Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development

UK Biobank Eye and Vision Consortium

doi:10.1038/s42003-019-0387-5

Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development

UK Biobank Eye and Vision Consortium

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Abstract

A genetic contribution to refractive error has been confirmed by the discovery of more than 150 associated variants in genome-wide association studies (GWAS). Environmental factors such as education and time outdoors also demonstrate strong associations. Currently however, the extent of gene-environment or gene-gene interactions in myopia is unknown. We tested the hypothesis that refractive error-associated variants exhibit effect size heterogeneity, a hallmark feature of genetic interactions. Of 146 variants tested, evidence of non-uniform, non-linear effects were observed for 66 (45%) at Bonferroni-corrected significance (P < 1.1 × 10⁻⁴) and 128 (88%) at nominal significance (P < 0.05). LAMA2 variant rs12193446, for example, had an effect size varying from −0.20 diopters (95% CI −0.18 to −0.23) to −0.89 diopters (95% CI −0.71 to −1.07) in different individuals. SNP effects were strongest at the phenotype extremes and weaker in emmetropes. A parsimonious explanation for these findings is that gene-environment or gene-gene interactions in myopia are pervasive.

Original language	English
Article number	167
Journal	Communications Biology
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s42003-019-0387-5
Publication status	Published - 06 May 2019

Bibliographical note

Funding Information:
The work was funded by the National Eye Research Centre grant SAC015 (JAG, CW), and an NIHR Senior Research Fellowship award SRF-2015-08-005 (CW). UK Biobank was established by the Wellcome Trust; the UK Medical Research Council; the Department for Health (London, UK); Scottish Government (Edinburgh, UK); and the Northwest Regional Development Agency (Warrington, UK). It also received funding from the Welsh Assembly Government (Cardiff, UK); the British Heart Foundation; and Diabetes UK. Collection of eye and vision data was supported by The Department for Health through an award made by the NIHR to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, United Kingdom (grant no. BRC2_009). Additional support was provided by The Special Trustees of Moorfields Eye Hospital, London, United Kingdom (grant no. ST 12 09). Data analysis was carried out using the RAVEN computing cluster, maintained by the ARCCA group at Cardiff University ARCCA and the BLUE CRYSTAL3 computing cluster maintained by the HPC group at the University of Bristol.

Publisher Copyright:
© 2019, The Author(s).

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology
General Agricultural and Biological Sciences
Medicine (miscellaneous)

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Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Cite this

@article{0f19e10f8de2491582bb21867b31b71e,

title = "Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development",

abstract = "A genetic contribution to refractive error has been confirmed by the discovery of more than 150 associated variants in genome-wide association studies (GWAS). Environmental factors such as education and time outdoors also demonstrate strong associations. Currently however, the extent of gene-environment or gene-gene interactions in myopia is unknown. We tested the hypothesis that refractive error-associated variants exhibit effect size heterogeneity, a hallmark feature of genetic interactions. Of 146 variants tested, evidence of non-uniform, non-linear effects were observed for 66 (45%) at Bonferroni-corrected significance (P < 1.1 × 10−4) and 128 (88%) at nominal significance (P < 0.05). LAMA2 variant rs12193446, for example, had an effect size varying from −0.20 diopters (95% CI −0.18 to −0.23) to −0.89 diopters (95% CI −0.71 to −1.07) in different individuals. SNP effects were strongest at the phenotype extremes and weaker in emmetropes. A parsimonious explanation for these findings is that gene-environment or gene-gene interactions in myopia are pervasive.",

author = "Alfred Pozarickij and Cathy Williams and Hysi, {Pirro G.} and Guggenheim, {Jeremy A.} and Tariq Aslam and Barman, {Sarah A.} and Barrett, {Jenny H.} and Paul Bishop and Peter Blows and Catey Bunce and Carare, {Roxana O.} and Usha Chakravarthy and Michelle Chan and Chua, {Sharon Y.L.} and Crabb, {David P.} and Cumberland, {Philippa M.} and Alexander Day and Parul Desai and Bal Dhillon and Dick, {Andrew D.} and Cathy Egan and Sarah Ennis and Paul Foster and Marcus Fruttiger and Gallacher, {John E.J.} and Garway-Heath, {David F.} and Jane Gibson and Dan Gore and Hammond, {Chris J.} and Alison Hardcastle and Harding, {Simon P.} and Hogg, {Ruth E.} and Keane, {Pearse A.} and Khaw, {Sir Peng T.} and Khawaja, {Anthony P.} and Gerassimos Lascaratos and Lotery, {Andrew J.} and {Mac Gillivray}, Tom and Sarah Mackie and Keith Martin and Michelle McGaughey and Bernadette McGuinness and McKay, {Gareth J.} and Martin McKibbin and Danny Mitry and Tony Moore and Euan Paterson and Tunde Peto and David Steel and Woodside, {Jayne V.} and {UK Biobank Eye and Vision Consortium}",

note = "Funding Information: The work was funded by the National Eye Research Centre grant SAC015 (JAG, CW), and an NIHR Senior Research Fellowship award SRF-2015-08-005 (CW). UK Biobank was established by the Wellcome Trust; the UK Medical Research Council; the Department for Health (London, UK); Scottish Government (Edinburgh, UK); and the Northwest Regional Development Agency (Warrington, UK). It also received funding from the Welsh Assembly Government (Cardiff, UK); the British Heart Foundation; and Diabetes UK. Collection of eye and vision data was supported by The Department for Health through an award made by the NIHR to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, United Kingdom (grant no. BRC2_009). Additional support was provided by The Special Trustees of Moorfields Eye Hospital, London, United Kingdom (grant no. ST 12 09). Data analysis was carried out using the RAVEN computing cluster, maintained by the ARCCA group at Cardiff University ARCCA and the BLUE CRYSTAL3 computing cluster maintained by the HPC group at the University of Bristol. Publisher Copyright: {\textcopyright} 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = may,

day = "6",

doi = "10.1038/s42003-019-0387-5",

language = "English",

volume = "2",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Nature Research",

number = "1",

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TY - JOUR

T1 - Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development

AU - Pozarickij, Alfred

AU - Williams, Cathy

AU - Hysi, Pirro G.

AU - Guggenheim, Jeremy A.

AU - Aslam, Tariq

AU - Barman, Sarah A.

AU - Barrett, Jenny H.

AU - Bishop, Paul

AU - Blows, Peter

AU - Bunce, Catey

AU - Carare, Roxana O.

AU - Chakravarthy, Usha

AU - Chan, Michelle

AU - Chua, Sharon Y.L.

AU - Crabb, David P.

AU - Cumberland, Philippa M.

AU - Day, Alexander

AU - Desai, Parul

AU - Dhillon, Bal

AU - Dick, Andrew D.

AU - Egan, Cathy

AU - Ennis, Sarah

AU - Foster, Paul

AU - Fruttiger, Marcus

AU - Gallacher, John E.J.

AU - Garway-Heath, David F.

AU - Gibson, Jane

AU - Gore, Dan

AU - Hammond, Chris J.

AU - Hardcastle, Alison

AU - Harding, Simon P.

AU - Hogg, Ruth E.

AU - Keane, Pearse A.

AU - Khaw, Sir Peng T.

AU - Khawaja, Anthony P.

AU - Lascaratos, Gerassimos

AU - Lotery, Andrew J.

AU - Mac Gillivray, Tom

AU - Mackie, Sarah

AU - Martin, Keith

AU - McGaughey, Michelle

AU - McGuinness, Bernadette

AU - McKay, Gareth J.

AU - McKibbin, Martin

AU - Mitry, Danny

AU - Moore, Tony

AU - Paterson, Euan

AU - Peto, Tunde

AU - Steel, David

AU - Woodside, Jayne V.

AU - UK Biobank Eye and Vision Consortium

N1 - Funding Information: The work was funded by the National Eye Research Centre grant SAC015 (JAG, CW), and an NIHR Senior Research Fellowship award SRF-2015-08-005 (CW). UK Biobank was established by the Wellcome Trust; the UK Medical Research Council; the Department for Health (London, UK); Scottish Government (Edinburgh, UK); and the Northwest Regional Development Agency (Warrington, UK). It also received funding from the Welsh Assembly Government (Cardiff, UK); the British Heart Foundation; and Diabetes UK. Collection of eye and vision data was supported by The Department for Health through an award made by the NIHR to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, United Kingdom (grant no. BRC2_009). Additional support was provided by The Special Trustees of Moorfields Eye Hospital, London, United Kingdom (grant no. ST 12 09). Data analysis was carried out using the RAVEN computing cluster, maintained by the ARCCA group at Cardiff University ARCCA and the BLUE CRYSTAL3 computing cluster maintained by the HPC group at the University of Bristol. Publisher Copyright: © 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/5/6

Y1 - 2019/5/6

N2 - A genetic contribution to refractive error has been confirmed by the discovery of more than 150 associated variants in genome-wide association studies (GWAS). Environmental factors such as education and time outdoors also demonstrate strong associations. Currently however, the extent of gene-environment or gene-gene interactions in myopia is unknown. We tested the hypothesis that refractive error-associated variants exhibit effect size heterogeneity, a hallmark feature of genetic interactions. Of 146 variants tested, evidence of non-uniform, non-linear effects were observed for 66 (45%) at Bonferroni-corrected significance (P < 1.1 × 10−4) and 128 (88%) at nominal significance (P < 0.05). LAMA2 variant rs12193446, for example, had an effect size varying from −0.20 diopters (95% CI −0.18 to −0.23) to −0.89 diopters (95% CI −0.71 to −1.07) in different individuals. SNP effects were strongest at the phenotype extremes and weaker in emmetropes. A parsimonious explanation for these findings is that gene-environment or gene-gene interactions in myopia are pervasive.

AB - A genetic contribution to refractive error has been confirmed by the discovery of more than 150 associated variants in genome-wide association studies (GWAS). Environmental factors such as education and time outdoors also demonstrate strong associations. Currently however, the extent of gene-environment or gene-gene interactions in myopia is unknown. We tested the hypothesis that refractive error-associated variants exhibit effect size heterogeneity, a hallmark feature of genetic interactions. Of 146 variants tested, evidence of non-uniform, non-linear effects were observed for 66 (45%) at Bonferroni-corrected significance (P < 1.1 × 10−4) and 128 (88%) at nominal significance (P < 0.05). LAMA2 variant rs12193446, for example, had an effect size varying from −0.20 diopters (95% CI −0.18 to −0.23) to −0.89 diopters (95% CI −0.71 to −1.07) in different individuals. SNP effects were strongest at the phenotype extremes and weaker in emmetropes. A parsimonious explanation for these findings is that gene-environment or gene-gene interactions in myopia are pervasive.

U2 - 10.1038/s42003-019-0387-5

DO - 10.1038/s42003-019-0387-5

M3 - Article

C2 - 31924992

AN - SCOPUS:85071011090

SN - 2399-3642

VL - 2

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 167

ER -

Quantile regression analysis reveals widespread evidence for gene-environment or gene-gene interactions in myopia development

Abstract

Bibliographical note

ASJC Scopus subject areas

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