| Title: | Gene-Environment Interaction Loci Associated with Refractive Error: SCAMPI Analysis |
| Journal: | Ophthalmology Science |
| Published: | 5 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42293346/ |
| DOI: | https://doi.org/10.1016/j.xops.2026.101219 |
| URL: | https://www.ophthalmologyscience.org/article/S2666-9145(26)00157-0/pdf |
Publication 20654
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Abstract
Purpose: To compare the performance of a novel method for identifying candidate gene-environment interaction loci, Scalable Cauchy Aggregate test using Multiple Phenotypes to test Interactions (SCAMPI) (doi:10.1101/2024.09.10.612314v1), to widely used existing methods, Levene's test and conditional quantile regression (CQR). The 3 methods were evaluated for refractive error, a trait known to exhibit widespread gene-environment interaction effects.</p>
Design: A cohort study; a genome-wide association study to investigate variance heterogeneity of refractive error.</p>
Participants: A discovery sample of 77 880 UK Biobank participants with records of both refractive error and age of onset of spectacle wear (AOSW) and a validation sample of 257 265 UK Biobank participants with known AOSW.</p>
Methods: SCAMPI, Levene's tests, and CQR were applied in the discovery sample. Variance quantitative trait loci (vQTLs) identified using SCAMPI were assessed in the independent validation sample. The SCAMPI vQTLs were further assessed for evidence of genotype-by-education interaction or gene-gene interaction, using linear regression.</p>
Main Outcome Measures: Genetic variance heterogeneity associated with refractive error (phenotypic variance differences across genotypes).</p>
Results: SCAMPI identified 15 independent vQTLs with P <5.0e-08 while 3 and 11 were found using Levene's test and CQR, respectively. Of the 15 SCAMPI vQTLs, 12 (80%) were supported in the validation data set after accounting for multiple testing. The lead SCAMPI variants included known vQTL associated with refractive error, such as rs12193556 (LAMA2) and rs685352 (GJD2), as well as 3 novel candidate gene-environment interaction loci. Among these novel candidates was rs7077247, an intronic variant in the TCF7L2 gene, which was associated with a -0.085 D greater shift toward myopia in participants with a university degree (P = 9.43e-04). This variant is known to be associated with the risk of diabetes and TCF7L2 is a component of the Wnt signaling pathway. The SCAMPI vQTLs demonstrated minimal evidence for gene-gene interactions.</p>
Conclusions: The SCAMPI outperformed Levene's test and CQR in identifying candidate gene-environment interaction loci associated with refractive error. Our results suggest that a variant in the TCF7L2 gene may confer susceptibility to myopia to a greater extent in those with higher vs. lower educational attainment and suggests a molecular link to Wnt signaling and the risk of myopia associated with intensive education.</p>
Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p>
84 Authors
- Xi He
- Louise Terry
- Jeremy A. Guggenheim
- Biobank Eye and Vision Consortium
- Naomi Allen
- Tariq Aslam
- Denize Atan
- Konstantinos Balaskas
- Sarah Barman
- Jenny Barrett
- Paul Bishop
- Graeme Black
- Tasanee Braithwaite
- Roxana Carare
- Usha Chakravarthy
- Michelle Chan
- Sharon Chua
- Annegret Dahlmann-Noor
- Alexander Day
- Parul Desai
- Bal Dhillon
- Andrew Dick
- Alexander Doney
- Cathy Egan
- Sarah Ennis
- Paul Foster
- Marcus Fruttiger
- John Gallacher
- David Garway-Heath
- Jane Gibson
- Jeremy Guggenheim
- Chris Hammond
- Alison Hardcastley
- Simon Harding
- Ruth Hogg
- Pirro Hysi
- Pearse Keane
- Peng Tee Khaw
- Anthony Khawaja
- Gerassimos Lascaratos
- Thomas Littlejohns
- Andrew Lotery
- Robert Luben
- Phil Luthert
- Tom Macgillivray
- Sarah Mackie
- Savita Madhusudhan
- Bernadette Mcguinness
- Gareth Mckay
- Martin Mckibbint
- Tony Moore
- James Morgan
- Eoin O'Sullivan
- Richard Oram
- Chris Owen
- Praveen Patel
- Euan Paterson
- Tunde Peto
- Axel Petzold
- Nikolas Pontikos
- Jugnoo Rahi
- Alicja Rudnicka
- Naveed Sattar
- Jay Self
- Panagiotis Sergouniotis
- Sobha Sivaprasad
- David Steel
- Irene Stratton
- Nicholas Strouthidis
- Cathie Sudlow
- Zihan Sun
- Robyn Tapp
- Dhanes Thomas
- Mervyn Thomas
- Emanuele Trucco
- Adnan Tufail
- Ananth Viswanathan
- Veronique Vitart
- Mike Weedon
- Katie Williams
- Cathy Williams
- Jayne Woodside
- Max Yates
- Yalin Zheng
1 Application
| Application ID | Title |
|---|---|
| 83325 | Genetic and lifestyle risk factors for refractive error |
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