Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

Anthony M. Musolf, Annechien E.G. Haarman, Consortium for Refractive Error and Myopia (CREAM), Robert N. Luben, Jue Sheng Ong, Karina Patasova, Rolando Hernandez Trapero, Joseph Marsh, Ishika Jain, Riya Jain, Paul Zhiping Wang, Deyana D. Lewis, Milly S. Tedja, Adriana I. Iglesias, Hengtong Li, Cameron S. Cowan, Paul Nigel Baird, Amutha Barathi Veluchamy, Kathryn P. Burdon, Harry CampbellLi Jia Chen, Ching Yu Cheng, Emily Y. Chew, Jamie E. Craig, Phillippa M. Cumberland, Margaret M. Deangelis, Cécile Delcourt, Xiaohu Ding, David M. Evans, Qiao Fan, Maurizio Fossarello, Paul J. Foster, Puya Gharahkhani, Jeremy A. Guggenheim, Xiaobo Guo, Xikun Han, Mingguang He, Alex W. Hewitt, Quan V. Hoang, Sudha K. Iyengar, Jost B. Jonas, Mika Kähönen, Jaakko Kaprio, Barbara E. Klein, Jonathan H. Lass, Ya Xing Wang, Cornelia M. van Duijn, Virginie J.M. Verhoeven*, Caroline C.W. Klaver*, Joan E. Bailey-Wilson*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.

Original languageEnglish
Article number6
JournalCommunications Biology
Volume6
Issue number1
DOIs
Publication statusPublished - 3 Jan 2023

Bibliographical note

Funding Information:
REHS: The core management of the Raine Study is funded by the University of Western Australia, Australia; the Telethon Institute for Child Health Research, Australia; Raine Medical Research Foundation, Australia; Women’s and Infant’s Research Foundation, Australia; Curtin University, Australia; Murdoch University, Australia; Edith Cowan University, Australia; and the University of Notre Dame, Australia. The Generation-2 20-year follow-up of the Raine Study was funded by the National Health and Medical Research Council (NHMRC), Australia: project grant no.: 1 021 105. The Generation-2 28-year follow-up of the Raine Study was funded by the NHMRC, Australia: project grants 1 121 979 and 1 126 494.

Funding Information:
FITSA: FITSA was supported by ENGAGE (FP7-HEALTH-F4-2007, 201413); European Union through the GENOMEUTWIN project (QLG2-CT-2002-01254); the Academy of Finland Center of Excellence in Complex Disease Genetics (213506, 129680); the Academy of Finland Ageing Programme; and the Finnish Ministry of Culture and Education and University of Jyväskylä. FITSA acknowledges the contributions of Emmi Tikkanen, Samuli Ripatti, Markku Kauppinen, Taina Rantanen and Jaakko Kaprio.

Funding Information:
TwinsUK: TwinsUK received funding from the Wellcome Trust; the European Union MyEuropia Marie Curie Research Training Network; Guide Dogs for the Blind Association; the European 18 Community’s FP7 (HEALTHF22008201865GEFOS); ENGAGE (HEALTHF42007201413); the FP-5 GenomEUtwin Project (QLG2CT200201254); US National Institutes of Health/National Eye Institute (1RO1EY018246); NIH Center for Inherited Disease Research; the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ National Health Service Foundation Trust partnering with King’s College London. P.G.H. is the recipient of a Fight for Sight ECI award. We acknowledge the contribution of Drs Toby Andrew, Margarida Lopes, Samantha Fahy and Diana Kozareva.

Funding Information:
RSI, ERF: The Rotterdam Study and ERF were supported by European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant 648268), Netherlands Organisation for Scientific Research (NWO, grant 91815655 to C.C.W.K. and NWO Veni 91617076 to V.J.M.V.), Ammodo Award (to C.C.W.K.), Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam; the Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Jacoba Breen Fonds, Topcon Europe; Ada Hooghart, Corina Brussee, Riet Bernaerts-Biskop, Amal Hamimida, Patricia van Hilten, Pascal Arp, Jeanette Vergeer, Sander Bervoets. The generation and management of the Illumina exome chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810); the Netherlands Organization for Scientific Research (NWO; project number 184021007) and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl ). We thank Ms. Mila Jhamai, Ms. Sarah Higgins, and Mr. Marijn Verkerk for their help in creating the exome chip database. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists.

Funding Information:
The authors gratefully acknowledge Sana Wajid of the Bioinformatics Core of the University of Pennsylvania for her quality control work on these data. This work was funded in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The acknowledgments for each individual study cohort are given alphabetically by study below. A.P.K. is supported by a UKRI Future Leaders Fellowship. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. AREDS : AREDS was supported by the National Eye Institute (grants R01EY16482, R21EY015145, and P30EY11373) and by Research to Prevent Blindness and the Ohio Lions Eye Research Foundation. AREDS was also supported by contracts from National Eye Institute/National Institutes of Health, Bethesda, MD, with additional support from Bausch & Lomb Inc, Rochester, NY. The genotyping costs were supported by the National Eye Institute (R01EY020483 to D.S.) and some of the analyses were supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, USA. AREDS acknowledges Frederick Ferris, National Eye Institute, National Institutes of Health, Bethesda, MD; and the Center for Inherited Disease Research, Baltimore, MD where SNP genotyping was carried out. The investigators gratefully acknowledge the advice and guidance of Hemin Chin of the National Eye Institute. BDES : BDES was supported by the National Eye Institute of the National Institutes of Health under award numbers EY06594 (R. Klein and B. E. K. Klein), EY10605 (B. E. K. Klein) and R01EY021531 (A.P.K. and P.D.) and some of the analyses were supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, USA. Croatia-Korcula : The Croatia-Korcula study was funded by the Medical Research Council (UK) “QTL in health and disease” programme core grants, currently MC_UU_00007/10, as well as grants from the Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302; 216-1080315-0302) and the Croatian Science Foundation (8875). The study acknowledge Dr. Biljana Andrijević Derk, Valentina Lacmanović Lončar, Krešimir Mandić, Antonija Mandić, Ivan Škegro, Jasna Pavičić Astaloš, Ivana Merc, Miljenka Martinović, Petra Kralj, Tamara Knežević and Katja Barać-Juretić as well as the recruitment team from the Croatian Centre for Global Health, University of Split and the Institute of Anthropological Research in Zagreb for the ophthalmological data collection; the Wellcome Trust Clinical facility (Edinburgh, United Kingdom) for Exome array genotyping. EGCUT : EGCUT was supported by the European Union H2020 grant 692145, Est.RC grant IUT20-60 and the European Regional Development Fund, in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure’s Roadmap and the University of Tartu (SP1GVARENG). This research was supported by NIH grant 5R01 DK07 57 87 -13, under subward-agreement GENFDOOO1B52751; the European Union through Horizon 2020 research and innovation programme under grant 633589 and the European Regional Development Fund (Project No. 2014-2020.4.01.16-0125). This research was also supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.16-0125) and the Estonian Research Council grant PUT (PRG687) European Union H2020 grant 654248 (Corbel). EGCUT acknowledges the High Performance Computing Center of the University of Tartu. EPIC-Norfolk : The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048).We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. FITSA: FITSA was supported by ENGAGE (FP7-HEALTH-F4-2007, 201413); European Union through the GENOMEUTWIN project (QLG2-CT-2002-01254); the Academy of Finland Center of Excellence in Complex Disease Genetics (213506, 129680); the Academy of Finland Ageing Programme; and the Finnish Ministry of Culture and Education and University of Jyväskylä. FITSA acknowledges the contributions of Emmi Tikkanen, Samuli Ripatti, Markku Kauppinen, Taina Rantanen and Jaakko Kaprio. Ogliastra : The Ogliastra Study gratefully acknowledges the population of Ogliastra, Sardinia, Italy. The Ogliastra study was funded by a grant from the Italian Ministry of Education, University and Research (MIUR) n°: 5571/DSPAR/2002. RSI, ERF : The Rotterdam Study and ERF were supported by European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant 648268), Netherlands Organisation for Scientific Research (NWO, grant 91815655 to C.C.W.K. and NWO Veni 91617076 to V.J.M.V.), Ammodo Award (to C.C.W.K.), Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam; the Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Jacoba Breen Fonds, Topcon Europe; Ada Hooghart, Corina Brussee, Riet Bernaerts-Biskop, Amal Hamimida, Patricia van Hilten, Pascal Arp, Jeanette Vergeer, Sander Bervoets. The generation and management of the Illumina exome chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810); the Netherlands Organization for Scientific Research (NWO; project number 184021007) and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl). We thank Ms. Mila Jhamai, Ms. Sarah Higgins, and Mr. Marijn Verkerk for their help in creating the exome chip database. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. REHS : The core management of the Raine Study is funded by the University of Western Australia, Australia; the Telethon Institute for Child Health Research, Australia; Raine Medical Research Foundation, Australia; Women’s and Infant’s Research Foundation, Australia; Curtin University, Australia; Murdoch University, Australia; Edith Cowan University, Australia; and the University of Notre Dame, Australia. The Generation-2 20-year follow-up of the Raine Study was funded by the National Health and Medical Research Council (NHMRC), Australia: project grant no.: 1 021 105. The Generation-2 28-year follow-up of the Raine Study was funded by the NHMRC, Australia: project grants 1 121 979 and 1 126 494. SCES, SiMES, SINDI : The Singapore studies (SCES, SiMES, SINDI) were supported by the National Medical Research Council, Singapore (NMRC 0796/2003, NMRC 1176/2008, STaR/0003/2008; CG/SERI/2010), Biomedical Research Council, Singapore (06/1/21/19/466, 09/1/35/19/616 and 08/1/35/19/550). The Singapore Tissue Network and the Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore provided services. TwinsUK : TwinsUK received funding from the Wellcome Trust; the European Union MyEuropia Marie Curie Research Training Network; Guide Dogs for the Blind Association; the European 18 Community’s FP7 (HEALTHF22008201865GEFOS); ENGAGE (HEALTHF42007201413); the FP-5 GenomEUtwin Project (QLG2CT200201254); US National Institutes of Health/National Eye Institute (1RO1EY018246); NIH Center for Inherited Disease Research; the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ National Health Service Foundation Trust partnering with King’s College London. P.G.H. is the recipient of a Fight for Sight ECI award. We acknowledge the contribution of Drs Toby Andrew, Margarida Lopes, Samantha Fahy and Diana Kozareva.

Funding Information:
EGCUT: EGCUT was supported by the European Union H2020 grant 692145, Est.RC grant IUT20-60 and the European Regional Development Fund, in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure’s Roadmap and the University of Tartu (SP1GVARENG). This research was supported by NIH grant 5R01 DK07 57 87 -13, under subward-agreement GENFDOOO1B52751; the European Union through Horizon 2020 research and innovation programme under grant 633589 and the European Regional Development Fund (Project No. 2014-2020.4.01.16-0125). This research was also supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.16-0125) and the Estonian Research Council grant PUT (PRG687) European Union H2020 grant 654248 (Corbel). EGCUT acknowledges the High Performance Computing Center of the University of Tartu.

Funding Information:
Ogliastra: The Ogliastra Study gratefully acknowledges the population of Ogliastra, Sardinia, Italy. The Ogliastra study was funded by a grant from the Italian Ministry of Education, University and Research (MIUR) n°: 5571/DSPAR/2002.

Funding Information:
SCES, SiMES, SINDI: The Singapore studies (SCES, SiMES, SINDI) were supported by the National Medical Research Council, Singapore (NMRC 0796/2003, NMRC 1176/2008, STaR/0003/2008; CG/SERI/2010), Biomedical Research Council, Singapore (06/1/21/19/466, 09/1/35/19/616 and 08/1/35/19/550). The Singapore Tissue Network and the Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore provided services.

Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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