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.

A multi-ethnic meta-analysis of exome array data from over 27,000 participants identifies several rare variants that could contribute to risk of ocular refractive error.

Details

Title
Rare variant analyses across multiethnic cohorts identify novel genes for refractive error
Author
Musolf, Anthony M. 1 ; Haarman, Annechien E. G. 2   VIAFID ORCID Logo  ; Luben, Robert N. 3 ; Ong, Jue-Sheng 4   VIAFID ORCID Logo  ; Patasova, Karina 5 ; Trapero, Rolando Hernandez 6 ; Marsh, Joseph 6   VIAFID ORCID Logo  ; Jain, Ishika 1 ; Jain, Riya 1 ; Wang, Paul Zhiping 7 ; Lewis, Deyana D. 1 ; Tedja, Milly S. 8   VIAFID ORCID Logo  ; Iglesias, Adriana I. 8   VIAFID ORCID Logo  ; Li, Hengtong 9 ; Cowan, Cameron S. 10 ; Baird, Paul Nigel 11 ; Veluchamy, Amutha Barathi 12 ; Burdon, Kathryn P. 13 ; Campbell, Harry 14 ; Chen, Li Jia 15 ; Cheng, Ching-Yu 16 ; Chew, Emily Y. 17 ; Craig, Jamie E. 18 ; Cumberland, Phillippa M. 19 ; Deangelis, Margaret M. 20 ; Delcourt, Cécile 21 ; Ding, Xiaohu 22 ; Evans, David M. 23 ; Fan, Qiao 24 ; Fossarello, Maurizio 25 ; Foster, Paul J. 26 ; Gharahkhani, Puya 27 ; Guggenheim, Jeremy A. 28 ; Guo, Xiaobo 29 ; Han, Xikun 27 ; He, Mingguang 30 ; Hewitt, Alex W. 31 ; Hoang, Quan V. 32 ; Iyengar, Sudha K. 33 ; Jonas, Jost B. 34 ; Kähönen, Mika 35 ; Kaprio, Jaakko 36 ; Klein, Barbara E. 37 ; Lass, Jonathan H. 38 ; Lee, Kris 37 ; Lehtimäki, Terho 39 ; Lewis, Deyana 1 ; Li, Qing 1 ; Li, Shi-Ming 40 ; Lyytikäinen, Leo-Pekka 39 ; MacGregor, Stuart 27 ; Mackey, David A. 31 ; Martin, Nicholas G. 41 ; Meguro, Akira 42 ; Middlebrooks, Candace 1 ; Miyake, Masahiro 43 ; Mizuki, Nobuhisa 42 ; Musolf, Anthony 1 ; Nickels, Stefan 44 ; Oexle, Konrad 45 ; Pang, Chi Pui 15 ; Paterson, Andrew D. 46 ; Pennell, Craig 47 ; Pfeiffer, Norbert 44 ; Polasek, Ozren 48 ; Rahi, Jugnoo S. 49 ; Raitakari, Olli 50 ; Rudan, Igor 14 ; Sahebjada, Srujana 11 ; Simpson, Claire L. 51 ; Tai, E-Shyong 52 ; Tideman, J. Willem L. 2 ; Tsujikawa, Akitaka 43 ; Wang, Ningli 40 ; Bin Wei, Wen 53 ; Williams, Cathy 54 ; Williams, Katie M. 5 ; Wilson, James F. 55 ; Wojciechowski, Robert 56 ; Wang, Ya Xing 40 ; Yamashiro, Kenji 57 ; Yam, Jason C. S. 15 ; Yap, Maurice K. H. 58 ; Yazar, Seyhan 47 ; Yip, Shea Ping 59 ; Young, Terri L. 37 ; Zhou, Xiangtian 60 ; Biino, Ginevra 61 ; Klein, Alison P. 62   VIAFID ORCID Logo  ; Duggal, Priya 63   VIAFID ORCID Logo  ; Hayward, Caroline 6   VIAFID ORCID Logo  ; Haller, Toomas 64   VIAFID ORCID Logo  ; Metspalu, Andres 64   VIAFID ORCID Logo  ; Wedenoja, Juho 65   VIAFID ORCID Logo  ; Pärssinen, Olavi 66 ; Saw, Seang-Mei 67 ; Stambolian, Dwight 68 ; Hysi, Pirro G. 5   VIAFID ORCID Logo  ; Khawaja, Anthony P. 3   VIAFID ORCID Logo  ; Vitart, Veronique 6   VIAFID ORCID Logo  ; Hammond, Christopher J. 5   VIAFID ORCID Logo  ; van Duijn, Cornelia M. 69   VIAFID ORCID Logo  ; Verhoeven, Virginie J. M. 70   VIAFID ORCID Logo  ; Klaver, Caroline C. W. 71   VIAFID ORCID Logo  ; Bailey-Wilson, Joan E. 1   VIAFID ORCID Logo 

1  National Institutes of Health, Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
2  Erasmus Medical Center, Department of Ophthalmology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); Erasmus Medical Center, Department of Epidemiology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
3  University of Cambridge School of Clinical Medicine, MRC Epidemiology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, NIHR Biomedical Research Centre, London, UK (GRID:grid.436474.6) (ISNI:0000 0000 9168 0080) 
4  QIMR Berghofer Medical Research Institute, Statistical Genetics Laboratory, Department of Genetics and Computational Biology, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
5  King’s College London, Department of Twin Research and Genetic Epidemiology, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
6  University of Edinburgh, Western General Hospital, MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
7  University of Pennsylvania, Institute for Biomedical Sciences, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
8  Erasmus Medical Center, Department of Ophthalmology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
9  Singapore National Eye Centre, Data Science Unit, Singapore Eye Research Institute, Singapore, Singapore (GRID:grid.419272.b) (ISNI:0000 0000 9960 1711) 
10  Institute for Molecular and Clinical Ophthalmology Basel, Basel, Switzerland (GRID:grid.508836.0) 
11  University of Melbourne, Royal Victorian Eye and Ear Hospital, Centre for Eye Research Australia, Ophthalmology, Department of Surgery, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
12  Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore (GRID:grid.419272.b) (ISNI:0000 0000 9960 1711); Duke-NUS Medical School, Singapore, Singapore (GRID:grid.428397.3) (ISNI:0000 0004 0385 0924); National University Health Systems, National University of Singapore, Department of Ophthalmology, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431) 
13  University of Tasmania, Department of Ophthalmology, Menzies Institute of Medical Research, Hobart, Australia (GRID:grid.1009.8) (ISNI:0000 0004 1936 826X) 
14  University of Edinburgh, Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
15  The Chinese University of Hong Kong, Hong Kong Eye Hospital, Department of Ophthalmology and Visual Sciences, Kowloon, Hong Kong (GRID:grid.490089.c) (ISNI:0000 0004 1803 8779) 
16  DUKE-National University of Singapore, Centre for Quantitative Medicine, Singapore, Singapore (GRID:grid.428397.3) (ISNI:0000 0004 0385 0924); Singapore National Eye Centre, Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore, Singapore (GRID:grid.419272.b) (ISNI:0000 0000 9960 1711); National University of Singapore, Department of Ophthalmology, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431) 
17  National Eye Institute/National Institutes of Health, Division of Epidemiology and Clinical Applications, Bethesda, USA (GRID:grid.280030.9) (ISNI:0000 0001 2150 6316) 
18  Flinders University, Department of Ophthalmology, Adelaide, Australia (GRID:grid.1014.4) (ISNI:0000 0004 0367 2697) 
19  University College London, Great Ormond Street Institute of Child Health, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
20  University at Buffalo, Department of Ophthalmology, Buffalo, USA (GRID:grid.273335.3) (ISNI:0000 0004 1936 9887) 
21  Université de Bordeaux, Inserm, Bordeaux Population Health Research Center, team LEHA, UMR 1219, Bordeaux, France (GRID:grid.412041.2) (ISNI:0000 0001 2106 639X) 
22  Sun Yat-sen University, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
23  University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); University of Bristol, MRC Integrative Epidemiology Unit, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); Bristol Medical School, Department of Population Health Sciences, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
24  DUKE-National University of Singapore, Centre for Quantitative Medicine, Singapore, Singapore (GRID:grid.428397.3) (ISNI:0000 0004 0385 0924) 
25  University Hospital ‘San Giovanni di Dio’, Cagliari, Italy (GRID:grid.428397.3) 
26  Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, NIHR Biomedical Research Centre, London, UK (GRID:grid.436474.6) (ISNI:0000 0000 9168 0080) 
27  QIMR Berghofer Medical Research Institute, Statistical Genetics, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
28  Cardiff University, School of Optometry & Vision Sciences, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
29  Sun Yat-sen University, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X); Sun Yat-Sen University, Department of Statistical Science, School of Mathematics, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
30  University of Melbourne, Royal Victorian Eye and Ear Hospital, Centre for Eye Research Australia, Ophthalmology, Department of Surgery, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Sun Yat-sen University, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
31  University of Western Australia, Centre for Ophthalmology and Visual Science, Lions Eye Institute, Perth, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910); University of Melbourne, Royal Victorian Eye and Ear Hospital, Centre for Eye Research Australia, Ophthalmology, Department of Surgery, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); University of Tasmania, Department of Ophthalmology, Menzies Institute of Medical Research, Hobart, Australia (GRID:grid.1009.8) (ISNI:0000 0004 1936 826X) 
32  Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore (GRID:grid.419272.b) (ISNI:0000 0000 9960 1711); Columbia University, Department of Ophthalmology, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
33  Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847); Case Western Reserve University and University Hospitals Eye Institute, Department of Ophthalmology and Visual Sciences, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847); Case Western Reserve University, Department of Genetics, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847) 
34  Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Department of Ophthalmology, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373); Capital Medical University, Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X) 
35  Tampere University Hospital and School of Medicine, University of Tampere, Department of Clinical Physiology, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254); University of Tampere, Finnish Cardiovascular Research Center, Faculty of Medicine and Life Sciences, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
36  University of Helsinki and Helsinki University Hospital, Department of Ophthalmology, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); University of Helsinki, Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
37  University of Wisconsin–Madison, Department of Ophthalmology and Visual Sciences, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
38  Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847); Case Western Reserve University and University Hospitals Eye Institute, Department of Ophthalmology and Visual Sciences, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847) 
39  University of Tampere, Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254); University of Tampere, Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
40  Capital Medical University, Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X) 
41  QIMR Berghofer Medical Research Institute, Genetic Epidemiology, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
42  Yokohama City University School of Medicine, Department of Ophthalmology, Yokohama, Japan (GRID:grid.268441.d) (ISNI:0000 0001 1033 6139) 
43  Kyoto University Graduate School of Medicine, Department of Ophthalmology and Visual Sciences, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033) 
44  University Medical Center of the Johannes Gutenberg University Mainz, Department of Ophthalmology, Mainz, Germany (GRID:grid.410607.4) 
45  German Research Centre for Environmental Health, Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
46  Hospital for Sick Children and University of Toronto, Program in Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
47  University of Western Australia, Centre for Ophthalmology and Visual Science, Lions Eye Institute, Perth, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
48  Gen-info Ltd, Zagreb, Croatia (GRID:grid.410607.4); University of Split School of Medicine, Soltanska 2, Split, Croatia (GRID:grid.38603.3e) (ISNI:0000 0004 0644 1675) 
49  Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, NIHR Biomedical Research Centre, London, UK (GRID:grid.436474.6) (ISNI:0000 0000 9168 0080); University College London, Great Ormond Street Institute of Child Health, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Ulverscroft Vision Research Group, University College London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
50  University of Turku, Research Centre of Applied and Preventive Cardiovascular Medicine, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371); Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku, Finland (GRID:grid.410552.7) (ISNI:0000 0004 0628 215X) 
51  University of Tennessee Health Sciences Center, Department of Genetics, Genomics and Informatics, Memphis, USA (GRID:grid.267301.1) (ISNI:0000 0004 0386 9246) 
52  Singapore National Eye Centre, Myopia Research Group, Singapore Eye Research Institute, Singapore, Singapore (GRID:grid.419272.b) (ISNI:0000 0000 9960 1711) 
53  Capital Medical University, Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing Tongren Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X) 
54  Bristol Medical School, Department of Population Health Sciences, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
55  University of Edinburgh, Western General Hospital, MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988); University of Edinburgh, Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
56  Johns Hopkins University, The Bloomberg School of Public Health, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins Medical Institutions, Wilmer Eye Institute, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
57  Otsu Red Cross Hospital, Department of Ophthalmology, Nagara, Japan (GRID:grid.417352.6) (ISNI:0000 0004 1764 710X) 
58  The Hong Kong Polytechnic University, Centre for Myopia Research, School of Optometry, Hong Kong, Hong Kong (GRID:grid.16890.36) (ISNI:0000 0004 1764 6123) 
59  The Hong Kong Polytechnic University, Department of Health Technology and Informatics, Hong Kong, Hong Kong (GRID:grid.16890.36) (ISNI:0000 0004 1764 6123) 
60  Wenzhou Medical University, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou, China (GRID:grid.268099.c) (ISNI:0000 0001 0348 3990) 
61  National Research Council of Italy, Institute of Molecular Genetics, Pavia, Italy (GRID:grid.5326.2) (ISNI:0000 0001 1940 4177) 
62  Johns Hopkins University Bloomberg School of Public Health, Department of Epidemiology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
63  Johns Hopkins University, The Bloomberg School of Public Health, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
64  University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
65  University of Helsinki and Helsinki University Hospital, Department of Ophthalmology, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); University of Helsinki, Department of Public Health, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
66  Central Hospital of Central Finland, Department of Ophthalmology, Jyväskylä, Finland (GRID:grid.460356.2) (ISNI:0000 0004 0449 0385); University of Jyväskylä, Gerontology Research Center, Faculty of Sport and Health Sciences, Jyväskylä, Finland (GRID:grid.9681.6) (ISNI:0000 0001 1013 7965) 
67  National University Health Systems, National University of Singapore, Saw Swee Hock School of Public Health, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); Singapore National Eye Centre, Myopia Research Group, Singapore Eye Research Institute, Singapore, Singapore (GRID:grid.419272.b) (ISNI:0000 0000 9960 1711) 
68  University of Pennsylvania, Department of Ophthalmology, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
69  University of Oxford, Nuffield Department of Population Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
70  Erasmus Medical Center, Department of Ophthalmology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); Erasmus Medical Center, Department of Epidemiology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); Erasmus Medical Center, Department of Clinical Genetics, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
71  Erasmus Medical Center, Department of Ophthalmology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); Erasmus Medical Center, Department of Epidemiology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); Institute for Molecular and Clinical Ophthalmology Basel, Basel, Switzerland (GRID:grid.508836.0); Radboud University Medical Centre, Department of Ophthalmology, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
Pages
6
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-022-04323-7
ProQuest document ID
2760394128
Copyright
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.