Meta-Analysis

. 2025 Aug 23;16(1):7890.

doi: 10.1038/s41467-025-62456-9.

Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking

Weixiong He^{1

2}, Peter J van der Most³, Jue-Sheng Ong⁴, Liang-Dar Hwang⁵, Yeda Wu⁴, Morten S Magnø^{6

7

8}, Jelle Vehof^{9

10

11}, Kristi Krebs¹², Laura Mauring^{13

14

15}, Katrin Õunap^{13

14}, Erik Abner¹², Nicholas G Martin⁴, Denis Plotnikov¹⁶, Chen Jiang¹⁷, Ronald B Melles¹⁷, Puya Gharahkhani^{4

18}, Harold Snieder³, Teele Palumaa^{12

19}, Kuldar Kaljurand^{15

20}, Jeremy A Guggenheim²¹, David A Mackey²², Elizabeth C Engle^{23

24

25}, Hélène Choquet¹⁷; Lifelines Cohort Study; Stuart MacGregor^{4

18}

Collaborators, Affiliations

Collaborators

Lifelines Cohort Study:
Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A Kuivenhoven, Esteban A Lopera Maya, Ilja M Nolte, Serena Sanna, Morris A Swertz, Peter M Visscher, Judith M Vonk, Cisca Wijmenga, Naomi Wray

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. weixiong.he@uq.net.au.
² Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. weixiong.he@uq.net.au.
³ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
⁶ Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁷ Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway.
⁸ Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
⁹ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁰ Department of Ophthalmology, University of Groningen, Groningen, The Netherlands.
¹¹ Department of Ophthalmology, Vestfold Hospital Trust, Tønsberg, Norway.
¹² Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
¹³ Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁴ Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹⁵ Eye Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁶ Central Research Laboratory, Kazan State Medical University, Kazan, Russia.
¹⁷ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
¹⁸ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹⁹ Eye Clinic, East Tallinn Central Hospital, Tallinn, Estonia.
²⁰ Department of Eye Clinic, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
²¹ School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK.
²² Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA, Australia.
²³ Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
²⁴ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
²⁵ Howard Hughes Medical Institute, Chevy Chase, MD, USA.

PMID: 40849414
PMCID: PMC12375114
DOI: 10.1038/s41467-025-62456-9

Meta-Analysis

Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking

Weixiong He et al. Nat Commun. 2025.

. 2025 Aug 23;16(1):7890.

doi: 10.1038/s41467-025-62456-9.

Authors

Collaborators

Lifelines Cohort Study:
Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A Kuivenhoven, Esteban A Lopera Maya, Ilja M Nolte, Serena Sanna, Morris A Swertz, Peter M Visscher, Judith M Vonk, Cisca Wijmenga, Naomi Wray

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. weixiong.he@uq.net.au.
² Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. weixiong.he@uq.net.au.
³ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
⁶ Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁷ Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway.
⁸ Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
⁹ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁰ Department of Ophthalmology, University of Groningen, Groningen, The Netherlands.
¹¹ Department of Ophthalmology, Vestfold Hospital Trust, Tønsberg, Norway.
¹² Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
¹³ Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁴ Department of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹⁵ Eye Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁶ Central Research Laboratory, Kazan State Medical University, Kazan, Russia.
¹⁷ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
¹⁸ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹⁹ Eye Clinic, East Tallinn Central Hospital, Tallinn, Estonia.
²⁰ Department of Eye Clinic, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
²¹ School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK.
²² Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA, Australia.
²³ Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
²⁴ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
²⁵ Howard Hughes Medical Institute, Chevy Chase, MD, USA.

PMID: 40849414
PMCID: PMC12375114
DOI: 10.1038/s41467-025-62456-9

Abstract

Strabismus is a common pediatric eye misalignment and has complex genetic and environmental causes. Previous genome-wide association studies (GWAS) encountered difficulties in identifying strabismus risk variants due to heterogeneity and small samples. We performed large meta-analyses of 11 European-ancestry GWAS (7 sources), analysing broad strabismus (20,464 cases, 954,921 controls) and subtypes (esotropia/exotropia). We discovered 4 loci (e.g., NPLOC4-TSPAN10-PDE6G-FAAP100, COL6A1) for strabismus and 5 additional loci (e.g., CHRNA4, MAD1L1) for strabismus subtypes and we successfully replicated the previously reported strabismus variant near NPLOC4-TSPAN10-PDE6G-FAAP100. Using mendelian randomisation, we found genetic evidence supporting maternal smoking as a causal risk factor for strabismus in offspring.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

**Fig. 1. Manhattan plots and QQ-plots of three strabismus phenotypes.**
The red line in Manhattan plots represents the genome-wide significant threshold (P = 5 × 10⁻⁸), the green line represents the suggestive significance threshold (P = 1 × 10⁻⁵). The red line in QQ-plots represents the expected distribution of the p values, and blue/yellow/green trend represents the observed distribution. Shades represent the 95% confidence interval of the expected distribution.

**Fig. 2. Locus zoom plots for strabismus, esotropia and exotropia significant loci.**
Genome build for chromosome position is Homo sapiens (human) genome assembly GRCh37 (hg19) and LD (r²) is calculated from 1000 Genome European population. The blue line represents the recombination rate (cMMb). The most significant SNPs are indicated by the purple dots. The x-axis shows genes located in the genomic regions (1MB) and y-axis indicates the significance of SNP associations (−log10(P)).

**Fig. 3. Venn diagram of seven GWAS-significant loci.**
The GWAS summary statistics of the three strabismus phenotypes shared a subset of associated loci. Genes in the blue/red/green circle represent the genetic loci associated with strabismus/esotropia/exotropia. Genetic loci in bold represent the loci also associated with myopia or refractive errors.

**Fig. 4. Comparison of epidemiology and MR-based estimates of the relationship between birth weight and strabismus subtypes.**
We compared odds ratios (ORs) change from our Mendelian randomisation (MR) analysis of birth weight on esotropia (a) and exotropia (b) with observational results published by Torp-Pedersen et al. The x-axis contains different groups based on per 500 g birth weight increase. The birth weight changes were labelled as 3000–3499 g, 3500–3999 g and 4000–4499 g in the original paper, we re-labelled them to ‘500 g increase from 2500 g’, ‘500 g increase from 3000 g’ and ‘500 g increase from 3500 g’ and present the ORs change per 500 g increase on birth weight (green points in a, yellow points in b). Error bars are the 95% confidence interval of ORs change. The red point represents the MR OR per 500 g increase in birth weight, and the red error bars represent the 95% confidence interval of MR OR.

See this image and copyright information in PMC

References

1. Donahue, S. P. Pediatric Strabismus. N. Engl. J. Med.356, 1040–1047 (2007). - PubMed
1. Hashemi, H. et al. Global and regional prevalence of strabismus: a comprehensive systematic review and meta-analysis. Strabismus27, 54–65 (2019). - PubMed
1. Michaelides, M. & Moore, A. T. The genetics of strabismus. J. Med. Genet.41, 641–646 (2004). - PMC - PubMed
1. Harrad, R. & Williams, C. Risk, causes and outcomes of visual impairment after loss of vision in the non-amblyopic eye, a population-based study. Surv. Ophthalmol.48, 235–236 (2003). - PubMed
1. Yang, Y. et al. Maternal smoking during pregnancy and the risk of strabismus in offspring: a meta-analysis. Acta Ophthalmol.97, 353–363 (2019). - PubMed

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Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking

Collaborators

Affiliations

Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous