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

Lifelines Cohort Study; Weixiong He; Peter J van der Most; Jue-Sheng Ong; Liang-Dar Hwang; Yeda Wu; Morten S Magnø; Jelle Vehof; Kristi Krebs; Laura Mauring; Katrin Õunap; Erik Abner; Nicholas G Martin; Denis Plotnikov; Chen Jiang; Ronald B Melles; Puya Gharahkhani; Harold Snieder; Teele Palumaa; Kuldar Kaljurand; Jeremy A Guggenheim; David A Mackey; Elizabeth C Engle; Hélène Choquet; Stuart MacGregor

doi:10.1038/s41467-025-62456-9

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

Lifelines Cohort Study, Weixiong He^*, Peter J van der Most, Jue-Sheng Ong, Liang-Dar Hwang, Yeda Wu, Morten S Magnø, Jelle Vehof, Kristi Krebs, Laura Mauring, Katrin Õunap, Erik Abner, Nicholas G Martin, Denis Plotnikov, Chen Jiang, Ronald B Melles, Puya Gharahkhani, Harold Snieder, Teele Palumaa, Kuldar KaljurandJeremy A Guggenheim, David A Mackey, Elizabeth C Engle, Hélène Choquet, Stuart MacGregor

^*Corresponding author voor dit werk

Onderzoeksoutput: Article › Academic › peer review

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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.

Originele taal-2	English
Artikelnummer	7890
Aantal pagina's	14
Tijdschrift	Nature Communications
Volume	16
DOI's	https://doi.org/10.1038/s41467-025-62456-9
Status	Published - 23-aug.-2025

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10.1038/s41467-025-62456-9Licentie: CC BY-NC-ND

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Lifelines Cohort Study, He, W., van der Most, P. J., Ong, J.-S., Hwang, L.-D., Wu, Y., Magnø, M. S., Vehof, J., Krebs, K., Mauring, L., Õunap, K., Abner, E., Martin, N. G., Plotnikov, D., Jiang, C., Melles, R. B., Gharahkhani, P., Snieder, H., Palumaa, T., ... MacGregor, S. (2025). Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking. Nature Communications, 16, Artikel 7890. https://doi.org/10.1038/s41467-025-62456-9

@article{43a07502583942db9d9fe9d4ea10ae78,

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

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.",

keywords = "Humans, Genome-Wide Association Study, Female, Strabismus/genetics, Smoking/adverse effects, Genetic Predisposition to Disease, Risk Factors, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis, Male, Pregnancy",

author = "\{Lifelines Cohort Study\} and Weixiong He and \{van der Most\}, \{Peter J\} and Jue-Sheng Ong and Liang-Dar Hwang and Yeda Wu and Magn{\o}, \{Morten S\} and Jelle Vehof and Kristi Krebs and Laura Mauring and Katrin {\~O}unap and Erik Abner and Martin, \{Nicholas G\} and Denis Plotnikov and Chen Jiang and Melles, \{Ronald B\} and Puya Gharahkhani and Harold Snieder and Teele Palumaa and Kuldar Kaljurand and Guggenheim, \{Jeremy A\} and Mackey, \{David A\} and Engle, \{Elizabeth C\} and H{\'e}l{\`e}ne Choquet and Stuart MacGregor and \{Aguirre Gamboa\}, Raul and Patrick Deelen and Lude Franke and Kuivenhoven, \{Jan Albert\} and \{Lopera Maya\}, Esteban and Nolte, \{Ilja M.\} and Serena Sanna and Swertz, \{Morris A.\} and Peter Visscher and Vonk, \{Judith M.\} and C Wijmenga",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = aug,

day = "23",

doi = "10.1038/s41467-025-62456-9",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Lifelines Cohort Study, He, W, van der Most, PJ, Ong, J-S, Hwang, L-D, Wu, Y, Magnø, MS , Vehof, J, Krebs, K, Mauring, L, Õunap, K, Abner, E, Martin, NG, Plotnikov, D, Jiang, C, Melles, RB, Gharahkhani, P, Snieder, H, Palumaa, T, Kaljurand, K, Guggenheim, JA, Mackey, DA, Engle, EC, Choquet, H & MacGregor, S 2025, 'Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking', Nature Communications, vol. 16, 7890. https://doi.org/10.1038/s41467-025-62456-9

TY - JOUR

T1 - Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking

AU - Lifelines Cohort Study

AU - He, Weixiong

AU - van der Most, Peter J

AU - Ong, Jue-Sheng

AU - Hwang, Liang-Dar

AU - Wu, Yeda

AU - Magnø, Morten S

AU - Vehof, Jelle

AU - Krebs, Kristi

AU - Mauring, Laura

AU - Õunap, Katrin

AU - Abner, Erik

AU - Martin, Nicholas G

AU - Plotnikov, Denis

AU - Jiang, Chen

AU - Melles, Ronald B

AU - Gharahkhani, Puya

AU - Snieder, Harold

AU - Palumaa, Teele

AU - Kaljurand, Kuldar

AU - Guggenheim, Jeremy A

AU - Mackey, David A

AU - Engle, Elizabeth C

AU - Choquet, Hélène

AU - MacGregor, Stuart

AU - Aguirre Gamboa, Raul

AU - Deelen, Patrick

AU - Franke, Lude

AU - Kuivenhoven, Jan Albert

AU - Lopera Maya, Esteban

AU - Nolte, Ilja M.

AU - Sanna, Serena

AU - Swertz, Morris A.

AU - Visscher, Peter

AU - Vonk, Judith M.

AU - Wijmenga, C

PY - 2025/8/23

Y1 - 2025/8/23

N2 - 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.

AB - 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.

KW - Humans

KW - Genome-Wide Association Study

KW - Female

KW - Strabismus/genetics

KW - Smoking/adverse effects

KW - Genetic Predisposition to Disease

KW - Risk Factors

KW - Polymorphism, Single Nucleotide

KW - Mendelian Randomization Analysis

KW - Male

KW - Pregnancy

U2 - 10.1038/s41467-025-62456-9

DO - 10.1038/s41467-025-62456-9

M3 - Article

C2 - 40849414

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 7890

ER -

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

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