with an autosomal dominant cataract phenotype, and a pathogenic mutation is identified in exon 4 area of the gene. Mutational analysis reveals that CRYBA4 is associated with CRYBB2, the protein implicated in microphthalmia, thus demonstrating the role of CRYBA4 in both cataractogenesis and microphthalmia.
Published: 2006

21. Erratum. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 2019;68:441—456

Author: Pollack, Samuela, primary, Igo, Robert P., additional, Jensen, Richard A., additional, Christiansen, Mark, additional, Li, Xiaohui, additional, Cheng, Ching-Yu, additional, Ng, Maggie C.Y., additional, Smith, Albert V., additional, Rossin, Elizabeth J., additional, Segrè, Ayellet V., additional, Davoudi, Samaneh, additional, Tan, Gavin S., additional, Ida Chen, Yii-Der, additional, Kuo, Jane Z., additional, Dimitrov, Latchezar M., additional, Stanwyck, Lynn K., additional, Meng, Weihua, additional, Hosseini, S. Mohsen, additional, Imamura, Minako, additional, Nousome, Darryl, additional, Kim, Jihye, additional, Hai, Yang, additional, Jia, Yucheng, additional, Ahn, Jeeyun, additional, Leong, Aaron, additional, Shah, Kaanan, additional, Park, Kyu Hyung, additional, Guo, Xiuqing, additional, Ipp, Eli, additional, Taylor, Kent D., additional, Adler, Sharon G., additional, Sedor, John R., additional, Freedman, Barry I., additional, Lee, I-Te, additional, Sheu, Wayne H.-H., additional, Kubo, Michiaki, additional, Takahashi, Atsushi, additional, Hadjadj, Samy, additional, Marre, Michel, additional, Tregouet, David-Alexandre, additional, Mckean-Cowdin, Roberta, additional, Varma, Rohit, additional, McCarthy, Mark I., additional, Groop, Leif, additional, Ahlqvist, Emma, additional, Lyssenko, Valeriya, additional, Agardh, Elisabet, additional, Morris, Andrew, additional, Doney, Alex S.F., additional, Colhoun, Helen M., additional, Toppila, Iiro, additional, Sandholm, Niina, additional, Groop, Per-Henrik, additional, Maeda, Shiro, additional, Hanis, Craig L., additional, Penman, Alan, additional, Chen, Ching J., additional, Hancock, Heather, additional, Mitchell, Paul, additional, Craig, Jamie E., additional, Chew, Emily Y., additional, Paterson, Andrew D., additional, Grassi, Michael A., additional, Palmer, Colin, additional, Bowden, Donald W., additional, Yaspan, Brian L., additional, Siscovick, David, additional, Cotch, Mary Frances, additional, Wang, Jie Jin, additional, Burdon, Kathryn P., additional, Wong, Tien Y., additional, Klein, Barbara E.K., additional, Klein, Ronald, additional, Rotter, Jerome I., additional, Iyengar, Sudha K., additional, Price, Alkes L., additional, and Sobrin, Lucia, additional
Published: 2020
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22. A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose

Author: Paterson, Andrew D., Waggott, Daryl, Boright, Andrew P., Hosseini, S. Mohsen, Shen, Enqing, Sylvestre, Marie-Pierre, Wong, Isidro, Bharaj, Bhupinder, Cleary, Patricia A., Lachin, John M., Below, Jennifer E., Nicolae, Dan, Cox, Nancy J., Canty, Angelo J., Sun, Lei, and Bull, Shelley B.
Published: 2010

23. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Author: Fan, Qiao, Guo, Xiaobo, Tideman, J Willem L, Williams, Katie M, Yazar, Seyhan, Hosseini, S Mohsen, Howe, Laura D, Pourcain, Beaté St, Evans, David M, Timpson, Nicholas J, McMahon, George, Hysi, Pirro G, Krapohl, Eva, Wang, Ya Xing, Jonas, Jost B, Baird, Paul Nigel, Wang, Jie Jin, Cheng, Ching-Yu, Teo, Yik-Ying, Wong, Tien-Yin, Ding, Xiaohu, Wojciechowski, Robert, Young, Terri L, Pärssinen, Olavi, Oexle, Konrad, Pfeiffer, Norbert, Bailey-Wilson, Joan E, Paterson, Andrew D, Klaver, Caroline CW, Plomin, Robert, Hammond, Christopher J, Mackey, David A, He, Mingguang, Saw, Seang-Mei, Williams, Cathy, Guggenheim, Jeremy A, CREAM Consortium, Hosseini, S Mohsen [0000-0003-3626-9928], and Apollo - University of Cambridge Repository
Subjects: Male, Adolescent, Refractive Errors, Polymorphism, Single Nucleotide, Article, White People, Asian People, Myopia, Humans, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Longitudinal Studies, Age of Onset, Child, Genome-Wide Association Study
Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).
Published: 2016

24. 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, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., Klaver, C.C.W., 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, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., and Klaver, C.C.W.
Abstract: Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
Published: 2018

25. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

Author: Lionel, Anath C., primary, Costain, Gregory, additional, Monfared, Nasim, additional, Walker, Susan, additional, Reuter, Miriam S., additional, Hosseini, S. Mohsen, additional, Thiruvahindrapuram, Bhooma, additional, Merico, Daniele, additional, Jobling, Rebekah, additional, Nalpathamkalam, Thomas, additional, Pellecchia, Giovanna, additional, Sung, Wilson W.L., additional, Wang, Zhuozhi, additional, Bikangaga, Peter, additional, Boelman, Cyrus, additional, Carter, Melissa T., additional, Cordeiro, Dawn, additional, Cytrynbaum, Cheryl, additional, Dell, Sharon D., additional, Dhir, Priya, additional, Dowling, James J., additional, Heon, Elise, additional, Hewson, Stacy, additional, Hiraki, Linda, additional, Inbar-Feigenberg, Michal, additional, Klatt, Regan, additional, Kronick, Jonathan, additional, Laxer, Ronald M., additional, Licht, Christoph, additional, MacDonald, Heather, additional, Mercimek-Andrews, Saadet, additional, Mendoza-Londono, Roberto, additional, Piscione, Tino, additional, Schneider, Rayfel, additional, Schulze, Andreas, additional, Silverman, Earl, additional, Siriwardena, Komudi, additional, Snead, O. Carter, additional, Sondheimer, Neal, additional, Sutherland, Joanne, additional, Vincent, Ajoy, additional, Wasserman, Jonathan D., additional, Weksberg, Rosanna, additional, Shuman, Cheryl, additional, Carew, Chris, additional, Szego, Michael J., additional, Hayeems, Robin Z., additional, Basran, Raveen, additional, Stavropoulos, Dimitri J., additional, Ray, Peter N., additional, Bowdin, Sarah, additional, Meyn, M. Stephen, additional, Cohn, Ronald D., additional, Scherer, Stephen W., additional, and Marshall, Christian R., additional
Published: 2018
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26. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia:The CREAM Consortium

Author: Fan, Qiao, Guo, Xiaobo, Tideman, J. Willem L, Williams, Katie M., Yazar, Seyhan, Hosseini, S. Mohsen, Howe, Laura D., Pourcain, Beaté St, Evans, David M., Timpson, Nicholas J., McMahon, George, Hysi, Pirro G., Krapohl, Eva, Wang, Ya Xing, Jonas, Jost B., Baird, Paul Nigel, Wang, Jie Jin, Cheng, Ching Yu, Teo, Yik Ying, Wong, Tien Yin, Ding, Xiaohu, Wojciechowski, Robert, Young, Terri L., Pärssinen, Olavi, Oexle, Konrad, Pfeiffer, Norbert, Bailey-Wilson, Joan E., Paterson, Andrew D., Klaver, Caroline C W, Plomin, Robert, Hammond, Christopher J., He, Mingguang, Saw, Seang Mei, Guggenheim, Jeremy A., Meguro, Akira, Wright, Alan F., Hewitt, Alex W., Young, Alvin L., Veluchamy, Amutha Barathi, Metspalu, Andres, Döring, Angela, Khawaja, Anthony P., Klein, Barbara E., St Pourcain, Beate, Fleck, Brian, Hayward, Caroline, Williams, Cathy, Delcourt, Cécile, Pang, Chi Pui, Khor, Chiea Chuen, Gieger, Christian, Simpson, Claire L., Van Duijn, Cornelia M., Mackey, David A., Stambolian, Dwight, Chew, Emily, Tai, E. Shyong, Mihailov, Evelin, Smith, George Davey, Biino, Ginevra, Campbell, Harry, Rudan, Igor, Seppälä, Ilkka, Kaprio, Jaakko, Wilson, James F., Craig, Jamie E., Ried, Janina S., Korobelnik, Jean François, Fondran, Jeremy R., Liao, Jiemin, Zhao, Jing Hua, Xie, Jing, Kemp, John P., Lass, Jonathan H., Rahi, Jugnoo S., Wedenoja, Juho, Mäkelä, Kari Matti, Burdon, Kathryn P., Khaw, Kay Tee, Yamashiro, Kenji, Chen, Li Jia, Xu, Liang, Farrer, Lindsay, Ikram, M. Kamran, Deangelis, Margaret M., Morrison, Margaux, Schache, Maria, Pirastu, Mario, Miyake, Masahiro, Yap, Maurice K H, Fossarello, Maurizio, Kähönen, Mika, Tedja, Milly S., Yoshimura, Nagahisa, Martin, Nicholas G., Wareham, Nick J., Mizuki, Nobuhisa, Raitakari, Olli, Polasek, Ozren, Tam, Pancy O., Foster, Paul J., Mitchell, Paul, Chen, Peng, Cumberland, Phillippa, Gharahkhani, Puya, Höhn, René, Fogarty, Rhys D., Luben, Robert N., Igo, Robert P., Klein, Ronald, Janmahasatian, Sarayut, Yip, Shea Ping, Feng, Sheng, Vaccargiu, Simona, Panda-Jonas, Songhomitra, MacGregor, Stuart, Iyengar, Sudha K., Rantanen, Taina, Lehtimäki, Terho, Meitinger, Thomas, Aung, Tin, Haller, Toomas, Vitart, Veronique, Nangia, Vinay, Verhoeven, Virginie J M, Jhanji, Vishal, Zhao, Wanting, Chen, Wei, Zhou, Xiangtian, Lu, Yi, and Vatavuk, Zoran
Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).
Published: 2016
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27. Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

Author: 90812793, Fan, Qiao, Verhoeven, Virginie J. M., Wojciechowski, Robert, Barathi, Veluchamy A., Hysi, Pirro G., Guggenheim, Jeremy A., Höhn, René, Vitart, Veronique, Khawaja, Anthony P., Yamashiro, Kenji, Hosseini, S Mohsen, Lehtimäki, Terho, Lu, Yi, Haller, Toomas, Xie, Jing, Delcourt, Cécile, Pirastu, Mario, Wedenoja, Juho, Gharahkhani, Puya, Venturini, Cristina, Miyake, Masahiro, Hewitt, Alex W., Guo, Xiaobo, Mazur, Johanna, Huffman, Jenifer E., Williams, Katie M., Polasek, Ozren, Campbell, Harry, Rudan, Igor, Vatavuk, Zoran, Wilson, James F., Joshi, Peter K., McMahon, George, St Pourcain, Beate, Evans, David M., Simpson, Claire L., Schwantes-An, Tae-Hwi, Igo, Robert P., Mirshahi, Alireza, Cougnard-Gregoire, Audrey, Bellenguez, Céline, Blettner, Maria, Raitakari, Olli, Kähönen, Mika, Seppälä, Ilkka, Zeller, Tanja, Meitinger, Thomas, Ried, Janina S., Gieger, Christian, Portas, Laura, van Leeuwen, Elisabeth M., Amin, Najaf, Uitterlinden, André G., Rivadeneira, Fernando, Hofman, Albert, Vingerling, Johannes R., Wang, Ya Xing, Wang, Xu, Tai-Hui Boh, Eileen, Ikram, M. Kamran, Sabanayagam, Charumathi, Gupta, Preeti, Tan, Vincent, Zhou, Lei, Ho, Candice E. H., Lim, Wan’e, Beuerman, Roger W., Siantar, Rosalynn, Tai, E-Shyong, Vithana, Eranga, Mihailov, Evelin, Khor, Chiea-Chuen, Hayward, Caroline, Luben, Robert N., Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Wong, Hoi-Suen, Mitchell, Paul, Metspalu, Andres, Aung, Tin, Young, Terri L., He, Mingguang, Pärssinen, Olavi, van Duijn, Cornelia M., Jin Wang, Jie, Williams, Cathy, Jonas, Jost B., Teo, Yik-Ying, Mackey, David A., Oexle, Konrad, Yoshimura, Nagahisa, Paterson, Andrew D., Pfeiffer, Norbert, Wong, Tien-Yin, Baird, Paul N., Stambolian, Dwight, Wilson, Joan E. Bailey, Cheng, Ching-Yu, Hammond, Christopher J., Klaver, Caroline C. W., Saw, Seang-Mei, 90812793, Fan, Qiao, Verhoeven, Virginie J. M., Wojciechowski, Robert, Barathi, Veluchamy A., Hysi, Pirro G., Guggenheim, Jeremy A., Höhn, René, Vitart, Veronique, Khawaja, Anthony P., Yamashiro, Kenji, Hosseini, S Mohsen, Lehtimäki, Terho, Lu, Yi, Haller, Toomas, Xie, Jing, Delcourt, Cécile, Pirastu, Mario, Wedenoja, Juho, Gharahkhani, Puya, Venturini, Cristina, Miyake, Masahiro, Hewitt, Alex W., Guo, Xiaobo, Mazur, Johanna, Huffman, Jenifer E., Williams, Katie M., Polasek, Ozren, Campbell, Harry, Rudan, Igor, Vatavuk, Zoran, Wilson, James F., Joshi, Peter K., McMahon, George, St Pourcain, Beate, Evans, David M., Simpson, Claire L., Schwantes-An, Tae-Hwi, Igo, Robert P., Mirshahi, Alireza, Cougnard-Gregoire, Audrey, Bellenguez, Céline, Blettner, Maria, Raitakari, Olli, Kähönen, Mika, Seppälä, Ilkka, Zeller, Tanja, Meitinger, Thomas, Ried, Janina S., Gieger, Christian, Portas, Laura, van Leeuwen, Elisabeth M., Amin, Najaf, Uitterlinden, André G., Rivadeneira, Fernando, Hofman, Albert, Vingerling, Johannes R., Wang, Ya Xing, Wang, Xu, Tai-Hui Boh, Eileen, Ikram, M. Kamran, Sabanayagam, Charumathi, Gupta, Preeti, Tan, Vincent, Zhou, Lei, Ho, Candice E. H., Lim, Wan’e, Beuerman, Roger W., Siantar, Rosalynn, Tai, E-Shyong, Vithana, Eranga, Mihailov, Evelin, Khor, Chiea-Chuen, Hayward, Caroline, Luben, Robert N., Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Wong, Hoi-Suen, Mitchell, Paul, Metspalu, Andres, Aung, Tin, Young, Terri L., He, Mingguang, Pärssinen, Olavi, van Duijn, Cornelia M., Jin Wang, Jie, Williams, Cathy, Jonas, Jost B., Teo, Yik-Ying, Mackey, David A., Oexle, Konrad, Yoshimura, Nagahisa, Paterson, Andrew D., Pfeiffer, Norbert, Wong, Tien-Yin, Baird, Paul N., Stambolian, Dwight, Wilson, Joan E. Bailey, Cheng, Ching-Yu, Hammond, Christopher J., Klaver, Caroline C. W., and Saw, Seang-Mei
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40, 036 adults from 25 studies of European ancestry and 10, 315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Published: 2016

28. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error

Author: University of Helsinki, Clinicum, Li, Qing, Wojciechowski, Robert, Simpson, Claire L., Hysi, Pirro G., Verhoeven, Virginie J. M., Ikram, Mohammad Kamran, Hoehn, Rene, Vitart, Veronique, Hewitt, Alex W., Oexle, Konrad, Makela, Kari-Matti, MacGregor, Stuart, Pirastu, Mario, Fan, Qiao, Cheng, Ching-Yu, St Pourcain, Beat, 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, Polasek, 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, Andre, 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, Lehtimaki, Terho, Kahonen, 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, Parssinen, Olavi, Stambolian, Dwight, Hammond, Christopher J., Klaver, Caroline C. W., Williams, Cathy, Paterson, Andrew D., Bailey-Wilson, Joan E., Guggenheim, Jeremy A., CREAM Consortium, University of Helsinki, Clinicum, Li, Qing, Wojciechowski, Robert, Simpson, Claire L., Hysi, Pirro G., Verhoeven, Virginie J. M., Ikram, Mohammad Kamran, Hoehn, Rene, Vitart, Veronique, Hewitt, Alex W., Oexle, Konrad, Makela, Kari-Matti, MacGregor, Stuart, Pirastu, Mario, Fan, Qiao, Cheng, Ching-Yu, St Pourcain, Beat, 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, Polasek, 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, Andre, 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, Lehtimaki, Terho, Kahonen, 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, Parssinen, Olavi, Stambolian, Dwight, Hammond, Christopher J., Klaver, Caroline C. W., Williams, Cathy, Paterson, Andrew D., Bailey-Wilson, Joan E., Guggenheim, Jeremy A., and CREAM Consortium
Published: 2015

29. Relationship between trajectories of serum albumin levels and technique failure according to diabetic status in peritoneal dialysis patients: A joint modeling approach.

Author: Khoshhali, Mehri, Kazemi, Iraj, Hosseini, S. Mohsen, and Seirafian, Shiva
Abstract: Background: In peritoneal dialysis, technique failure is an important metric to be considered. This study was performed in order to identify the relationship between trajectories of serum albumin levels and peritoneal dialysis technique failure on end-stage renal disease patients according to diabetic status. Furthermore, this study was performed to reveal predictors of serum albumin and technique failure simultaneously. Methods: This retrospective cohort study included 300 (189 non-diabetic and 111 diabetic) end-stage renal disease patients on continuous ambulatory peritoneal dialysis treated in Al-Zahra Hospital, Isfahan, Iran, from May 2005 to March 2015. Bayesian joint modeling was carried out in order to determine the relationship between trajectories of serum albumin levels and peritoneal dialysis technique failure in the patients according to diabetic status. Death from all causes was considered as a competing risk. Results: Using joint modeling approach, a relationship between trajectories of serum albumin with hazard of transfer to hemodialysis was estimated as -0.720 (95% confidence interval [CI], -0.971 to -0.472) for diabetic and -0.784 (95% CI, -0.963 to -0.587) for non-diabetic patients. From our findings it was showed that predictors of low serum albumin over time were time on peritoneal dialysis for diabetic patients and increase in age and time on peritoneal dialysis, history of previous hemodialysis, and lower body mass index in non-diabetic patients. Conclusion: The results of current study showed that controlling serum albumin over time in non-diabetic and diabetic patients undergoing continuous ambulatory peritoneal dialysis treatment can decrease risk of adverse outcomes during the peritoneal dialysis period. [ABSTRACT FROM AUTHOR]
Published: 2017
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30. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia

Author: Verhoeven, Virginie J M, Hysi, Pirro G, Wojciechowski, Robert, Fan, Qiao, Guggenheim, Jeremy A, Höhn, René, MacGregor, Stuart, Hewitt, Alex W, Nag, Abhishek, Cheng, Ching-Yu, Yonova-Doing, Ekaterina, Zhou, Xin, Ikram, M Kamran, Buitendijk, Gabriëlle H S, McMahon, George, Kemp, John P, Pourcain, Beate St, Simpson, Claire L, Mäkelä, Kari-Matti, Lehtimäki, Terho, Kähönen, Mika, Paterson, Andrew D, Hosseini, S Mohsen, Wong, Hoi Suen, Xu, Liang, Jonas, Jost B, Pärssinen, Olavi, Wedenoja, Juho, Yip, Shea Ping, Ho, Daniel W H, Pang, Chi Pui, Chen, Li Jia, Burdon, Kathryn P, Craig, Jamie E, Klein, Barbara E K, Klein, Ronald, Haller, Toomas, Metspalu, Andres, Khor, Chiea-Chuen, Tai, E-Shyong, Aung, Tin, Vithana, Eranga, Tay, Wan-Ting, Barathi, Veluchamy A, Chen, Peng, Li, Ruoying, Liao, Jiemin, Zheng, Yingfeng, Ong, Rick T, Döring, Angela, Evans, David M, Timpson, Nicholas J, Verkerk, Annemieke J M H, Meitinger, Thomas, Raitakari, Olli, Hawthorne, Felicia, Spector, Tim D, Karssen, Lennart C, Pirastu, Mario, Murgia, Federico, Ang, Wei, Mishra, Aniket, Montgomery, Grant W, Pennell, Craig E, Cumberland, Phillippa M, Cotlarciuc, Ioana, Mitchell, Paul, Wang, Jie Jin, Schache, Maria, Janmahasathian, Sarayut, Jr, Robert P Igo, Lass, Jonathan H, Chew, Emily, Iyengar, Sudha K, Gorgels, Theo G M F, Rudan, Igor, Hayward, Caroline, Wright, Alan F, Polasek, Ozren, Vatavuk, Zoran, Wilson, James F, Fleck, Brian, Zeller, Tanja, Mirshahi, Alireza, Müller, Christian, Uitterlinden, André G, Rivadeneira, Fernando, Vingerling, Johannes R, Hofman, Albert, Oostra, Ben A, Amin, Najaf, Bergen, Arthur A B, Teo, Yik-Ying, Rahi, Jugnoo S, Jankowski, Janusz, Vitart, Veronique, Williams, Cathy, Baird, Paul N, Wong, Tien-Yin, Oexle, Konrad, Pfeiffer, Norbert, Mackey, David A, Young, Terri L, van Duijn, Cornelia M, Saw, Seang-Mei, Bailey-Wilson, Joan E, Stambolian, Dwight, Klaver, Caroline C, Hammond, Christopher J, Verhoeven, Virginie J M, Hysi, Pirro G, Wojciechowski, Robert, Fan, Qiao, Guggenheim, Jeremy A, Höhn, René, MacGregor, Stuart, Hewitt, Alex W, Nag, Abhishek, Cheng, Ching-Yu, Yonova-Doing, Ekaterina, Zhou, Xin, Ikram, M Kamran, Buitendijk, Gabriëlle H S, McMahon, George, Kemp, John P, Pourcain, Beate St, Simpson, Claire L, Mäkelä, Kari-Matti, Lehtimäki, Terho, Kähönen, Mika, Paterson, Andrew D, Hosseini, S Mohsen, Wong, Hoi Suen, Xu, Liang, Jonas, Jost B, Pärssinen, Olavi, Wedenoja, Juho, Yip, Shea Ping, Ho, Daniel W H, Pang, Chi Pui, Chen, Li Jia, Burdon, Kathryn P, Craig, Jamie E, Klein, Barbara E K, Klein, Ronald, Haller, Toomas, Metspalu, Andres, Khor, Chiea-Chuen, Tai, E-Shyong, Aung, Tin, Vithana, Eranga, Tay, Wan-Ting, Barathi, Veluchamy A, Chen, Peng, Li, Ruoying, Liao, Jiemin, Zheng, Yingfeng, Ong, Rick T, Döring, Angela, Evans, David M, Timpson, Nicholas J, Verkerk, Annemieke J M H, Meitinger, Thomas, Raitakari, Olli, Hawthorne, Felicia, Spector, Tim D, Karssen, Lennart C, Pirastu, Mario, Murgia, Federico, Ang, Wei, Mishra, Aniket, Montgomery, Grant W, Pennell, Craig E, Cumberland, Phillippa M, Cotlarciuc, Ioana, Mitchell, Paul, Wang, Jie Jin, Schache, Maria, Janmahasathian, Sarayut, Jr, Robert P Igo, Lass, Jonathan H, Chew, Emily, Iyengar, Sudha K, Gorgels, Theo G M F, Rudan, Igor, Hayward, Caroline, Wright, Alan F, Polasek, Ozren, Vatavuk, Zoran, Wilson, James F, Fleck, Brian, Zeller, Tanja, Mirshahi, Alireza, Müller, Christian, Uitterlinden, André G, Rivadeneira, Fernando, Vingerling, Johannes R, Hofman, Albert, Oostra, Ben A, Amin, Najaf, Bergen, Arthur A B, Teo, Yik-Ying, Rahi, Jugnoo S, Jankowski, Janusz, Vitart, Veronique, Williams, Cathy, Baird, Paul N, Wong, Tien-Yin, Oexle, Konrad, Pfeiffer, Norbert, Mackey, David A, Young, Terri L, van Duijn, Cornelia M, Saw, Seang-Mei, Bailey-Wilson, Joan E, Stambolian, Dwight, Klaver, Caroline C, and Hammond, Christopher J
Abstract: Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
Published: 2013

31. New susceptibility loci associated with kidney disease in type 1 diabetes

Author: Sandholm, Niina, Salem, Rany M., McKnight, Amy Jayne, Brennan, Eoin P., Forsblom, Carol, Isakova, Tamara, McKay, Gareth J., Williams, Winfred W., Sadlier, Denise M., Makinen, Ville-Petteri, Swan, Elizabeth J., Palmer, Cameron, Boright, Andrew P., Ahlqvist, Emma, Deshmukh, Harshal A., Keller, Benjamin J., Huang, Huateng, Ahola, Aila J., Fagerholm, Emma, Gordin, Daniel, Harjutsalo, Valma, He, Bing, Heikkila, Outi, Hietala, Kustaa, Kyto, Janne, Lahermo, Paivi, Lehto, Markku, Lithovius, Raija, Osterholm, Anne-May, Parkkonen, Maija, Pitkaniemi, Janne, Rosengard-Barlund, Milla, Saraheimo, Markku, Sarti, Cinzia, Soderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M., Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Waden, Johan, Gill, Geoffrey V., Prior, Sarah, Guiducci, Candace, Mirel, Daniel B., Taylor, Andrew, Hosseini, S. Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Ladenvall, Claes, Alhenc-Gelas, Francois, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Mollsten, Anna, Cimponeriu, Danut, Ioana, Mihai, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L., Nelson, Robert G., Kretzler, Matthias, Colhoun, Helen M., Panduru, Nicolae Mircea, Gu, Harvest F., Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B., Waggott, Daryl, Paterson, Andrew D., Savage, David A., Bain, Stephen C., Martin, Finian, Hirschhorn, Joel N., Godson, Catherine, Florez, Jose C., Groop, Per-Henrik, Maxwell, Alexander P., Sandholm, Niina, Salem, Rany M., McKnight, Amy Jayne, Brennan, Eoin P., Forsblom, Carol, Isakova, Tamara, McKay, Gareth J., Williams, Winfred W., Sadlier, Denise M., Makinen, Ville-Petteri, Swan, Elizabeth J., Palmer, Cameron, Boright, Andrew P., Ahlqvist, Emma, Deshmukh, Harshal A., Keller, Benjamin J., Huang, Huateng, Ahola, Aila J., Fagerholm, Emma, Gordin, Daniel, Harjutsalo, Valma, He, Bing, Heikkila, Outi, Hietala, Kustaa, Kyto, Janne, Lahermo, Paivi, Lehto, Markku, Lithovius, Raija, Osterholm, Anne-May, Parkkonen, Maija, Pitkaniemi, Janne, Rosengard-Barlund, Milla, Saraheimo, Markku, Sarti, Cinzia, Soderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M., Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Waden, Johan, Gill, Geoffrey V., Prior, Sarah, Guiducci, Candace, Mirel, Daniel B., Taylor, Andrew, Hosseini, S. Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Ladenvall, Claes, Alhenc-Gelas, Francois, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Mollsten, Anna, Cimponeriu, Danut, Ioana, Mihai, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L., Nelson, Robert G., Kretzler, Matthias, Colhoun, Helen M., Panduru, Nicolae Mircea, Gu, Harvest F., Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B., Waggott, Daryl, Paterson, Andrew D., Savage, David A., Bain, Stephen C., Martin, Finian, Hirschhorn, Joel N., Godson, Catherine, Florez, Jose C., Groop, Per-Henrik, and Maxwell, Alexander P.
Abstract: Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Published: 2012
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32. New susceptibility loci associated with kidney disease in type 1 diabetes

Author: University of Helsinki, Clinicum, University of Helsinki, Nefrologian yksikkö, University of Helsinki, Department of Public Health (-2009), University of Helsinki, Lääketieteellisen tiedekunnan kanslia, University of Helsinki, Department of Ophthalmology and Otorhinolaryngology, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hjelt Institute, University of Helsinki, Department of Medicine, Sandholm, Niina, Salem, Rany M., McKnight, Amy Jayne, Brennan, Eoin P., Forsblom, Carol, Isakova, Tamara, McKay, Gareth J., Williams, Winfred W., Sadlier, Denise M., Mäkinen, Ville-Petteri, Swan, Elizabeth J., Palmer, Cameron, Boright, Andrew P., Ahlqvist, Emma, Deshmukh, Harshal A., Keller, Benjamin J., Huang, Huateng, Ahola, Aila, Fagerholm, Emma, Gordin, Ted Daniel, Harjutsalo, Valma, He, Bing, Heikkilä, Outi, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Lithovius, Raija, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne Mikael, Rosengård-Bärlund, Milla, Saraheimo, Markku, Sarti, Cinzia, Söderlun, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena, Tikkanen, Heikki Olavi, Tolonen, Nina Emilia, Tryggvason, Karl, Tuomilehto, Jaakko, Waden, Johan, Gill, Geoffrey V., Prior, Sarah, Guiducci, Candace, Mirel, Daniel B., Taylor, Andrew, Hosseini, S. Mohsen, EDIC Research Group, DCCT/, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Ladenvall, Claes, Alhenc-Gelas, Francois, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Falhammar, Henrik, Gu, Tianwei, Möllsten, Anna, Cimponeriu, Danut, Ioana, Mihai, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L., Nelson, Robert G., Kretzler, Matthias, Colhoun, Helen M., Panduru, Nicolae Mircea, Gu, Harvest F., Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B., Waggott, Daryl, Paterson, Andrew D., Savage, David A., Bain, Stephen C., Martin, Finian, Hirschhorn, Joel N., Godson, Catherine, Florez, Jose C., Groop, Per Henrik, Maxwell, Alexander P., University of Helsinki, Clinicum, University of Helsinki, Nefrologian yksikkö, University of Helsinki, Department of Public Health (-2009), University of Helsinki, Lääketieteellisen tiedekunnan kanslia, University of Helsinki, Department of Ophthalmology and Otorhinolaryngology, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hjelt Institute, University of Helsinki, Department of Medicine, Sandholm, Niina, Salem, Rany M., McKnight, Amy Jayne, Brennan, Eoin P., Forsblom, Carol, Isakova, Tamara, McKay, Gareth J., Williams, Winfred W., Sadlier, Denise M., Mäkinen, Ville-Petteri, Swan, Elizabeth J., Palmer, Cameron, Boright, Andrew P., Ahlqvist, Emma, Deshmukh, Harshal A., Keller, Benjamin J., Huang, Huateng, Ahola, Aila, Fagerholm, Emma, Gordin, Ted Daniel, Harjutsalo, Valma, He, Bing, Heikkilä, Outi, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Lithovius, Raija, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne Mikael, Rosengård-Bärlund, Milla, Saraheimo, Markku, Sarti, Cinzia, Söderlun, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena, Tikkanen, Heikki Olavi, Tolonen, Nina Emilia, Tryggvason, Karl, Tuomilehto, Jaakko, Waden, Johan, Gill, Geoffrey V., Prior, Sarah, Guiducci, Candace, Mirel, Daniel B., Taylor, Andrew, Hosseini, S. Mohsen, EDIC Research Group, DCCT/, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Ladenvall, Claes, Alhenc-Gelas, Francois, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Falhammar, Henrik, Gu, Tianwei, Möllsten, Anna, Cimponeriu, Danut, Ioana, Mihai, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L., Nelson, Robert G., Kretzler, Matthias, Colhoun, Helen M., Panduru, Nicolae Mircea, Gu, Harvest F., Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B., Waggott, Daryl, Paterson, Andrew D., Savage, David A., Bain, Stephen C., Martin, Finian, Hirschhorn, Joel N., Godson, Catherine, Florez, Jose C., Groop, Per Henrik, and Maxwell, Alexander P.
Abstract: Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Published: 2012

33. Variation in SLC19A3 and Protection From Microvascular Damage in Type 1 Diabetes.

Author: Porta, Massimo, Toppila, Iiro, Sandholm, Niina, Hosseini, S. Mohsen, Forsblom, Carol, Hietala, Kustaa, Borio, Lorenzo, Harjutsalo, Valma, Klein, Barbara E., Klein, Ronald, Paterson, Andrew D., Groop, Per-Henrik, DCCT/EDIC Research Group, and FinnDiane Study Group
Subjects: TYPE 1 diabetes, SINGLE nucleotide polymorphisms, THIAMINE transporter proteins, TRANSCRIPTION factors, DIABETIC retinopathy, DIABETIC angiopathies, DIABETIC nephropathies, DISEASE susceptibility, GENETIC polymorphisms, META-analysis, PHARMACOLOGY, RESEARCH funding, CASE-control method, SEQUENCE analysis, MEMBRANE transport proteins, DISEASE complications
Abstract: The risk of long-term diabetes complications is not fully explained by diabetes duration or long-term glycemic exposure, suggesting the involvement of genetic factors. Because thiamine regulates intracellular glucose metabolism and corrects for multiple damaging effects of high glucose, we hypothesized that variants in specific thiamine transporters are associated with risk of severe retinopathy and/or severe nephropathy because they modify an individual's ability to achieve sufficiently high intracellular thiamine levels. We tested 134 single nucleotide polymorphisms (SNPs) in two thiamine transporters (SLC19A2/3) and their transcription factors (SP1/2) for an association with severe retinopathy or nephropathy or their combination in the FinnDiane cohort. Subsequently, the results were examined for replication in the DCCT/EDIC and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) cohorts. We found two SNPs in strong linkage disequilibrium in the SLC19A3 locus associated with a reduced rate of severe retinopathy and the combined phenotype of severe retinopathy and end-stage renal disease. The association for the combined phenotype reached genome-wide significance in a meta-analysis that included the WESDR cohort. These findings suggest that genetic variations in SLC19A3 play an important role in the pathogenesis of severe diabetic retinopathy and nephropathy and may explain why some individuals with type 1 diabetes are less prone than others to develop microvascular complications. [ABSTRACT FROM AUTHOR]
Published: 2016
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34. Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma.

Author: van Koolwijk, Leonieke M. E., Ramdas, Wishal D., Ikram, M. Kamran, Jansonius, Nomdo M., Pasutto, Francesca, Hysi, Pirro G., Macgregor, Stuart, Janssen, Sarah F., Hewitt, Alex W., Viswanathan, Ananth C., Brink, Jacoline B. ten, Hosseini, S. Mohsen, Amin, Najaf, Despriet, Dominiek D. G., Willemse-Assink, Jacqueline J. M., Kramer, Rogier, Rivadeneira, Fernando, Struchalin, Maksim, Aulchenko, Yurii S., and Weisschuh, Nicole
Subjects: GLAUCOMA, EYE diseases, BLINDNESS, GENETICS, INTRAOCULAR pressure
Abstract: Glaucoma is a major eye disease in the elderly and is the second leading cause of blindness worldwide. The numerous familial glaucoma cases, as well as evidence from epidemiological and twin studies, strongly support a genetic component in developing glaucoma. However, it has proven difficult to identify the specific genes involved. Intraocular pressure (IOP) is the major risk factor for glaucoma and the only target for the current glaucoma therapy. IOP has been shown to be highly heritable. We investigated the role of common genetic variants in IOP by performing a genome-wide association study. Discovery analyses in 11,972 participants and subsequent replication analyses in a further 7,482 participants yielded two common genetic variants that were associated with IOP. The first (rs11656696) is located in GAS7 at chromosome 17, the second (rs7555523) in TMCO1 at chromosome 1. Both variants were associated with glaucoma in a meta-analysis of 4 case-control studies. GAS7 and TMCO1 are expressed in the ocular tissues that are involved in glaucoma. Both genes functionally interact with the known glaucoma disease genes. These data suggest that we have identified two genes involved in IOP regulation and glaucomatous neuropathy. [ABSTRACT FROM AUTHOR]
Published: 2012
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35. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

Author: Fan, Qiao, Verhoeven, Virginie J. M., Wojciechowski, Robert, Barathi, Veluchamy A., Hysi, Pirro G., Guggenheim, Jeremy A., Höhn, René, Vitart, Veronique, Khawaja, Anthony P., Yamashiro, Kenji, Hosseini, S Mohsen, Lehtimäki, Terho, Lu, Yi, Haller, Toomas, Xie, Jing, Delcourt, Cécile, Pirastu, Mario, Wedenoja, Juho, Gharahkhani, Puya, and Venturini, Cristina
Published: 2016
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36. [18F]-Fluorodeoxyglucose Uptake as a Marker of Residual Anaplastic and Poorly Differentiated Thyroid Carcinoma Following BRAF-Targeted Therapy.

Author: Dagher SA, Learned KO, Dagher R, Wang JR, Zhao X, Hosseini SM, Maniakas A, Cabanillas ME, Busaidy NL, Dadu R, Iyer P, Zafereo ME, and Khalaf AM
Abstract: Background and Purpose: Neoadjuvant BRAF-directed therapy and immunotherapy followed by surgery improves survival in patients with BRAF V600E -mutant anaplastic thyroid carcinoma (ATC), more so in those who have complete ATC pathologic response. This study assesses the ability of FDG-PET to non-invasively detect residual high-risk pathologies including ATC and poorly differentiated thyroid carcinoma (PDTC) in the preoperative setting., Materials and Methods: This retrospective, single-center study included consecutive BRAF V600E -mutant ATC patients treated with at least 30 days of neoadjuvant BRAF-directed therapy and who underwent FDG-PET/CT within 30 days prior to surgery. The highest pathologic grade observed for every head and neck lesion resected was recorded. Each lesion on pre-operative PET/CT was retrospectively characterized. The primary endpoint was to contrast the standardized uptake normalized by lean body mass (SULmax) for lesions with residual high-risk (ATC, PDTC) versus low-risk pathologies (papillary thyroid carcinoma, negative). An optimal SULmax threshold was then identified using a ROC analysis, and the ability of this threshold to non-invasively and preoperatively risk-stratify patients by overall survival was then evaluated with a Kaplan-Meier plot., Results: 30 patients (mean age 66.5±9.0; 17 males) were included in this study, with 94 surgically sampled lesions. Of these lesions, 57 (60.6%) were low-risk (39 negative, 18 papillary thyroid carcinoma) and 37 (39.4%) were high-risk (29 ATC, 8 PDTC). FDG uptake was higher for high-risk compared to low-risk pathologies: median SULmax 5.01 [IQR 2.81 - 10.95] versus 1.29 [IQR 1.06 - 3.1] (P<.001, Mann-Whitney U test). The sensitivity, specificity, and accuracy for detecting high-risk pathologies at the optimal threshold of SULmax ≥ 2.75 were 0.784 [95% CI 0.628-0.886], 0.702 [95% CI 0.573-0.805], and 0.734 [95% CI 0.637-0.813], respectively. Patients with at least 1 high-risk lesion identified with the aforementioned cut-off had a worse prognosis compared to patients without high-risk lesions in the head and neck: median OS for the former group was 259 days and was not attained for the latter (P=.038, log-rank test)., Conclusions: Preoperative FDG-PET non-invasively identifies lesions with residual high-risk pathologies following neoadjuvant BRAF-directed targeted therapy and immunotherapy for BRAF-mutated ATC. FDG-PET avidity may serve as an early prognostic marker which correlates with residual high-risk pathology in BRAF-mutated ATC following neoadjuvant therapy., Abbreviations: ATC = anaplastic thyroid carcinoma; IQR = interquartile range; OS = overall survival; PDTC = poorly differentiated thyroid carcinoma; PTC = papillary thyroid carcinoma; ROC = receiver operating characteristic; SUL= standardized uptake value normalized by lean body mass., Competing Interests: The authors declare no conflicts of interest related to the content of this article., (© 2024 by American Journal of Neuroradiology.)
Published: 2024
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37. New Locus for Skin Intrinsic Fluorescence in Type 1 Diabetes Also Associated With Blood and Skin Glycated Proteins.

Author: Roshandel D, Klein R, Klein BE, Wolffenbuttel BH, van der Klauw MM, van Vliet-Ostaptchouk JV, Atzmon G, Ben-Avraham D, Crandall JP, Barzilai N, Bull SB, Canty AJ, Hosseini SM, Hiraki LT, Maynard J, Sell DR, Monnier VM, Cleary PA, Braffett BH, and Paterson AD
Subjects: Alleles, Diabetes Mellitus, Type 1 diagnostic imaging, Diabetes Mellitus, Type 1 metabolism, Fluorescence, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Skin diagnostic imaging, Diabetes Mellitus, Type 1 genetics, Genetic Loci, Skin metabolism
Abstract: Skin fluorescence (SF) noninvasively measures advanced glycation end products (AGEs) in the skin and is a risk indicator for diabetes complications. N-acetyltransferase 2 (NAT2) is the only known locus influencing SF. We aimed to identify additional genetic loci influencing SF in type 1 diabetes (T1D) through a meta-analysis of genome-wide association studies (N = 1,359) including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). A locus on chromosome 1, rs7533564 (P = 1.9 × 10(-9)), was associated with skin intrinsic fluorescence measured by SCOUT DS (excitation 375 nm, emission 435-655 nm), which remained significant after adjustment for time-weighted HbA1c (P = 1.7 × 10(-8)). rs7533564 was associated with mean HbA1c in meta-analysis (P = 0.0225), mean glycated albumin (P = 0.0029), and glyoxal hydroimidazolones (P = 0.049), an AGE measured in skin biopsy collagen, in DCCT. rs7533564 was not associated with diabetes complications in DCCT/EDIC or with SF in subjects without diabetes (nondiabetic [ND]) (N = 8,721). In conclusion, we identified a new locus associated with SF in T1D subjects that did not show similar effect in ND subjects, suggesting a diabetes-specific effect. This association needs to be investigated in type 2 diabetes., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
Published: 2016
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38. New susceptibility loci associated with kidney disease in type 1 diabetes.

Author: Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, McKay GJ, Williams WW, Sadlier DM, Mäkinen VP, Swan EJ, Palmer C, Boright AP, Ahlqvist E, Deshmukh HA, Keller BJ, Huang H, Ahola AJ, Fagerholm E, Gordin D, Harjutsalo V, He B, Heikkilä O, Hietala K, Kytö J, Lahermo P, Lehto M, Lithovius R, Osterholm AM, Parkkonen M, Pitkäniemi J, Rosengård-Bärlund M, Saraheimo M, Sarti C, Söderlund J, Soro-Paavonen A, Syreeni A, Thorn LM, Tikkanen H, Tolonen N, Tryggvason K, Tuomilehto J, Wadén J, Gill GV, Prior S, Guiducci C, Mirel DB, Taylor A, Hosseini SM, Parving HH, Rossing P, Tarnow L, Ladenvall C, Alhenc-Gelas F, Lefebvre P, Rigalleau V, Roussel R, Tregouet DA, Maestroni A, Maestroni S, Falhammar H, Gu T, Möllsten A, Cimponeriu D, Ioana M, Mota M, Mota E, Serafinceanu C, Stavarachi M, Hanson RL, Nelson RG, Kretzler M, Colhoun HM, Panduru NM, Gu HF, Brismar K, Zerbini G, Hadjadj S, Marre M, Groop L, Lajer M, Bull SB, Waggott D, Paterson AD, Savage DA, Bain SC, Martin F, Hirschhorn JN, Godson C, Florez JC, Groop PH, and Maxwell AP
Subjects: Diabetes Mellitus, Type 1 complications, Diabetic Nephropathies etiology, Diabetic Nephropathies pathology, Fibrosis genetics, Fibrosis metabolism, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Tubules metabolism, Kidney Tubules pathology, Polymorphism, Single Nucleotide, Quantitative Trait Loci genetics, Receptor, ErbB-4, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Diabetes Mellitus, Type 1 genetics, Diabetic Nephropathies genetics, ErbB Receptors genetics, Kidney Failure, Chronic etiology, Kidney Failure, Chronic genetics, Kidney Failure, Chronic pathology, Nuclear Proteins genetics
Abstract: Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN., Competing Interests: JC Florez has received consulting honoraria from Novartis, Lilly, and Pfizer. M Kretzler received grant support from Hoffman La Roche and Fibrotech. P-H Groop has received lecture honorariums from Abbot, Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Novartis, Novo Nordisk, MSD, and research grants from Eli Lilly and Roche. P-H Groop is also an advisory board member of Boehringer Ingelheim and Novartis.
Published: 2012
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39. Genome-wide association identifies the ABO blood group as a major locus associated with serum levels of soluble E-selectin.

Author: Paterson AD, Lopes-Virella MF, Waggott D, Boright AP, Hosseini SM, Carter RE, Shen E, Mirea L, Bharaj B, Sun L, and Bull SB
Subjects: Alleles, Diabetes Mellitus, Type 1 blood, Female, Genotype, Humans, Male, Multivariate Analysis, Polymorphism, Single Nucleotide, Reference Values, Solubility, ABO Blood-Group System genetics, Diabetes Mellitus, Type 1 genetics, E-Selectin blood, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: Background: Elevated serum soluble E-selectin levels have been associated with a number of diseases. Although E-selectin levels are heritable, little is known about the specific genetic factors involved. E-selectin levels have been associated with the ABO blood group phenotype., Methods and Results: We performed a high-resolution genome-wide association study of serum soluble E-selectin levels in 685 white individuals with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study to identify major loci influencing levels. Highly significant evidence for association (P=10(-29)) was observed for rs579459 near the ABO blood group gene, accounting for 19% of the variance in E-selectin levels. Levels of E-selectin were higher in O/O than O/A heterozygotes, which were likewise higher than A/A genotypes. Analysis of subgroups of A alleles reveals heterogeneity in the association, and even after this was accounted for, an intron 1 SNP remained significantly associated. We replicate the ABO association in nondiabetic individuals., Conclusions: ABO is a major locus for serum soluble E-selectin levels. We excluded population stratification, fine-mapped the association to sub-A alleles, and also document association with additional variation in the ABO region.
Published: 2009
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40. Genetic analysis of chromosome 20-related posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three candidate genes.

Author: Hosseini SM, Herd S, Vincent AL, and Héon E
Subjects: Adult, Aged, Cell Cycle Proteins genetics, Cornea metabolism, DNA-Binding Proteins genetics, Exons, Eye Proteins metabolism, Fetus, Genetic Variation, Homeodomain Proteins metabolism, Humans, Infant, Infant, Newborn, Intracellular Signaling Peptides and Proteins genetics, Mutation, Neoplasm Proteins genetics, Protein Isoforms, RNA, Messenger, Repressor Proteins genetics, Sodium-Calcium Exchanger genetics, Chromosomes, Human, Pair 20, Corneal Dystrophies, Hereditary genetics, Eye Proteins genetics, Genetic Heterogeneity, Homeodomain Proteins genetics
Abstract: Purpose: Posterior polymorphous corneal dystrophy (PPCD) is a genetically heterogeneous autosomal dominant condition which maps to the pericentromeric region of chromosome 20. Mutations in the VSX1 transcription factor have been reported in patients affected with PPCD, keratoconus, or a combination of both phenotypes. However, no mutation was identified in the coding region of VSX1 in the family used for the original mapping. To clarify the genetic basis of PPCD1, a thorough analysis was performed on the original PPCD1 family and two other PPCD1-linked families. As part of the analysis, the expression profile, transcript variants, and evolutionary conserved regions of VSX1, a key candidate gene within the linkage interval, were characterized., Methods: Haplotype analysis was performed using highly informative markers on the pericentromeric region of chromosome 20. VSX1 transcript variants were identified using RT-PCR and characterized by 3'RACE assay. Temporal expression profile of VSX1 was evaluated using semi-quantitative real-time RT-PCR on human tissues. Evolutionary conserved regions (ECRs) were identified in the vicinity of VSX1 using publicly available sequence alignments (UCSC and rVista) and sequenced for mutation analysis., Results: Recombination events were identified that narrow the PPCD1-disease interval from 20 to 16.44 cM. This smaller interval includes the CHED1 locus and a recently described PPCD locus in Czech families. The three strongest candidate genes of the PPCD1-CHED1 overlap region (RBBP9, ZNF133, SLC24A3) did not show any mutations in our PPCD1-linked families. Semi-quantitative real-time RT-PCR detected VSX1 expression in neonatal human cornea. Six transcript variants of VSX1 were characterized. Four of the transcript variants spliced to two novel exons downstream of the gene. Mutation analysis of the PPCD1-linked families did not reveal any mutations in the full genomic sequence of VSX1 (considering all splice variants) or in the six cis- regulatory modules predicted in the vicinity of VSX1 (100 kb)., Conclusions: This is the first documentation of VSX1 expression in human neonatal cornea. We provide evidence for genetic heterogeneity of chromosome 20-related PPCD and refinement of the original PPCD1 interval. The full genomic sequence of VSX1 and coding exons of three other candidate genes were excluded from being pathogenic in the original PPCD1 family.
Published: 2008

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