title: Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract.
abstract: Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4569 Asians (including 2369 Malays and 2200 Indians), and replicated our analysis in 2481 Chinese from two independent cohorts (1768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n = 7140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta = 2.30 × 10(-8); random-effect Pmeta = 1.08 × 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta = 2.77 × 10(-8); random-effect Pmeta = 1.98 × 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Liao
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Su
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing 100730, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Ophthalmology.
authors.forename: Lennard
authors.initials: L
authors.lastname: Thean
authors.affiliation: Department of Ophthalmology.
authors.forename: Clement
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Ophthalmology, Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Sydney, NSW 2145, Australia.
authors.forename: Ava G
authors.initials: AG
authors.lastname: Tan
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Tay
authors.affiliation: Department of Medicine (Biomedical Genetics), Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA, Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Gyungah
authors.initials: G
authors.lastname: Jun
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore.
authors.forename: Merwyn
authors.initials: M
authors.lastname: Chew
authors.affiliation: Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing 100730, China.
authors.forename: Ya Xing
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore.
authors.forename: Queenie S
authors.initials: QS
authors.lastname: Tan
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Veluchamy A
authors.initials: VA
authors.lastname: Barathi
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Klein
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology, Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Seang-Mei
authors.initials: SM
authors.lastname: Saw
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology.
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.affiliation: Department of Medicine, National University of Singapore and National University Health System, Singapore 119228, Singapore, Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
authors.forename: E-Shyong
authors.initials: ES
authors.lastname: Tai
authors.affiliation: Department of Epidemiology and Biostatistics, Department of Genetics and Genome Sciences, Center for Clinical Investigation, Case Western Reserve University, Cleveland, OH 44106, USA, Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, OH 44106, USA.
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.affiliation: Department of Ophthalmology, Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Sydney, NSW 2145, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Department of Ophthalmology, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore 138672, Singapore.
authors.forename: Chiea-Chuen
authors.initials: CC
authors.lastname: Khor
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology.
authors.forename: Tin
authors.initials: T
authors.lastname: Aung
authors.affiliation: Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore, Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne VIC 3002, Australia and.
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing 100730, China, Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, 68167 Mannheim, Germany.
authors.forename: Jost B
authors.initials: JB
authors.lastname: Jonas
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore, Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore.
authors.forename: Yik-Ying
authors.initials: YY
authors.lastname: Teo
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology, Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore.
authors.forename: Tien Yin
authors.initials: TY
authors.lastname: Wong
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Center, Singapore 168751, Singapore, Department of Ophthalmology, Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore, ching-yu_cheng@nuhs.edu.sg.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Cheng
mesh_terms: D000368:Aged; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D002386:Cataract / Q000208:ethnology / Q000235:genetics*; D015331:Cohort Studies; D003459:Crystallins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000235:genetics*; D008297:Male; D008875:Middle Aged
chemical_list: C511246:CRYAA protein, human; D003459:Crystallins; C097044:KCNAB1 protein, human; D051664:Kv1.3 Potassium Channel