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

the CREAM consortium

Qing Li, Robert Wojciechowski, Claire Simpson, Pirro G. Hysi, Virginie J.M. Verhoeven, Mohammad Kamran Ikram, 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 & 69 others Phillippa M. Cumberland, Nicholas G. Martin, Paul G. Sanfilippo, Yi Lu, Ya Xing Wang, Caroline Hayward, Ozren Polašek, Harry Campbell, Goran Bencic, Alan F. Wright, Juho Wedenoja, Tanja Zeller, Arne Schillert, Alireza Mirshahi, Karl Lackner, Shea Ping Yip, Maurice K.H. Yap, Janina S. Ried, Christian Gieger, Federico Murgia, James F. Wilson, Brian Fleck, Seyhan Yazar, Johannes R. Vingerling, Albert Hofman, André Uitterlinden, Fernando Rivadeneira, Najaf Amin, Lennart Karssen, Ben A. Oostra, Xin Zhou, Yik Ying Teo, E. Shyong Tai, Eranga Vithana, Veluchamy Barathi, Yingfeng Zheng, Rosalynn Grace Siantar, Kumari Neelam, Youchan Shin, Janice Lam, Ekaterina Yonova-Doing, Cristina Venturini, S. Mohsen Hosseini, Hoi Suen Wong, Terho Lehtimäki, Mika Kähönen, Olli Raitakari, Nicholas J. Timpson, David M. Evans, Chiea Chuen Khor, Tin Aung, Terri L. Young, Paul Mitchell, Barbara Klein, Cornelia M. van Duijn, Thomas Meitinger, Jost B. Jonas, Paul N. Baird, David A. Mackey, Tien Yin Wong, Seang Mei Saw, Olavi Pärssinen, Dwight Stambolian, Christopher J. Hammond, Caroline C.W. Klaver, Cathy Williams, Andrew D. Paterson, Joan E. Bailey-Wilson, Jeremy A. Guggenheim

Research output: Contribution to journalArticle

12 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 languageEnglish (US)
Pages (from-to)131-146
Number of pages16
JournalHuman genetics
Volume134
Issue number2
DOIs
StatePublished - Jan 13 2015

Fingerprint

Refractive Errors
Astigmatism
Genome-Wide Association Study
Meta-Analysis
Genotype
Genome
Genetic Predisposition to Disease
Genes
Logistic Models
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error : the CREAM consortium. / Li, Qing; Wojciechowski, Robert; Simpson, Claire; Hysi, Pirro G.; Verhoeven, Virginie J.M.; Ikram, Mohammad Kamran; Höhn, René; Vitart, Veronique; Hewitt, Alex W.; Oexle, Konrad; Mäkelä, Kari Matti; MacGregor, Stuart; Pirastu, Mario; Fan, Qiao; Cheng, Ching Yu; St Pourcain, Beaté; McMahon, George; Kemp, John P.; Northstone, Kate; Rahi, Jugnoo S.; Cumberland, Phillippa M.; Martin, Nicholas G.; Sanfilippo, Paul G.; Lu, Yi; Wang, Ya Xing; Hayward, Caroline; Polašek, Ozren; Campbell, Harry; Bencic, Goran; Wright, Alan F.; Wedenoja, Juho; Zeller, Tanja; Schillert, Arne; Mirshahi, Alireza; Lackner, Karl; Yip, Shea Ping; Yap, Maurice K.H.; Ried, Janina S.; Gieger, Christian; Murgia, Federico; Wilson, James F.; Fleck, Brian; Yazar, Seyhan; Vingerling, Johannes R.; Hofman, Albert; Uitterlinden, André; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart; Oostra, Ben A.; Zhou, Xin; Teo, Yik Ying; Tai, E. Shyong; Vithana, Eranga; Barathi, Veluchamy; Zheng, Yingfeng; Siantar, Rosalynn Grace; Neelam, Kumari; Shin, Youchan; Lam, Janice; Yonova-Doing, Ekaterina; Venturini, Cristina; Hosseini, S. Mohsen; Wong, Hoi Suen; Lehtimäki, Terho; Kähönen, Mika; Raitakari, Olli; Timpson, Nicholas J.; Evans, David M.; Khor, Chiea Chuen; Aung, Tin; Young, Terri L.; Mitchell, Paul; Klein, Barbara; van Duijn, Cornelia M.; Meitinger, Thomas; Jonas, Jost B.; Baird, Paul N.; Mackey, David A.; Wong, Tien Yin; Saw, Seang Mei; Pärssinen, Olavi; Stambolian, Dwight; Hammond, Christopher J.; Klaver, Caroline C.W.; Williams, Cathy; Paterson, Andrew D.; Bailey-Wilson, Joan E.; Guggenheim, Jeremy A.

In: Human genetics, Vol. 134, No. 2, 13.01.2015, p. 131-146.

Research output: Contribution to journalArticle

Li, Q, Wojciechowski, R, Simpson, C, Hysi, PG, Verhoeven, VJM, Ikram, MK, Höhn, R, Vitart, V, Hewitt, AW, Oexle, K, Mäkelä, KM, MacGregor, S, Pirastu, M, Fan, Q, Cheng, CY, 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, Wright, AF, Wedenoja, J, Zeller, T, Schillert, A, Mirshahi, A, Lackner, K, Yip, SP, Yap, MKH, Ried, JS, Gieger, C, Murgia, F, Wilson, JF, Fleck, B, Yazar, S, Vingerling, JR, Hofman, A, Uitterlinden, A, Rivadeneira, F, Amin, N, Karssen, L, Oostra, BA, Zhou, X, Teo, YY, Tai, ES, Vithana, E, Barathi, V, Zheng, Y, Siantar, RG, Neelam, K, Shin, Y, Lam, J, Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, HS, Lehtimäki, T, Kähönen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, CC, Aung, T, Young, TL, Mitchell, P, Klein, B, van Duijn, CM, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, SM, Pärssinen, O, Stambolian, D, Hammond, CJ, Klaver, CCW, Williams, C, Paterson, AD, Bailey-Wilson, JE & Guggenheim, JA 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. 131-146. https://doi.org/10.1007/s00439-014-1500-y
Li, Qing ; Wojciechowski, Robert ; Simpson, Claire ; Hysi, Pirro G. ; Verhoeven, Virginie J.M. ; Ikram, Mohammad Kamran ; Höhn, René ; Vitart, Veronique ; Hewitt, Alex W. ; Oexle, Konrad ; Mäkelä, Kari Matti ; MacGregor, Stuart ; Pirastu, Mario ; Fan, Qiao ; Cheng, Ching Yu ; St Pourcain, Beaté ; McMahon, George ; Kemp, John P. ; Northstone, Kate ; Rahi, Jugnoo S. ; Cumberland, Phillippa M. ; Martin, Nicholas G. ; Sanfilippo, Paul G. ; Lu, Yi ; Wang, Ya Xing ; Hayward, Caroline ; Polašek, Ozren ; Campbell, Harry ; Bencic, Goran ; Wright, Alan F. ; Wedenoja, Juho ; Zeller, Tanja ; Schillert, Arne ; Mirshahi, Alireza ; Lackner, Karl ; Yip, Shea Ping ; Yap, Maurice K.H. ; Ried, Janina S. ; Gieger, Christian ; Murgia, Federico ; Wilson, James F. ; Fleck, Brian ; Yazar, Seyhan ; Vingerling, Johannes R. ; Hofman, Albert ; Uitterlinden, André ; Rivadeneira, Fernando ; Amin, Najaf ; Karssen, Lennart ; Oostra, Ben A. ; Zhou, Xin ; Teo, Yik Ying ; Tai, E. Shyong ; Vithana, Eranga ; Barathi, Veluchamy ; Zheng, Yingfeng ; Siantar, Rosalynn Grace ; Neelam, Kumari ; Shin, Youchan ; Lam, Janice ; Yonova-Doing, Ekaterina ; Venturini, Cristina ; Hosseini, S. Mohsen ; Wong, Hoi Suen ; Lehtimäki, Terho ; Kähönen, Mika ; Raitakari, Olli ; Timpson, Nicholas J. ; Evans, David M. ; Khor, Chiea Chuen ; Aung, Tin ; Young, Terri L. ; Mitchell, Paul ; Klein, Barbara ; van Duijn, Cornelia M. ; Meitinger, Thomas ; Jonas, Jost B. ; Baird, Paul N. ; Mackey, David A. ; Wong, Tien Yin ; Saw, Seang Mei ; Pärssinen, Olavi ; Stambolian, Dwight ; Hammond, Christopher J. ; Klaver, Caroline C.W. ; Williams, Cathy ; Paterson, Andrew D. ; Bailey-Wilson, Joan E. ; Guggenheim, Jeremy A. / Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error : the CREAM consortium. In: Human genetics. 2015 ; Vol. 134, No. 2. pp. 131-146.
@article{90ac2b8f3453405285648391511d155e,
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.",
author = "Qing Li and Robert Wojciechowski and Claire Simpson and Hysi, {Pirro G.} and Verhoeven, {Virginie J.M.} and Ikram, {Mohammad Kamran} and Ren{\'e} H{\"o}hn and Veronique Vitart and Hewitt, {Alex W.} and Konrad Oexle and M{\"a}kel{\"a}, {Kari Matti} and Stuart MacGregor and Mario Pirastu and Qiao Fan and Cheng, {Ching Yu} 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 Polašek and Harry Campbell and Goran Bencic and Wright, {Alan F.} 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 Wilson, {James F.} and Brian Fleck and Seyhan Yazar and Vingerling, {Johannes R.} and Albert Hofman and Andr{\'e} Uitterlinden and Fernando Rivadeneira and Najaf Amin and Lennart Karssen and Oostra, {Ben A.} and Xin Zhou and Teo, {Yik Ying} and Tai, {E. Shyong} and Eranga Vithana and Veluchamy Barathi and Yingfeng Zheng and Siantar, {Rosalynn Grace} and Kumari Neelam and Youchan Shin and Janice Lam and Ekaterina Yonova-Doing and Cristina Venturini and Hosseini, {S. Mohsen} and Wong, {Hoi Suen} and Terho Lehtim{\"a}ki and Mika K{\"a}h{\"o}nen and Olli Raitakari and Timpson, {Nicholas J.} and Evans, {David M.} and Khor, {Chiea Chuen} and Tin Aung and Young, {Terri L.} and Paul Mitchell and Barbara Klein and {van Duijn}, {Cornelia M.} and Thomas Meitinger and Jonas, {Jost B.} and Baird, {Paul N.} and Mackey, {David A.} and Wong, {Tien Yin} and Saw, {Seang Mei} and Olavi P{\"a}rssinen and Dwight Stambolian and Hammond, {Christopher J.} and Klaver, {Caroline C.W.} and Cathy Williams and Paterson, {Andrew D.} and Bailey-Wilson, {Joan E.} and Guggenheim, {Jeremy A.}",
year = "2015",
month = "1",
day = "13",
doi = "10.1007/s00439-014-1500-y",
language = "English (US)",
volume = "134",
pages = "131--146",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "2",

}

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

AU - Hysi, Pirro G.

AU - Verhoeven, Virginie J.M.

AU - Ikram, Mohammad Kamran

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 - Wright, Alan F.

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 - Wilson, James F.

AU - Fleck, Brian

AU - Yazar, Seyhan

AU - Vingerling, Johannes R.

AU - Hofman, Albert

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - Amin, Najaf

AU - Karssen, Lennart

AU - Oostra, Ben A.

AU - Zhou, Xin

AU - Teo, Yik Ying

AU - Tai, E. Shyong

AU - Vithana, Eranga

AU - Barathi, Veluchamy

AU - Zheng, Yingfeng

AU - Siantar, Rosalynn Grace

AU - Neelam, Kumari

AU - Shin, Youchan

AU - Lam, Janice

AU - Yonova-Doing, Ekaterina

AU - Venturini, Cristina

AU - Hosseini, S. Mohsen

AU - Wong, Hoi Suen

AU - Lehtimäki, Terho

AU - Kähönen, Mika

AU - Raitakari, Olli

AU - Timpson, Nicholas J.

AU - Evans, David M.

AU - Khor, Chiea Chuen

AU - Aung, Tin

AU - Young, Terri L.

AU - Mitchell, Paul

AU - Klein, Barbara

AU - van Duijn, Cornelia M.

AU - Meitinger, Thomas

AU - Jonas, Jost B.

AU - Baird, Paul N.

AU - Mackey, David A.

AU - Wong, Tien Yin

AU - Saw, Seang Mei

AU - Pärssinen, Olavi

AU - Stambolian, Dwight

AU - Hammond, Christopher J.

AU - Klaver, Caroline C.W.

AU - Williams, Cathy

AU - Paterson, Andrew D.

AU - Bailey-Wilson, Joan E.

AU - Guggenheim, Jeremy A.

PY - 2015/1/13

Y1 - 2015/1/13

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.

UR - http://www.scopus.com/inward/record.url?scp=84925501566&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925501566&partnerID=8YFLogxK

U2 - 10.1007/s00439-014-1500-y

DO - 10.1007/s00439-014-1500-y

M3 - Article

VL - 134

SP - 131

EP - 146

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 2

ER -