Rare variant analyses across multiethnic cohorts identify novel genes for refractive error
Authors: Musolf Anthony M. , Haarman Annechien E. G. , Luben Robert N. , Ong Jue-Sheng , Patasova Karina , Trapero Rolando Hernandez , Marsh Joseph , Jain Ishika , Jain Riya , Wang Paul Zhiping , Lewis Deyana D. , Tedja Milly S. , Iglesias Adriana I. , Li Hengtong , Cowan Cameron S. ,   Consortium for Refractive Error and Myopia (CREAM), Baird Paul Nigel , Veluchamy Amutha Barathi , Burdon Kathryn P. , Campbell Harry , Chen Li Jia , Cheng Ching-Yu , Chew Emily Y. , Craig Jamie E. , Cumberland Phillippa M. , Deangelis Margaret M. , Delcourt Cécile , Ding Xiaohu , Evans David M. , Fan Qiao , Fossarello Maurizio , Foster Paul J. , Gharahkhani Puya , Iglesias Adriana I. , Guggenheim Jeremy A. , Guo Xiaobo , Han Xikun , He Mingguang , Hewitt Alex W. , Hoang Quan V. , Iyengar Sudha K. , Jonas Jost B. , Kähönen Mika , Kaprio Jaakko , Klein Barbara E. , Lass Jonathan H. , Lee Kris , Lehtimäki Terho , Lewis Deyana , Li Qing , Li Shi-Ming , Lyytikäinen Leo-Pekka , MacGregor Stuart , Mackey David A. , Martin Nicholas G. , Meguro Akira , Middlebrooks Candace , Miyake Masahiro , Mizuki Nobuhisa , Musolf Anthony , Nickels Stefan , Oexle Konrad , Pang Chi Pui , Paterson Andrew D. , Pennell Craig , Pfeiffer Norbert , Polasek Ozren , Rahi Jugnoo S. , Raitakari Olli , Rudan Igor , Sahebjada Srujana , Simpson Claire L. , Tai E-Shyong , Tedja Milly S. , Tideman J. Willem L. , Tsujikawa Akitaka , Wang Ningli , Bin Wei Wen , Williams Cathy , Williams Katie M. , Wilson James F. , Wojciechowski Robert , Wang Ya Xing , Yamashiro Kenji , Yam Jason C. S. , Yap Maurice K. H. , Yazar Seyhan , Yip Shea Ping , Young Terri L. , Zhou Xiangtian , Biino Ginevra , Klein Alison P. , Duggal Priya , Mackey David A. , Hayward Caroline , Haller Toomas , Metspalu Andres , Wedenoja Juho , Pärssinen Olavi , Cheng Ching-Yu , Saw Seang-Mei , Stambolian Dwight , Hysi Pirro G. , Khawaja Anthony P. , Vitart Veronique , Hammond Christopher J. , van Duijn Cornelia M. , Verhoeven Virginie J. M. , Klaver Caroline C. W. , Bailey-Wilson Joan E. 
Published: January 2023

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.