Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Qing Li; Robert Wojciechowski; Claire L Simpson; Pirro G Hysi; Virginie J M Verhoeven; René Höhn; Veronique Vitart; Alex W Hewitt; Konrad Oexle; Kari-Matti Mäkelä; Stuart MacGregor; Mario Pirastu; Qiao Fan; Ching-Yu Cheng; Beaté St Pourcain; George McMahon; John P Kemp; Kate Northstone; Jugnoo S Rahi; Phillippa M Cumberland; Nicholas G Martin; Paul G Sanfilippo; Yi Lu; Ya Xing Wang; Caroline Hayward; Ozren Polašek; Harry Campbell; Goran Bencic; Juho Wedenoja; Tanja Zeller; Arne Schillert; Alireza Mirshahi; Karl Lackner; Shea Ping Yip; Maurice K H Yap; Janina S Ried; Christian Gieger; Federico Murgia; Brian Fleck; Seyhan Yazar; Johannes R Vingerling; Nicholas J Timpson; David M Evans; Paul Mitchell; Cathy Williams; Andrew D Paterson; Jeremy A Guggenheim; The CREAM Consortium

doi:10.1007/s00439-014-1500-y

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Qing Li, Robert Wojciechowski, Claire L Simpson, Pirro G Hysi, Virginie J M Verhoeven, René Höhn, Veronique Vitart, Alex W Hewitt, Konrad Oexle, Kari-Matti Mäkelä, Stuart MacGregor, Mario Pirastu, Qiao Fan, Ching-Yu Cheng, Beaté St Pourcain, George McMahon, John P Kemp, Kate Northstone, Jugnoo S Rahi, Phillippa M CumberlandNicholas G Martin, Paul G Sanfilippo, Yi Lu, Ya Xing Wang, Caroline Hayward, Ozren Polašek, Harry Campbell, Goran Bencic, Juho Wedenoja, Tanja Zeller, Arne Schillert, Alireza Mirshahi, Karl Lackner, Shea Ping Yip, Maurice K H Yap, Janina S Ried, Christian Gieger, Federico Murgia, Brian Fleck, Seyhan Yazar, Johannes R Vingerling, Nicholas J Timpson, David M Evans, Paul Mitchell, Cathy Williams, Andrew D Paterson, Jeremy A Guggenheim, The CREAM Consortium

Research output: Contribution to journal › Article (Academic Journal) › peer-review

24 Citations (Scopus)

Abstract

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

Original language	English
Pages (from-to)	131-46
Number of pages	16
Journal	Human Genetics
Volume	134
Issue number	2
DOIs	https://doi.org/10.1007/s00439-014-1500-y
Publication status	Published - Feb 2015

Keywords

Adult
Age Factors
Asian Continental Ancestry Group
Astigmatism
Cell Adhesion Molecules, Neuronal
Cohort Studies
European Continental Ancestry Group
Female
Genetic Markers
Genome-Wide Association Study
High Mobility Group Proteins
Humans
Male
Middle Aged
Nerve Tissue Proteins

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MRC UoB UNITE Unit - programme 3
Timpson, N. J. (Principal Investigator) & Timpson, N. J. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research

Professor Kate Northstone
- Kate.Northstonebristol.acuk
- Bristol Medical School (PHS) - Professor of Epidemiology and Medical Statistics
- Bristol Population Health Science Institute
- Cancer
Person: Academic , Member
Professor Nicholas John Timpson
- N.J.Timpsonbristol.acuk
- Bristol Medical School (PHS) - Professor of Genetic Epidemiology
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
- Cancer
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Professor Cathy E M Williams
- Cathy.Williamsbristol.acuk
- Bristol Medical School (PHS) - Professor of Paediatric Ophthalmology
- Bristol Population Health Science Institute
- Ophthalmology
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Cite this

Li, Q., Wojciechowski, R., Simpson, C. L., Hysi, P. G., Verhoeven, V. J. M., Höhn, R., Vitart, V., Hewitt, A. W., Oexle, K., Mäkelä, K.-M., MacGregor, S., Pirastu, M., Fan, Q., Cheng, C.-Y., St Pourcain, B., McMahon, G., Kemp, J. P., Northstone, K., Rahi, J. S., ... The CREAM Consortium (2015). Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium. Human Genetics, 134(2), 131-46. https://doi.org/10.1007/s00439-014-1500-y

@article{030633b219244ad99d8a5a55c2db9e04,

title = "Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium",

abstract = "To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.",

keywords = "Adult, Age Factors, Asian Continental Ancestry Group, Astigmatism, Cell Adhesion Molecules, Neuronal, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genome-Wide Association Study, High Mobility Group Proteins, Humans, Male, Middle Aged, Nerve Tissue Proteins",

author = "Qing Li and Robert Wojciechowski and Simpson, {Claire L} and Hysi, {Pirro G} and Verhoeven, {Virginie J M} and Ren{\'e} H{\"o}hn and Veronique Vitart and Hewitt, {Alex W} and Konrad Oexle and Kari-Matti M{\"a}kel{\"a} and Stuart MacGregor and Mario Pirastu and Qiao Fan and Ching-Yu Cheng and {St Pourcain}, Beat{\'e} and George McMahon and Kemp, {John P} and Kate Northstone and Rahi, {Jugnoo S} and Cumberland, {Phillippa M} and Martin, {Nicholas G} and Sanfilippo, {Paul G} and Yi Lu and Wang, {Ya Xing} and Caroline Hayward and Ozren Pola{\v s}ek and Harry Campbell and Goran Bencic and Juho Wedenoja and Tanja Zeller and Arne Schillert and Alireza Mirshahi and Karl Lackner and Yip, {Shea Ping} and Yap, {Maurice K H} and Ried, {Janina S} and Christian Gieger and Federico Murgia and Brian Fleck and Seyhan Yazar and Vingerling, {Johannes R} and Timpson, {Nicholas J} and Evans, {David M} and Paul Mitchell and Cathy Williams and Paterson, {Andrew D} and Guggenheim, {Jeremy A} and {The CREAM Consortium}",

year = "2015",

month = feb,

doi = "10.1007/s00439-014-1500-y",

language = "English",

volume = "134",

pages = "131--46",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Berlin Heidelberg",

number = "2",

}

Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, VJM, Höhn, R, Vitart, V, Hewitt, AW, Oexle, K, Mäkelä, K-M, MacGregor, S, Pirastu, M, Fan, Q, Cheng, C-Y, St Pourcain, B, McMahon, G, Kemp, JP, Northstone, K, Rahi, JS, Cumberland, PM, Martin, NG, Sanfilippo, PG, Lu, Y, Wang, YX, Hayward, C, Polašek, O, Campbell, H, Bencic, G, Wedenoja, J, Zeller, T, Schillert, A, Mirshahi, A, Lackner, K, Yip, SP, Yap, MKH, Ried, JS, Gieger, C, Murgia, F, Fleck, B, Yazar, S, Vingerling, JR, Timpson, NJ, Evans, DM, Mitchell, P, Williams, C, Paterson, AD, Guggenheim, JA & The CREAM Consortium 2015, 'Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium', Human Genetics, vol. 134, no. 2, pp. 131-46. https://doi.org/10.1007/s00439-014-1500-y

TY - JOUR

T1 - Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error

T2 - the CREAM consortium

AU - Li, Qing

AU - Wojciechowski, Robert

AU - Simpson, Claire L

AU - Hysi, Pirro G

AU - Verhoeven, Virginie J M

AU - Höhn, René

AU - Vitart, Veronique

AU - Hewitt, Alex W

AU - Oexle, Konrad

AU - Mäkelä, Kari-Matti

AU - MacGregor, Stuart

AU - Pirastu, Mario

AU - Fan, Qiao

AU - Cheng, Ching-Yu

AU - St Pourcain, Beaté

AU - McMahon, George

AU - Kemp, John P

AU - Northstone, Kate

AU - Rahi, Jugnoo S

AU - Cumberland, Phillippa M

AU - Martin, Nicholas G

AU - Sanfilippo, Paul G

AU - Lu, Yi

AU - Wang, Ya Xing

AU - Hayward, Caroline

AU - Polašek, Ozren

AU - Campbell, Harry

AU - Bencic, Goran

AU - Wedenoja, Juho

AU - Zeller, Tanja

AU - Schillert, Arne

AU - Mirshahi, Alireza

AU - Lackner, Karl

AU - Yip, Shea Ping

AU - Yap, Maurice K H

AU - Ried, Janina S

AU - Gieger, Christian

AU - Murgia, Federico

AU - Fleck, Brian

AU - Yazar, Seyhan

AU - Vingerling, Johannes R

AU - Timpson, Nicholas J

AU - Evans, David M

AU - Mitchell, Paul

AU - Williams, Cathy

AU - Paterson, Andrew D

AU - Guggenheim, Jeremy A

AU - The CREAM Consortium

PY - 2015/2

Y1 - 2015/2

N2 - To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

AB - To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

KW - Adult

KW - Age Factors

KW - Asian Continental Ancestry Group

KW - Astigmatism

KW - Cell Adhesion Molecules, Neuronal

KW - Cohort Studies

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Markers

KW - Genome-Wide Association Study

KW - High Mobility Group Proteins

KW - Humans

KW - Male

KW - Middle Aged

KW - Nerve Tissue Proteins

U2 - 10.1007/s00439-014-1500-y

DO - 10.1007/s00439-014-1500-y

M3 - Article (Academic Journal)

C2 - 25367360

SN - 0340-6717

VL - 134

SP - 131

EP - 146

JO - Human Genetics

JF - Human Genetics

IS - 2

ER -

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

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Keywords

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MRC UoB UNITE Unit - programme 3

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Professor Kate Northstone

Professor Nicholas John Timpson

Professor Cathy E M Williams

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