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1. Direct inference and control of genetic population structure from RNA sequencing data

Author

Muhamad Fachrul, Abhilasha Karkey, Mila Shakya, Louise M. Judd, Taylor Harshegyi, Kar Seng Sim, Susan Tonks, Sabina Dongol, Rajendra Shrestha, Agus Salim, STRATAA study group, Stephen Baker, Andrew J. Pollard, Chiea Chuen Khor, Christiane Dolecek, Buddha Basnyat, Sarah J. Dunstan, Kathryn E. Holt, and Michael Inouye

Subjects
Biology (General), QH301-705.5
Abstract

Abstract RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood samples from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data.

Published
2023
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2. A five-safes approach to a secure and scalable genomics data repository

Author

Chih Chuan Shih, Jieqi Chen, Ai Shan Lee, Nicolas Bertin, Maxime Hebrard, Chiea Chuen Khor, Zheng Li, Joanna Hui Juan Tan, Wee Yang Meah, Su Qin Peh, Shi Qi Mok, Kar Seng Sim, Jianjun Liu, Ling Wang, Eleanor Wong, Jingmei Li, Aung Tin, Ching-Yu Cheng, Chew-Kiat Heng, Jian-Min Yuan, Woon-Puay Koh, Seang Mei Saw, Yechiel Friedlander, Xueling Sim, Jin Fang Chai, Yap Seng Chong, Sonia Davila, Liuh Ling Goh, Eng Sing Lee, Tien Yin Wong, Neerja Karnani, Khai Pang Leong, Khung Keong Yeo, John C. Chambers, Su Chi Lim, Rick Siow Mong Goh, Patrick Tan, and Rajkumar Dorajoo

Subjects
Genomics, Data encryption, Data storage representation, Science
Abstract

Summary: Genomic researchers increasingly utilize commercial cloud service providers (CSPs) to manage data and analytics needs. CSPs allow researchers to grow Information Technology (IT) infrastructure on demand to overcome bottlenecks when combining large datasets. However, without adequate security controls, the risk of unauthorized access may be higher for data stored on the cloud. Additionally, regulators are mandating data access patterns and specific security protocols for the storage and use of genomic data. While CSP provides tools for security and regulatory compliance, building the necessary controls required for cloud solutions is not trivial. Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud-native genomics data repository and analytics platform that implements a “five-safes” framework to provide security and governance controls to data contributors and users, leveraging CSP for sharing and analysis of genomic datasets without the risk of security breaches or running afoul of regulations.

Published
2023
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3. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

Author

Xuling Chang, Resham L. Gurung, Ling Wang, Aizhen Jin, Zheng Li, Renwei Wang, Kenneth B. Beckman, Jennifer Adams-Haduch, Wee Yang Meah, Kar Seng Sim, Weng Khong Lim, Sonia Davila, Patrick Tan, Jing Xian Teo, Khung Keong Yeo, Yiamunaa M., Sylvia Liu, Su Chi Lim, Jianjun Liu, Rob M. van Dam, Yechiel Friedlander, Woon-Puay Koh, Jian-Min Yuan, Chiea Chuen Khor, Chew-Kiat Heng, and Rajkumar Dorajoo

Subjects
Biology (General), QH301-705.5
Abstract

Xuling Chang et al. study whether low frequency variants are associated with leukocyte telomere length and whether these variants predispose to incident cancers and mortalities among East Asians. They find that three East Asian specific variants at POT1, TERF1 and STN1 loci are associated with leukocyte telomere length and report a mechanistic pathway linking TERF1, leukocyte telomere length and incident colon cancer.

Published
2021
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4. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies

Author

Rajkumar Dorajoo, Xuling Chang, Resham Lal Gurung, Zheng Li, Ling Wang, Renwei Wang, Kenneth B. Beckman, Jennifer Adams-Haduch, Yiamunaa M, Sylvia Liu, Wee Yang Meah, Kar Seng Sim, Su Chi Lim, Yechiel Friedlander, Jianjun Liu, Rob M. van Dam, Jian-Min Yuan, Woon-Puay Koh, Chiea Chuen Khor, and Chew-Kiat Heng

Subjects
Science
Abstract

Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

Published
2019
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5. Cross‐Ancestry Genome‐Wide Association Study Defines the Extended <scp> CYP2D6 </scp> Locus as the Principal Genetic Determinant of Endoxifen Plasma Concentrations

Author

Chiea Chuen Khor, Stefan Winter, Natalia Sutiman, Thomas E. Mürdter, Sylvia Chen, Joanne Siok Liu Lim, Zheng Li, Jingmei Li, Kar Seng Sim, Boian Ganchev, Diana Eccles, Bryony Eccles, William Tapper, Nathalie K. Zgheib, Arafat Tfayli, Raymond Chee Hui Ng, Yoon Sim Yap, Elaine Lim, Mabel Wong, Nan Soon Wong, Peter Cher Siang Ang, Rebecca Dent, Roman Tremmel, Kathrin Klein, Elke Schaeffeler, Yitian Zhou, Volker M. Lauschke, Michel Eichelbaum, Matthias Schwab, Hiltrud B. Brauch, Balram Chowbay, and Werner Schroth

Subjects
Pharmacology, Pharmacology (medical)
Abstract

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (N = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (N = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (N = 287, N = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (N = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability.

Published
2023

6. RAPTOR: A Five-Safes approach to a secure, cloud native and serverless genomics data repository

Author

Chih Chuan Shih, Jieqi Chen, Ai Shan Lee, Nicolas Bertin, Maxime Hebrard, Chiea Chuen Khor, Zheng Li, Joanna Hui Juan Tan, Wee Yang Meah, Su Qin Peh, Shi Qi Mok, Kar Seng Sim, Jianjun Liu, Ling Wang, Eleanor Wong, Jingmei Li, Aung Tin, Ching-Yu Cheng, Chew-Kiat Heng, Jian-Min Yuan, Woon-Puay Koh, Seang Mei Saw, Yechiel Friedlander, Xueling Sim, Jin Fang Chai, Yap Seng Chong, Sonia Davila, Liuh Ling Goh, Eng Sing Lee, Tien Yin Wong, Neerja Karnani, Khai Pang Leong, Khung Keong Yeo, John C Chambers, Su Chi Lim, Rick Siow Mong Goh, Patrick Tan, and Rajkumar Dorajoo

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Abstract

Genomic researchers are increasingly utilizing commercial cloud platforms (CCPs) to manage their data and analytics needs. Commercial clouds allow researchers to grow their storage and analytics capacity on demand, keeping pace with expanding project data footprints and enabling researchers to avoid large capital expenditures while paying only for IT capacity consumed by their project. Cloud computing also allows researchers to overcome common network and storage bottlenecks encountered when combining or re-analysing large datasets. However, cloud computing presents a new set of challenges. Without adequate security controls, the risk of unauthorised access may be higher for data stored on the cloud. In addition, regulators are increasingly mandating data access patterns and specific security protocols on the storage and use of genomic data to safeguard rights of the study participants. While CCPs provide tools for security and regulatory compliance, utilising these tools to build the necessary controls required for cloud solutions is not trivial as such skill sets are not commonly found in a genomics lab. The Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud native genomics data repository and analytics platform focusing on security and regulatory compliance. Using a “five-safes” framework (Safe Purpose, Safe People, Safe Settings, Safe Data and Safe Output), RAPTOR provides security and governance controls to data contributors and users leveraging cloud computing for sharing and analysis of large genomic datasets without the risk of security breaches or running afoul of regulations. RAPTOR can also enable data federation with other genomic data repositories using GA4GH community-defined standards, allowing researchers to boost the statistical power of their work and overcome geographic and ancestry limitations of data sets

Published
2022

7. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies

Author

Xuling Chang, Resham L Gurung, Rajkumar Dorajoo, Jianjun Liu, Woon-Puay Koh, Yechiel Friedlander, Kenneth B. Beckman, Chew-Kiat Heng, Wee Yang Meah, Jennifer M. Adams-Haduch, Renwei Wang, Zheng Li, Ling Wang, Sylvia Liu, Su Chi Lim, Chiea Chuen Khor, Yiamunaa M, Jian-Min Yuan, Kar Seng Sim, and Rob M. van Dam

Subjects
0301 basic medicine, Adult, Male, Candidate gene, DNA Repair, Science, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, TINF2, Biology, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, White People, Article, Cohort Studies, 03 medical and health sciences, Young Adult, Telomere Homeostasis, Asian People, Genetics research, Leukocytes, Genetics, SNP, Humans, Prospective Studies, lcsh:Science, Respiratory Tract Infections, Genetic association, Aged, Aged, 80 and over, Singapore, Multidisciplinary, General Chemistry, Middle Aged, Telomere, 021001 nanoscience & nanotechnology, Phenotype, 3. Good health, 030104 developmental biology, Telomeres, lcsh:Q, Female, 0210 nano-technology, Genome-Wide Association Study
Abstract

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P, Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

Published
2019

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

Author

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

Subjects
Male, medicine.medical_specialty, Genotype, genetic structures, Open angle glaucoma, Population, Black People, Glaucoma, Genome-wide association study, Polymorphism, Single Nucleotide, 01 natural sciences, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Interquartile range, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, 0101 mathematics, education, Adaptor Proteins, Signal Transducing, Aged, Original Investigation, education.field_of_study, Amyloid beta-Peptides, business.industry, 010102 general mathematics, Case-control study, General Medicine, Odds ratio, Middle Aged, medicine.disease, Immunohistochemistry, eye diseases, Case-Control Studies, Female, Risk assessment, business, Glaucoma, Open-Angle, Genome-Wide Association Study
Abstract

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Published
2019

9. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

Author

Woon-Puay Koh, Yiamunaa M, Chiea Chuen Khor, Ling Wang, Kar Seng Sim, Kenneth B. Beckman, Yechiel Friedlander, Jianjun Liu, Renwei Wang, Jian-Min Yuan, Resham L Gurung, Jennifer M. Adams-Haduch, Jing Xian Teo, Zheng Li, Rob M. van Dam, Sonia Davila, Sylvia Liu, Weng Khong Lim, Xuling Chang, Patrick Tan, Aizhen Jin, Wee Yang Meah, Khung Keong Yeo, Rajkumar Dorajoo, Chew-Kiat Heng, and Su Chi Lim

Subjects
0301 basic medicine, Adult, Male, QH301-705.5, Colorectal cancer, Population, Telomere-Binding Proteins, Medicine (miscellaneous), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Shelterin Complex, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Asian People, Neoplasms, Genetics research, medicine, Leukocytes, SNP, Missense mutation, Humans, Prospective Studies, Biology (General), education, Cancer, Aged, Genetics, Aged, 80 and over, education.field_of_study, Singapore, Telomere Homeostasis, Middle Aged, medicine.disease, Telomere, 030104 developmental biology, Cross-Sectional Studies, 030220 oncology & carcinogenesis, Chronic Disease, Adenocarcinoma, Female, General Agricultural and Biological Sciences
Abstract

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10−14–6.94×10−10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers., Xuling Chang et al. study whether low frequency variants are associated with leukocyte telomere length and whether these variants predispose to incident cancers and mortalities among East Asians. They find that three East Asian specific variants at POT1, TERF1 and STN1 loci are associated with leukocyte telomere length and report a mechanistic pathway linking TERF1, leukocyte telomere length and incident colon cancer.

Published
2021

10. Genome-Wide Analysis of Protein-Coding Variants in Leprosy

Author

Meiwen Yu, Guocheng Zhang, Jun Yang, Liangbin Yan, Zhenhua Yue, Gongqi Yu, Sebastian Maurer-Stroh, Jiabao You, Ningli Wang, Hong Liu, Yi Li, Wee Yang Meah, Lele Sun, Shumin Chen, Jianjun Liu, Astrid Irwanto, Kar Seng Sim, Wenting Liu, Jinlan Li, Yongxiang Yu, Chiea Chuen Khor, Zhenzhen Wang, Chuan Wang, Herty Liany, Zhongyi Zheng, De Yun Wang, Jianping Shen, Yong Ning, Wenjun Yu, Qing Zhao, Jian Liu, Furen Zhang, Jinghui Li, Honglei Wang, Xi'an Fu, Ling Wang, Anand Kumar Andiappan, Jia Nee Foo, Rongde Yang, Tongsheng Chu, Vachiranee Limviphuvadh, Li Shi, Chaolong Wang, Guiye Niu, Xiujun Cheng, Zihao Mi, Yonghu Sun, Tin Aung, Fangfang Bao, and Na Wang

Subjects
Male, 0301 basic medicine, China, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Dermatology, Filaggrin Proteins, Biology, Polymorphism, Single Nucleotide, Biochemistry, Cohort Studies, 03 medical and health sciences, Asian People, Gene Frequency, Phagocytosis, Polymorphism (computer science), Leprosy, Genetic variation, Autophagy, Humans, Exome, Genetic Predisposition to Disease, Molecular Biology, Allele frequency, Alleles, Skin, Genetic association, Genetics, Case-control study, Genetic Variation, Reproducibility of Results, Cell Biology, Endocytosis, CARD Signaling Adaptor Proteins, 030104 developmental biology, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD ( P = 1.71 × 10 –9 , odds ratio [OR] = 4.35) and rs149308743 in CARD9 ( P = 2.09 × 10 –8 , OR = 4.75); three low-frequency variants: rs76418789 in IL23R ( P = 1.03 × 10 –10 , OR = 1.36), rs146466242 in FLG ( P = 3.39 × 10 –12 , OR = 1.45), and rs55882956 in TYK2 ( P = 1.04 × 10 –6 , OR = 1.30); and two common variants: rs780668 in SLC29A3 ( P = 2.17 × 10 –9 , OR = 1.14) and rs181206 in IL27 ( P = 1.08 × 10 –7 , OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.

Published
2017

11. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K, Khan, Muhammad Imran, Olawoye, Olusola O, Ashaye, Adeyinka O, Ugbede, Idakwo, Onakoya, Adeola, Kizor Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J, Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Grossmann, Rodolfo Perez, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A, Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W, Coote, Michael, Crowston, Jonathan G, Astakhov, Sergei Y, Akopov, Eugeny L, Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al Obeidan, Saleh A, Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q, Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O, Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su Ling, Hillmer, Axel M, Cheng, Ching Yu, Escudero Domínguez, Francisco A, González Sarmiento, Rogelio, Martinon Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Nari, Sakuntabhai, Anavaj, Nguyn, Hip X, Nguyn, Giang T. T, Nguyn, Trình V, Zenz, Werner, Binder, Alexander, Klobassa, Daniela S, Hibberd, Martin L, Davila, Sonia, Herms, Stefan, Nöthen, Markus M, Moebus, Susanne, Rautenbach, Robyn M, Ziskind, Ari, Carmichael, Trevor R, Ramsay, Michele, Álvarez, Lydia, García, Montserrat, González Iglesias, Héctor, Rodríguez Calvo, Pedro P, Cueto, Luis Fernández Vega, Oguz, Çilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasım, Burcu, Wilson, M. Roy, Coleman, Anne L, Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W, Kuchtey, John, Curtin, Karen, Chaya, Craig J, Crandall, Alan, Zangwill, Linda M, Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I, Vesti, Eija, Fingert, John H, Lee, Richard K, Sit, Arthur J, Shingleton, Bradford J, Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak Vance, Margaret A, Raychaudhuri, Soumya, Heegaard, Steffen, Kivelä, Tero, Reis, André, Kruse, Friedrich E, Weinreb, Robert N, Pasquale, Louis R, Haines, Jonathan L, Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N, Micheal, Shazia, Topouzis, Foti, Craig, Jamie E, Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L, Pasutto, Francesca, Khor, Chiea Chuen, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Helsinki

Subjects
0301 basic medicine, Male, Calcium Channels/genetics, Messenger, Medizin, PSEUDOEXFOLIATION SYNDROME, Genome-wide association study, BLOOD-PRESSURE, Disease, Exfoliation Syndrome, Eye, Exfoliation Syndrome/ethnology/genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, PARKINSONS-DISEASE, 80 and over, ta319, Missense mutation, Genetics, Aged, 80 and over, Amino Acid Oxidoreductases/genetics/physiology, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Extracellular Matrix, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Haplotypes, Humans, Molecular Chaperones, RNA, Messenger, Spheroids, Cellular, Genome-Wide Association Study, Mutation, Missense, Point Mutation, Metaanalysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, ALZHEIMERS-DISEASE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Chaperones/biosynthesis/genetics, Biology, SYNONYMOUS MUTATIONS, ta3111, Article, 03 medical and health sciences, Asian People, Asian Continental Ancestry Group/genetics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Eye/metabolism, Aged, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Individuals, Glaucoma, Odds ratio, Extracellular Matrix/metabolism, RNA, Messenger/biosynthesis, MACULAR DEGENERATION, RISK LOCI, eye diseases, COMMON SEQUENCE VARIANTS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030221 ophthalmology & optometry, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cellular, Spheroids, Missense, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Polymorphisms, purl.org/pe-repo/ocde/ford#1.06.07 [https], INFLAMMATORY-BOWEL-DISEASE
Abstract

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017

12. Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye

Author

Mineo Ozaki, Marcelo T. Nicolela, Theofanis Pappas, Fotis Topouzis, Andrés Fernández-Vega Cueto, Panayiota Founti, Eray Atalay, Nilgun Yildirim, Chie Sotozono, Christina Keskini, Yosai Mori, Luis Fernández-Vega Cueto, Andrew C. Orr, Murat Irkec, Yuanhan Li, Deepak P. Edward, Satoko Nakano, Yury S. Astakhov, Tsutomu Ohashi, Daniel Gaston, George Chichua, Evangelia S Panagiotou, Ursula Schlötzer-Schrehardt, Jae H. Kang, Sergo Tabagari, Federico Martinón-Torres, Akitoshi Yoshida, Lesya M. Shuba, Masaru Inatani, Ken Hayashi, Takako Sugimoto, Shamira A. Perera, Takanori Mizoguchi, Kar Seng Sim, Friedrich E. Kruse, Shin-ichi Manabe, Andreas Giessl, Joseph Saunders, Ewa Kosior-Jarecka, Christian Y. Mardin, Wai Leong Tam, Hui Meng Soo, Makoto Aihara, Yoshiaki Kiuchi, Tomomi Higashide, Wee Yang Meah, Rahat Husain, Tin Aung, Sergei Y. Astakhov, Zheng Li, Dimitrios G. Mikropoulos, André Reis, Eleftherios Anastasopoulos, Jessica N. Cooke Bailey, Anastasios G. P. Konstas, Toshiya Sakurai, Dilek Aktas, Montserrat García, Bilge Batu, Hideki Chuman, Shigeru Kinoshita, Matthias Zenkel, Ying Swan Ho, Nevbahar Tamçelik, Masakazu Nakano, Jonathan L. Haines, Nino Kobakhidze, Kazuhiko Mori, Esther Kai Lay Peh, Francesca Pasutto, Georg Mossböck, Anthi Chatzikyriakidou, Robert P. Igo, Etsuo Chihara, Kazuhisa Sugiyama, Janey L. Wiggs, Michael V. Dubina, Shuwen Chen, Paul E Rafuse, Xiao Yin Chen, Trevor R. Carmichael, Kei Tashiro, Miguel Coca-Prados, Claus Hellerbrand, Shigeyasu Kazama, Çilingir Oguz, Alexandros Lambropoulos, Patrick Tan, Michael A. Hauser, Burcu Kasım, Michèle Ramsay, Morio Ueno, Kana Tokumo, Kenji Inoue, Robert Ritch, Tomasz Zarnowski, Toshiaki Kubota, Sonia Davila, Steffen Heegaard, Ryuichi Ideta, Lydia Álvarez, Yoko Ikeda, Chiea Chuen Khor, Susan Williams, Satoshi Ishiko, Louis R. Pasquale, Eugeny L. Akopov, Antonio Salas, Alina Popa-Cherecheanu, Monisha E. Nongpiur, Héctor González-Iglesias, Urszula Lukasik, Jia Nee Foo, Augustine Cheong, Zhenxun Wang, Mei Chin Lee, Anita Chan, and Kazunori Miyata

Subjects
Risk, Loxl1, medicine.medical_specialty, Glaucoma, Gene, 01 natural sciences, Exfoliation syndrome, 03 medical and health sciences, Low-Frequency, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Disease, 030212 general & internal medicine, 0101 mathematics, Exfoliation (botany), Exome sequencing, Original Investigation, business.industry, Protein, 010102 general mathematics, Case-control study, General Medicine, Odds ratio, medicine.disease, Pseudoexfoliation Syndrome, Susceptibility, Cohort, business
Abstract

IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 x 10(-6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 x 10(-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4%[interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings. National Research Foundation of SingaporeNational Research Foundation, Singapore [NRF-NRFI2018-01]; US National Eye Institute of the National Institutes of Health [R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, EY015473]; Glaucoma Research Foundation of Canada [X052, CIRG17may053]; National Medical Research Council of SingaporeNational Medical Research Council, Singapore The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.

Published
2021

13. Variation at HLA-DRB1 is associated with resistance to enteric fever

Author

Jeremy Farrar, Tin Aung, Amit Arjyal, Nguyen Phu Huong Lan, Kar Seng Sim, Le Thi Phuong, Trinh T. B. Tram, Phat Voong Vinh, Cameron P. Simmons, Soumya Raychaudhuri, Stephen Baker, Tran Tinh Hien, Nguyen Tran Chinh, Jia Nee Foo, Nga Tran Vu Thieu, Buddha Basnyat, Zheng Li, Nguyen Thi Hue, Abhilasha Karkey, Yukinori Okada, Katherine L. Anders, Do Nu Hon, Sarah J. Dunstan, Martin L. Hibberd, Olita Shilpakar, Christopher M. Parry, Yik Ying Teo, Ha Vinh, Paul I.W. de Bakker, Chiea Chuen Khor, Buhm Han, Mai Ngoc Lanh, Tan Do, Christiane Dolecek, Sabina Dongol, and Samir Koirala

Subjects
Genetic Markers, Genotype, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Typhoid fever, Article, Nepal, Genetics, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Allele, Typhoid Fever, HLA-DRB1, Alleles, Antigen Presentation, Principal Component Analysis, Models, Statistical, Chromosome Mapping, Odds ratio, medicine.disease, Virology, Minor allele frequency, Vietnam, Genetic marker, Immunology, biology.protein, Regression Analysis, Biomarkers, HLA-DRB1 Chains
Abstract

Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C1. We conducted a genome-wide association study of 432 individuals with blood culture–confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10−10), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10−11) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.

Published
2016

14. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study

Author

Miriam Tao, Suk Teng Chin, Li Na Feng, Richard Quek, Choon Kiat Ong, Yukinori Okada, Yi Xin Zeng, Qing Qing Cai, Yan Hui Liu, Lay Poh Khoo, Wen Sheng Liu, Yurike Laurensia, Wee Yang Meah, Fen Zhang, Maarja-Liisa Nairismagi, Jing Cui, Soo Yong Tan, Wee Joo Chng, Richard P. Ebstein, Jeslin Chian Hung Ha, Farid Mohamad, Kar Seng Sim, Soumya Raychaudhuri, Rou Jun Peng, Yi Xia, Jia Nee Foo, Chi Pui Pang, Colin Phipps Diong, Qi Sheng Feng, Li Zhen Chen, Jianjun Liu, Tiffany Tang, Siok Bian Ng, Soon Thye Lim, Chiea Chuen Khor, Soo Hong Chew, Jin Xin Bei, Wen Tan, Tin Aung, Balram Chowbay, Hong Min Li, Yun Miao Guo, Bin Tean Teh, Jie Rong Chen, Zheng Li, and Li Jia Chen

Subjects
0301 basic medicine, Adult, Male, Linkage disequilibrium, China, Herpesvirus 4, Human, Lymphoma, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Risk Factors, Biomarkers, Tumor, Medicine, Humans, Genetic Predisposition to Disease, Young adult, Aged, Neoplasm Staging, business.industry, Haplotype, Case-control study, Odds ratio, Middle Aged, Prognosis, Lymphoma, Extranodal NK-T-Cell, Killer Cells, Natural, 030104 developmental biology, Oncology, Case-Control Studies, Natural Killer T-Cells, Female, business, Imputation (genetics), Demography, Follow-Up Studies, Genome-Wide Association Study
Abstract

Summary Background Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. Methods We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Findings Associations exceeding the genome-wide significance threshold (p −8 ) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1 ) having the strongest association with NKTCL susceptibility (p=4·21 × 10 −19 , odds ratio [OR] 1·84 [95% CI 1·61–2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10 −14 ). This association is distinct from MHC associations with Epstein-Barr virus infection. Interpretation To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. Funding Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).

Published
2016

15. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma

Author

Tina T. Wong, Yaan Fun Chong, Kathryn P. Burdon, Sancy Low, Ningli Wang, Tuan Anh Tran, Emma Rusmayani, Alexander C Day, Kei Tashiro, Tam Thi Luu, Aye Thi Han, Christine A. Kiire, Nay Lin Oo, Hiroshi Sakai, Ewa Kosior-Jarecka, Sripriya Sarangapani, Mimiwati Zahari, Widya Artini Wiyogo, Seng-Chee Loon, Rigo Daniel Reyes, Rrima Dada, Robert Ritch, E-Shyong Tai, Jin-Xin Bei, Ren-Yi Wu, Balekudaru Shantha, Leyla Al-Jasim, Giulia Consolandi, Ya Xing Wang, Saleh A. Al-Obeidan, Tomasz Zarnowski, Shazia Micheal, Maria Luisa Guevara-Fujita, Raquel Quino, Yuzhen Jiang, Monisha E. Nongpiur, Yik Y. Teo, Francesca Pasutto, Hailin Meng, Mani Baskaran, Shigeru Kinoshita, Sunee Chansangpetch, Clement C Y Tham, Eranga N. Vithana, Paul J. Foster, Greet J. Boland, Deepak P. Edward, Young Hoon Hwang, Daniel H. Su, Ricardo Fujita, Huan Nguyen Pham, Yong Ho Sohn, Mark Seielstad, Rengaraj Venkatesh, Paul Mitchell, Morio Ueno, Chaw Chaw Khaing, Thanh Thu Nguyen, Celso Tello, Anita S. Chan, Muhammad Imran Khan, Vernon Yong, Eileen Png, Takanori Mizoguchi, Nguyen Van Vinh Chau, Soo Hong Chew, Laura Dallorto, Chunyan Qiao, Donald T.H. Tan, Norlina Ramli, Mei Chin Lee, Rahat Husain, Kar Seng Sim, Sarah J. Dunstan, Kyu Hyung Park, Stephen A Vernon, Thi Nguyen, Rodolfo A. Perez-Grossmann, Jelinar Mohamed-Noor, Jeeyun Ahn, David Lozano-Giral, Tan Do, Yin Mon Aung, Prin Rojanapongpun, Naris Kitnarong, Martin L. Hibberd, Chan-Yun Kim, Mineo Ozaki, Manchima Makornwattana, Ronnie George, José Paulo Cabral de Vasconcellos, Huong T T Bui, Chona S Liao, Saw Htoo Set, Chi Pui Pang, Paul T K Chew, Aliza Jap, Naushin Waseem, Toshiaki Kubota, Tanuj Dada, Hyoung Won Bae, Tin Aung, Ricardo Y. Abe, Khin Thida Oo, Periasamy Sundaresan, Jose Maria Martinez, Visanee Tantisevi, Shomi S. Bhattacharya, Anneke I. den Hollander, Vira Wardhana Istiantoro, Rohit Shetty, Boonsong Wanichwecharungruang, Liang Xu, Seng Kheong Fang, Masakazu Nakano, E. Randy Craven, Richard P. Ebstein, Ching-Lin Ho, Arkasubhra Ghosh, Jeanne J. Ogle, Hongyan Jia, Muneeb A. Faiq, Yasuo Kurimoto, Michiko Yonahara, Richard Stead, Li Jia Chen, Satoko Nakano, Anavaj Sakuntabhai, Masako Kuroda, Thayanithi Sandragasu, Leonard W. Yip, Lerprat Mangkornkanokpong, Pancy O. S. Tam, Seang-Mei Saw, Ching-Yu Cheng, Saravanan Vijayan, Jia Nee Foo, M B Melo, Wing Lau Ho, Ahmad Tajudin Liza-Sharmini, Alex W. Hewitt, Mary Ann T Catacutan, Carlo Lavia, Curt Hartleben-Matkin, Hon-Tym Wong, Daniela Paoli, Srinivasan Kavitha, Su Nyunt Zaw, Soon Thye Lim, Owen Hee, Yee Yee Aung, Shuang Ru Goh, Chiea Chuen Khor, Maria Cecilia Aquino, Jonathan C.H. Chan, Buddha Basnyat, Zeiras Eka Djamal, Nhu Hon Do, Tuyet Bach Trinh, John H. Fingert, Z. Xie, Thi Lam Huong Dao, Urszula Lukasik, Bruno Batista de Souza, Khaled K. Abu-Amero, Yoko Ikeda, Guillermo Barreto Fong, Eng Hui Gan, Guangxian Tang, Sami Al-Shahwan, Tien Dat Tran, Jost B. Jonas, Xiao Yin Chen, Nagaswamy Soumittra, David Goh, Ramanjit Sihota, Xiao-Yu Ng, Ki Ho Park, Mona S Awadalla, Sujie Fan, Edgar U Leuenberger, Hlaing May Than, Jimmy S. M. Lai, Yi Xin Zeng, Shamira A. Perera, Bonnie Nga Kwan Choy, Jie Jin Wang, Roopam Duvesh, Antonio Maria Fea, Anita Manassakorn, Victor H. K. Yong, Abhilasha Karkey, John F Salmon, Kessara Pathanapitoon, Raheel Qamar, Juan Carlos Zenteno, Jin Wook Jeoung, Jovell Ian M Peregrino, Harm Snippe, Yaakub Azhany, Humaira Ayub, Vania Castro Tamanaja, Paolo Frezzotti, Tung S Hoan, Rajesh S. Kumar, Chelvin C A Sng, Jamie E Craig, Anuwat Prutthipongsit, Vital Paulino Costa, Subbiah. R. Krishnadas, Kuldeep Mohanty, Michael A. Hauser, Vi Huyen Doan, Irene R Felarca, Lingam Vijaya, Jennifer W. H. Shum, Farah Akhtar, R. Rand Allingham, Nuttamon Srisamran, Desmond Quek, Huaizhou Wang, Thipnapa Patthanathamrongkasem, Giulia Pignata, Suman S Thapa, Kazuhiko Mori, Jamil Miguel Neto, Tien Yin Wong, Boon-Ang Lim, Zheng Li, Genome Institute of Singapore (GIS), National University of Singapore (NUS), Vietnam National Institute of Ophthalmology (VNIO), Beijing Tongren Hospital, Kyoto University [Kyoto], Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This research is supported by the Singapore Ministry of Health's National Medical Research Council under its Translational and Clinical Research (TCR) Flagship Programme Grant Stratified Medicine for Primary Angle Closure Glaucoma (NMRC/TCR/008-SERI/2013) and the Singapore Translational Research (STaR) Investigator Award Singapore Angle Closure Glaucoma Program Characterization, Prevention, and Management (NMRC/STAR/0023/2014), as well as the Biomedical Research Council, Agency for Science, Technology and Research (A-STAR), Singapore. A.T.L.-S. gratefully acknowledges support from grants RUI 1001/PPSP/812101 and RUI 1001/PPSP/812152 from the Universiti Sains Malaysia. H.J., C.Q., and N. Wang acknowledge support from the Program of Beijing Scholars (2013), Leading Talents–High-Level Talents of the Health System of Beijing (2009-1-05), and the National Major Scientific and Technological Special Project for 'Significant New Drugs Development' (2011ZX09302-007-05), as well as Project of the National Natural Science Foundation of China (81570837) grants., Kyoto University, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, MESH: Gene Expression, Genotype, Population, Gene Expression, Glaucoma, Genome-wide association study, Biology, Primary angle-closure glaucoma, MESH: Genetic Loci, Cell Line, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, education, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Genetic Predisposition to Disease, Chromosome Mapping, Odds ratio, medicine.disease, MESH: Male, 3. Good health, MESH: Cell Line, 030104 developmental biology, Genetic Loci, MESH: Genome-Wide Association Study, 030221 ophthalmology & optometry, Susceptibility locus, MESH: Glaucoma, Angle-Closure, Female, Glaucoma, Angle-Closure, MESH: Chromosome Mapping, MESH: Female, Genome-Wide Association Study
Abstract

International audience; Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Published
2016

16. Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies

Author

Federico Martinón-Torres, Ana Vega, J I Muñoz Bonet, Á Ortega, J López-Bayón, Sara Pischedda, Martin L. Hibberd, M C León León, A B Arriortua, C P Caballero Macarrón, M L Millán Miralles, Victoria J. Wright, Simon Nadel, Kar Seng Sim, E E Torné, Nazareth Martinón-Torres, García, A H Doce, F G Sánchez, Ruth Barral-Arca, Dominguez, R Payo, F P Sánchez, J M Sánchez Granados, Carmen Rodríguez-Tenreiro, E Morteruel, M S Cancela, Á Barba, N G Sánchez, M. J. Curras-Tuala, Jacobo Pardo-Seco, E O Bergara, M L Navarro Gómez, David Inwald, S P Rosso, Sergio Alonso, Marcela Fernández, Garzón Mgr., A R Romero, J De La Cruz Moreno, Antonio Salas, García Mdmb., A J Grande, C C Monge, A C Torre, Enitan D. Carrol, S C Palazón, Laura Fachal, N M Menchón, J L García Rodríguez, M O Pallares, Michael Levin, Sonia Davila, O S Ayestarán, Alberto Gómez-Carballa, Chiea Chuen Khor, Irene Rivero Calle, Miriam Cebey, De Aguilar Pag., Eileen Png, Angel Carracedo, José María Martinón-Sánchez, Xavier Martinez, Martínez-Padilla Mdc., Lorenzo Redondo-Collazo, Fachal Vilar, Laura [0000-0002-7256-9752], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Databases, Factual, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Disease, Meningococcal disease, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Odds Ratio, Missense mutation, SNP, Humans, genetics, 030212 general & internal medicine, Genetics, Multidisciplinary, business.industry, Odds ratio, medicine.disease, Immunity, Innate, 3. Good health, Meningococcal Infections, 030104 developmental biology, Genetic Loci, Spain, Meta-analysis, Complement Factor H, genetic association study, business, Genome-Wide Association Study
Abstract

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10−8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52–0.73; P-value = 9.62 × 10−9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55–0.76, P-value = 3.25 × 10−8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

Published
2016

17. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy

Author

Kar Seng Sim, Rongshan Li, Li Zhu, Xianyong Yin, Hong Zhang, Jian Xin Wan, Jin Quan Wang, Jianjun Liu, Jian Chen, Wei Wang, Xue Qing Tang, Zhi Jian Li, Li Fan, Ming Li, Xin Wei, Zhang Suo Liu, Xuejun Zhang, Xueqing Yu, Yi Li, Hui Qi Low, Liangdan Sun, Xiao Jun Huang, Liu Zhihong, Jia Nee Foo, and Tan Qi Lou

Subjects
Male, alpha-Defensins, Tumor Necrosis Factor Ligand Superfamily Member 13, Genome-wide association study, Single-nucleotide polymorphism, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Nephropathy, Major Histocompatibility Complex, Asian People, Polymorphism (computer science), Genetics, medicine, Humans, Genetic Predisposition to Disease, Proteinuria, Case-control study, Glomerulonephritis, IGA, Glomerulonephritis, medicine.disease, Immunoglobulin A, Genetic Loci, Case-Control Studies, Immunology, biology.protein, Female, medicine.symptom, Genome-Wide Association Study
Abstract

We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10(-11), OR = 1.21; rs4227, P = 4.31 × 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10(-20), OR = 1.34; rs1794275, P = 3.43 × 10(-13), OR = 1.30; rs2523946, P = 1.74 × 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.

Published
2011

18. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Author

Hsin Chi, Nagib Dahdah, Paul Mitchell, J Ottenkamp, Luan-Yin Chang, Min Seob Song, Adriana H. Tremoulet, Fu Yuan Huang, Kar Seng Sim, Jer-Yuarn Wu, Xiao Jing Ma, Kwi Joo Kim, Kao Pin Huang, Pamela Palasanthiran, Gi Young Jang, Stanford T. Shulman, Young Mi Hong, Rolando Cimaz, Maarten H Biezeveld, Frank T. Christiansen, Yu-Lung Lau, Jie Jin Wang, Luc Filippini, Judy Geissler, Myung Ki Han, Robert Booy, Paul A. Brogan, Chi Di Liang, Betau Hwang, Jane W. Newburger, Miranda Odam, Ho-Chang Kuo, Ming-Ren Chen, Yhu Chering Huang, Hyoung Doo Lee, Elena Rochtchina, Jae-Jung Kim, Wilbert H. Mason, Clare Nourse, Hyo Kyoung Nam, John Attia, Taco W. Kuijpers, Jung Hye Byeon, Vanita Shah, Li-Min Huang, Ananth C. Viswanathan, Willemijn B. Breunis, Jeng Sheng Chang, Junxiong Pang, Sin Weon Yun, Kee Soo Ha, Elizabeth G. Holliday, Tien Yin Wong, David Burgner, Dong Soo Kim, Colin Michie, Rodney J. Scott, Michael Levin, Ja Young Hwang, Stephen B. Harrap, Paul N. Goldwater, Delane Shingadia, Jane C. Burns, Meng Luen Lee, Michael D. Nissen, Anu Bose, Jae Moo Lee, Sejung Sohn, Martin L. Hibberd, Jung Woo Rhim, Nigel Klein, Marian E. Melish, Young-Mi Park, Kyung-Yil Lee, In Sook Park, Irene M. Kuipers, Yi-Ching Lee, Guo Ying Huang, Thomas Mukasa, Nan Chang Chiu, Jing Zhang, Fuu Jen Tsai, Chiea Chuen Khor, Jeong Jin Yoo, Yiu-fai Cheung, Pi Chang Lee, Rae S. M. Yeung, Chisato Shimizu, Sonia Davila, Annette L. Baker, Nigel Curtis, Soo-Jong Hong, M J Dillon, Lin Wu, Carline E. Tacke, Jong-Keuk Lee, John B. Ziegler, Masato Takahashi, Robert Tulloh, Fang Liu, Victoria J. Wright, Wanling Yang, Dennis E.K. Tan, Anne H. Rowley, Campbell S. Witt, AII - Amsterdam institute for Infection and Immunity, General Paediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, ACS - Amsterdam Cardiovascular Sciences, Paediatric Cardiology, and Other departments

Subjects
Linkage disequilibrium, Population, Locus (genetics), Genome-wide association study, Mucocutaneous Lymph Node Syndrome, FCGR2A, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Pathogenesis, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Principal Component Analysis, education.field_of_study, Receptors, IgG, medicine.disease, Haplotypes, Chromosomes, Human, Pair 1, Genetic Loci, Case-Control Studies, Multigene Family, Immunology, Kawasaki disease, Chromosomes, Human, Pair 19, Genome-Wide Association Study
Abstract

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Published
2011

19. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease

Author

Chiea Chuen Khor, Peter W. M. Hermans, David Inwald, Enitan D. Carrol, Taco W. Kuijpers, Marieke Emonts, Victoria J. Wright, Chui Chin Lim, Kar Seng Sim, Sonia Davila, Ronald de Groot, Jan A. Hazelzet, Antonio Salas, Martin L. Hibberd, Willemijn B. Breunis, Simon Nadel, A. Binder, Federico Martinón-Torres, Werner Zenz, Michael Levin, Helen Betts, Paediatric Infectious Diseases / Rheumatology / Immunology, Paediatric Oncology, AII - Amsterdam institute for Infection and Immunity, and Pediatrics

Subjects
Adult, Male, Adolescent, Genetic Linkage, Population, CHILDREN, HAPLOTYPE, Single-nucleotide polymorphism, Genome-wide association study, Complement factor I, Neisseria meningitidis, Biology, medicine.disease_cause, Meningococcal disease, Polymorphism, Single Nucleotide, COMPLEMENT FACTOR-H, Young Adult, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, education, SYSTEMIC MENINGOCOCCEMIA, RISK, education.field_of_study, Infant, Newborn, Infant, Middle Aged, MACULAR DEGENERATION, medicine.disease, Complement system, Pathogenesis and modulation of inflammation [N4i 1], Meningococcal Infections, Case-Control Studies, Child, Preschool, Complement Factor H, Factor H, Host-Pathogen Interactions, Immunology, 4G/5G PROMOTER POLYMORPHISM, Female, Infection and autoimmunity [NCMLS 1], PLASMINOGEN-ACTIVATOR-INHIBITOR-1 GENE, Genome-Wide Association Study
Abstract

Contains fulltext : 88509.pdf (Publisher’s version ) (Closed access) Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D

Published
2010

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

Author

Liang Xu, Jessica N. Cooke Bailey, Seyhan Yazar, Janey L. Wiggs, Jost B. Jonas, Victor Koh, Adriana I Iglesias, Yik Ying Teo, Henriët Springelkamp, Tim D. Spector, Puya Gharahkhani, Tin Aung, Nomdo M. Jansonius, Chiea Chuen Khor, Jonathan L. Haines, André G. Uitterlinden, Xiaoyan Luo, René Höhn, Arne Schillert, Paul G. Sanfilippo, Abhishek Nag, Christopher J Hammond, Louis R. Pasquale, Albert Hofman, Hannah Forward, Pirro G. Hysi, Hans G Lemij, Lisa S. Kearns, Ben A. Oostra, Elisabeth M. van Leeuwen, Ayse Demirkan, Caroline C W Klaver, Paulus T. V. M. de Jong, Ching-Yu Cheng, Najaf Amin, E-Shyong Tai, Roger C. W. Wolfs, Alex W. Hewitt, Stuart MacGregor, Cornelia M. van Duijn, Tiger Zhou, Wishal D. Ramdas, Fernando Rivadeneira, Jamie E Craig, Kathryn P. Burdon, David A. Mackey, Seng-Chee Loon, Norbert Pfeiffer, Johannes R. Vingerling, Sven J. van der Lee, Aniket Mishra, Kar Seng Sim, Terri L. Young, Tien Yin Wong, Seang-Mei Saw, Eranga N. Vithana, Karl J. Lackner, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, MUMC+: MA UECM Oogartsen ZL (9), MUMC+: MA UECM Oogartsen MUMC (9), RS: FHML non-thematic output, Netherlands Institute for Neuroscience (NIN), and Perceptual and Cognitive Neuroscience (PCN)

Subjects
Aging, genetic structures, Epidemiology, Optic disk, Glaucoma, Genome-wide association study, Neurodegenerative, Eye, Optic neuropathy, Optic Nerve Diseases, NERVE, GWAS, Genetics (clinical), Genetics, NEIGHBORHOOD Consortium, ATOH7, Asians, medicine.anatomical_structure, cup area, Optic nerve, Public Health and Health Services, OPEN-ANGLE GLAUCOMA, TRAITS, Optic disc, Asian Continental Ancestry Group, medicine.medical_specialty, Open angle glaucoma, European Continental Ancestry Group, Optic Disk, Quantitative Trait Loci, Biology, OCULAR-TISSUES, Retinal ganglion, Article, White People, Asian People, Ophthalmology, medicine, Humans, disc area, Eye Disease and Disorders of Vision, Whites, Human Genome, Neurosciences, GENOTYPES, medicine.disease, GENE, eye diseases, SIZE, glaucoma, sense organs, Genome-Wide Association Study
Abstract

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma. ? 2015

Published
2015

21. Corrigendum: New loci and coding variants confer risk for age-related macular degeneration in East Asians

Author

Peiquan Zhao, Ranjana Mathur, Rob M. van Dam, Nagahisa Yoshimura, Chui Ming Gemmy Cheung, Tock Han Lim, Jin Xin Bei, Kyu Hyung Park, Woon-Puay Koh, Eranga N. Vithana, Tomohiro Iida, Isao Nakata, Peng Chen, Suk-Kyun Yang, Chang Hua Wong, Dong Ho Park, Lulin Huang, Yasuo Kurimoto, Mayuri Bhargava, Norimoto Gotoh, Jian-Min Yuan, Woohyok Chang, Xin Jin, Gavin Tan, Jia Nee Foo, Masahiro Miyake, Min Sagong, Se Joon Woo, Kar Seng Sim, Hiroyuki Iijima, Tin Aung, Kenji Yamashiro, Yaoyao Sun, Mineo Ozaki, Lingam Gopal, Li Jia Chen, Sang Joon Lee, Bowen Zhao, E. Shyong Tai, Yoichi Sakurada, Jiemin Liao, Sang Jun Park, Xiongze Zhang, Chi Pui Pang, Xuefeng Xie, Shigeru Honda, Chew-Kiat Heng, Fang Lu, Ching-Yu Cheng, Yi Li, Rajkumar Dorajoo, Jinghong Sang, Lvzhen Huang, Junxiong Pang, Timothy Y Y Lai, Paul Mitchell, Shibo Tang, Takinori Mizoguchi, Yechiel Friedlander, Hyun Woong Kim, Peng Guan Ong, Shin Yoneya, Pancy O. S. Tam, Yik Ying Teo, Joo Young Shin, Bo Gong, Akitaka Tsujikawa, Jeeyun Ahn, Seang-Mei Saw, Peter Cackett, Sonia Davila, Chiea Chuen Khor, Keisuke Mori, Yi Xin Zeng, Thet Naing, Ningli Wang, Kyuyoung Song, Choi Mun Chan, Yi Shi, Xiaoxin Li, Jianjun Liu, Yin Lin, Martin L. Hibberd, In Taek Kim, Boon Kwang Loh, Fumihiko Matsuda, Feng Wen, Xiaoyan Ding, Augustinus Laude, Junpu Mei, Haoyu Chen, Zhenglin Yang, Jinlong Liang, Hum Chung, Adrian Koh, Yumiko Akagi-Kurashige, Shu Yen Lee, Ji Eun Lee, Hideo Nakanishi, Tien Yin Wong, Ian Yeo, Hyeong Gon Yu, Peng Zhou, and Doric Wong

Subjects
Research program, medicine.medical_specialty, media_common.quotation_subject, General Physics and Astronomy, Coronary Disease, Bioinformatics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, Macular Degeneration, Asian People, Risk Factors, Age related, Political science, medicine, Humans, Exome, Genetic Predisposition to Disease, media_common, Multidisciplinary, Cholesterol, HDL, Health technology, Reproducibility of Results, General Chemistry, Corrigenda, Cholesterol Ester Transfer Proteins, Genetic Loci, Family medicine, Case-Control Studies, Mutation, Christian ministry, Welfare, Genome-Wide Association Study
Abstract

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

Published
2015

22. New loci and coding variants confer risk for age-related macular degeneration in East Asians

Author

Yumiko Akagi-Kurashige, Yasuo Kurimoto, Feng Wen, Yi Xin Zeng, Min Sagong, Ji Eun Lee, Rob M. van Dam, Junpu Mei, Nagahisa Yoshimura, Ching-Yu Cheng, Eranga N. Vithana, Joo Young Shin, Kyu Hyung Park, Doric Wong, Mayuri Bhargava, Yi Li, Jian-Min Yuan, Gavin Tan, Se Joon Woo, Hideo Nakanishi, Jianjun Liu, Zhenglin Yang, Chui Ming Gemmy Cheung, Tien Yin Wong, Yik Ying Teo, Jiemin Liao, Bo Gong, Tin Aung, Shibo Tang, Woohyok Chang, Tomohiro Iida, Peng Chen, Boon Kwang Loh, Chang Hua Wong, Paul Mitchell, Lingam Gopal, Yechiel Friedlander, Jeeyun Ahn, Fang Lu, Hyun Woong Kim, Yi Shi, Shin Yoneya, Thet Naing, Yaoyao Sun, Sang Jun Park, Peng Guan Ong, Martin L. Hibberd, Kyuyoung Song, Choi Mun Chan, Ian Yeo, Akitaka Tsujikawa, Kar Seng Sim, Hiroyuki Iijima, Seang-Mei Saw, In Taek Kim, Mineo Ozaki, Woon-Puay Koh, Isao Nakata, Xiaoyan Ding, Rajkumar Dorajoo, Shu Yen Lee, Takanori Mizoguchi, Chiea Chuen Khor, Jinlong Liang, Norimoto Gotoh, Chi Pui Pang, Hyeong Gon Yu, Bowen Zhao, Peiquan Zhao, Hum Chung, Adrian Koh, Peng Zhou, Dong Ho Park, Jin Xin Bei, Chew-Kiat Heng, Xin Jin, Jia Nee Foo, Fumihiko Matsuda, Li Jia Chen, Sang Joon Lee, Peter Cackett, Junxiong Pang, Ningli Wang, Timothy Y Y Lai, Pancy O. S. Tam, Augustinus Laude, Haoyu Chen, Sonia Davila, Suk-Kyun Yang, Lulin Huang, Masahiro Miyake, Ying Lin, Tock Han Lim, Kenji Yamashiro, Yoichi Sakurada, E. Shyong Tai, Jinghong Sang, Xiongze Zhang, Xuefeng Xie, Shigeru Honda, Lvzhen Huang, Keisuke Mori, Xiaoxin Li, and Ranjana Mathur

Subjects
Genetics, Multidisciplinary, genetic structures, Case-control study, General Physics and Astronomy, Genome-wide association study, General Chemistry, Odds ratio, Disease, Macular degeneration, Biology, medicine.disease, Article, General Biochemistry, Genetics and Molecular Biology, eye diseases, 3. Good health, Biological sciences, Polymorphism (computer science), medicine, Exome, Cohort study
Abstract

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2, 119 patients with exudative AMD and 5, 691 controls, with independent replication in 4, 226 patients and 10, 289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10[-22]). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17mmoll-1 (P=5.82 × 10[-21]) in East Asians (n=7, 102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10[-18]), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10[-11]) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10[-8]). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature., 加齢黄斑変性の発症に関わるアジア人特有の遺伝子変異を発見. 京都大学プレスリリース. 2015-02-05., Updated 30 March 2015. [Corrigendum] doi:10.1038/ncomms7817

Published
2015

23. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

Author

Rashmi Gupta, Colin Theng, Jianjun Liu, Mona Ståhle, Jia Nee Foo, Yi Li, Wolfgang Lieb, Caihong Zhu, Wilson Liao, Kar Seng Sim, Fabio Sánchez, Ling Wang, Gerald G. Krueger, Xianbo Zuo, Herty Liany, Joseph J. Catanese, Xuejun Zhang, Yik-Ying Teo, Mark Seielstad, Philip L. De Jager, Hui Qi Low, Yonghong Li, Liangdan Sun, Leonid Padyukov, Kristina Callis Duffin, Abrar A. Qureshi, Eva Ellinghaus, Andre Franke, Michael Weichenthal, Changbing Shen, Sören Mucha, Xavier Estivill, Paul I.W. de Bakker, Anne M. Bowcock, Ishak D. Irwan, Jiali Han, Stephan Weidinger, Anping Zhang, and Xianyong Yin

Subjects
Interferon-Induced Helicase, IFIH1, Ethnic group, Genes, MHC Class I, General Physics and Astronomy, Genome-wide association study, Disease, DISEASE, DEAD-box RNA Helicases, Genetics, Multidisciplinary, Interleukin-12 Subunit p40, COMMON VARIANTS, 3. Good health, Multidisciplinary Sciences, HLA, DIFFERENTIATION, Core Binding Factor Alpha 2 Subunit, Science & Technology - Other Topics, Allelic heterogeneity, Asian Continental Ancestry Group, RUNX1, HAPLOTYPE MAP, European Continental Ancestry Group, Human leukocyte antigen, Biology, Article, White People, General Biochemistry, Genetics and Molecular Biology, Asian People, Psoriasis, MD Multidisciplinary, medicine, Humans, Genetic Predisposition to Disease, CHINESE POPULATION, Psoriasi, Science & Technology, Tumor Suppressor Proteins, Case-control study, General Chemistry, medicine.disease, RISK LOCI, Genetic architecture, Adaptor Proteins, Vesicular Transport, LUNG ADENOCARCINOMA, Case-Control Studies, EXPLAIN, Genome-Wide Association Study, Transcription Factors
Abstract

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations., Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here Yin et al. conduct a large trans-ethnic genome-wide meta-analysis and identify novel loci that contribute to population-specific susceptibility.

Published
2015

24. Natural positive selection and north–south genetic diversity in East Asia

Author

Jieming Chen, Jianjun Liu, E-Shyong Tai, Kar Seng Sim, Kee Seng Chia, Xuejun Zhang, Chen Suo, Wan Ting Tay, Tien Yin Wong, Chiea Chuen Khor, Xueling Sim, Yik Ying Teo, Haiyan Xu, Rick Th Ong, and Yi Xin Zeng

Subjects
Linkage disequilibrium, Population genetics, Genes, MHC Class I, Single-nucleotide polymorphism, HapMap Project, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Gene Frequency, Genetic variation, Genetics, Ethnicity, Humans, International HapMap Project, Selection, Genetic, Genetics (clinical), Genetic association, Genetic diversity, Asia, Eastern, Genome, Human, Altitude, Homozygote, Computational Biology, Genetic Variation, Genetics, Population, Haplotypes, Evolutionary biology, Imputation (genetics)
Abstract

Recent reports have identified a north–south cline in genetic variation in East and South-East Asia, but these studies have not formally explored the basis of these clinical differences. Understanding the origins of these variations may provide valuable insights in tracking down the functional variants in genomic regions identified by genetic association studies. Here we investigate the genetic basis of these differences with genome-wide data from the HapMap, the Human Genome Diversity Project and the Singapore Genome Variation Project. We implemented four bioinformatic measures to discover genomic regions that are considerably differentiated either between two Han Chinese populations in the north and south of China, or across 22 populations in East and South-East Asia. These measures prioritized genomic stretches with: (i) regional differences in the allelic spectrum for SNPs common to the two Han Chinese populations; (ii) differential evidence of positive selection between the two populations as quantified by integrated haplotype score (iHS) and cross-population extended haplotype homozygosity (XP-EHH); (iii) significant correlation between allele frequencies and geographical latitudes of the 22 populations. We also explored the extent of linkage disequilibrium variations in these regions, which is important in combining genetic association studies from North and South Chinese. Two of the regions that emerged are found in HLA class I and II, suggesting that the HLA imputation panel from the HapMap may not be directly applicable to every Chinese sample. This has important implications to autoimmune studies that plan to impute the classical HLA alleles to fine map the SNP association signals.

Published
2011

25. Erratum: Corrigendum: A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Author

Markus M. Nöthen, Jonathan G Crowston, Kazunori Miyata, Norimoto Gotoh, Masahide Yanagi, Stefan Herms, Steffen Heegaard, Ursula Schloetzer-Schrehardt, Shamira A. Perera, Axel M. Hillmer, Masaru Inatani, Yufen Goh, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Yildirim Nilgün, Aravind Haripriya, Lulin Huang, Daniela Paoli, Douglas J Rhee, Paul Mitchell, Mei Chin Lee, Inna May-Bolchakova, Masahiro Miyake, Ignacio Lischinsky, Toshiya Sakurai, Nagahisa Yoshimura, Makoto Aihara, Zhenglin Yang, Michael V. Dubina, Yoko Ikeda, Xueyi Chen, Yury S. Astakhov, Nihong Zhang, Ningli Wang, Kenji Inoue, Rhys A. Fogarty, John H. Fingert, Simon W. M. John, Kathryn P. Burdon, Steffen Uebe, Paolo Frezzotti, Pratap Challa, Alex W. Hewitt, Vera Vysochinskaya, Liang Xu, Fabian Lerner, Eleftherios Anastasopoulos, Satoshi Ishiko, Panayiota Founti, Rangappa Ramakrishnan, Kazuhisa Sugiyama, Janey L. Wiggs, Elke Schaeffeler, Etsuo Chihara, Morio Ueno, Matthew A. Brown, Louis R. Pasquale, Kai Yee Toh, Jie Jin Wang, Anne L. Coleman, Kazuhiko Mori, Jae H. Kang, Ewa Kosior-Jarecka, Christian Y. Mardin, Evgeny L. Akopov, Matthias Schwab, Saravanan Vijayan, Fumihiko Matsuda, Leyla Al-Jasim, Ya Xing Wang, Ken Hayashi, Juan Carlos Zenteno, David A. Mackey, Rajesh Kumar, Jost B. Jonas, Jia Nee Foo, Fotis Topouzis, Eranga N. Vithana, Yaz Yetkin, Yosai Mori, Wee Yang Meah, Kar Seng Sim, Rohit Shetty, Shahin Yazdani, Yik Ying Teo, Francesca Pasutto, Takanori Mizoguchi, Rahat Husain, Akitoshi Yoshida, Mohammad Pakravan, Ching-Yu Cheng, Tin Aung, Kei Tashiro, Tien Yin Wong, Trevor R. Carmichael, André Reis, Peiquan Zhao, Periasamy Sundaresan, Wallace L.M. Alward, Shigeyasu Kazama, Susan Williams, Zheng Li, Anthoula Chatzikyriakidou, Sergei Y. Astakhov, Su Ling Ho, Patricio G. Schlottmann, Essam A. Osman, Bowen Zhao, Urszula Lukasik, Balram Chowbay, Afsaneh Naderi Beni, Arkasubhra Ghosh, Ulrich Christoph Welge-Luessen, Nicole Weisschuh, Susanne Moebus, Shin Ichi Manabe, Chiea Chuen Khor, Ohoud Owaidhah, Paul Leo, Yoshiaki Kiuchi, Tomomi Higashide, Alexandros Lambropoulos, Anita S Y Chan, Michael A. Hauser, R. Rand Allingham, Deepak P. Edward, Jeffrey M. Harder, Mineo Ozaki, Takako Sugimoto, Çilingir Oaiuz, Su Qin Peh, Saleh A. Al-Obeidan, Robyn M. Rautenbach, Shigeru Kinoshita, Dalia Guadarrama-Vallejo, Robert Ritch, M. Roy Wilson, Tomasz Zarnowski, Khaled K. Abu-Amero, Michae Coote, Jinghong Sang, Ryuichi Ideta, Masakazu Nakano, Kenji Yamashiro, Gareth R. Howell, Andrew C. Orr, Leen Abu Safieh, Jeffrey M. Liebmann, Satoko Nakano, Liyun Jia, Kalpana Narendran, Yutao Liu, Toshiaki Kubota, Jamie E Craig, Sami Al Shahwan, Mandy Krumbiegel, Qisheng You, Ari Ziskind, Hideki Chuman, Allison E. Ashley Koch, and Rangaraj Venkatesh

Subjects
Genetics, Medizin, Biology, Exfoliation syndrome
Abstract

Corrigendum: A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Published
2015

26. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.

Author

Davila, Sonia, Wright, Victoria J., Chiea Chuen Khor, Kar Seng Sim, Binder, Alexander, Breunis, Willemijn B., Inwald, David, Nadel, Simon, Betts, Helen, Carrol, Enitan D., de Groot, Ronald, Hermans, Peter W. M., Hazelzet, Jan, Emonts, Marieke, Chui Chin Lim, Kuijpers, Taco W., Martinon-Torres, Federico, Salas, Antonio, Zenz, Werner, and Levin, Michael

Subjects
NEISSERIA meningitidis, CEREBROSPINAL meningitis, PATHOGENIC microorganisms, CARRIER proteins, COHORT analysis
Abstract

Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D−11) and in CFH-related protein 3 (CFHR3)(rs426736, P = 4.6 × 10−13). N. meningitidis is known to evade complement-mediated killing by the binding of host CFH to the meningococcal factor H–binding protein (fHbp). Our study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen. [ABSTRACT FROM AUTHOR]

Published
2010
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