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

Q Li; R Wojciechowski; CL Simpson; PG Hysi; Virginie Verhoeven; MK Ikram; R Hohn; V Vitart; AW Hewitt; K Oexle; KM Makela; S Macgregor; M Pirastu; Q Fan; CY (Ching-Yu) Cheng; B St Pourcain; G McMahon; JP Kemp; K Northstone; JS Rahi; PM Cumberland; NG Martin; PG Sanfilippo; Y (Yi) Lu; YX Wang; C Hayward; O Polasek; H Campbell; G Bencic; AF Wright; J Wedenoja; T Zeller; A Schillert; A Mirshahi; K Lackner; SP Yip; MKH Yap; JS Ried; C Gieger; F Murgia; JF Wilson; B Fleck; S Yazar; Hans Vingerling; Bert Hofman; André Uitterlinden; Fernando Rivadeneira; Najaf Amin; L Karssen; Ben Oostra; X Zhou; YY Teo; ES Tai; E Vithana; V Barathi; YF Zheng; RG Siantar; K Neelam; YC Shin; J (Jan) Lam; E Yonova-Doing; C Venturini; SM Hosseini; HS Wong; T Lehtimaki; M Kahonen; O Raitakari; NJ Timpson; DM Evans; CC Khor; T Aung; TL Young; P Mitchell; B Klein; Cornelia Duijn; T Meitinger; JB Jonas; PN Baird; DA Mackey; TY Wong; SM Saw; O Parssinen; D Stambolian; CJ Hammond; Caroline Klaver; C Williams; AD Paterson; JE Bailey-Wilson; JA Guggenheim

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

Q Li, R Wojciechowski, CL Simpson, PG Hysi, Virginie Verhoeven, MK Ikram, R Hohn, V Vitart, AW Hewitt, K Oexle, KM Makela, S Macgregor, M Pirastu, Q Fan, CY (Ching-Yu) Cheng, B St Pourcain, G McMahon, JP Kemp, K Northstone, JS RahiPM Cumberland, NG Martin, PG Sanfilippo, Y (Yi) Lu, YX Wang, C Hayward, O Polasek, H Campbell, G Bencic, AF Wright, J Wedenoja, T Zeller, A Schillert, A Mirshahi, K Lackner, SP Yip, MKH Yap, JS Ried, C Gieger, F Murgia, JF Wilson, B Fleck, S Yazar, Hans Vingerling, Bert Hofman, André Uitterlinden, Fernando Rivadeneira, Najaf Amin, L Karssen, Ben Oostra, X Zhou, YY Teo, ES Tai, E Vithana, V Barathi, YF Zheng, RG Siantar, K Neelam, YC Shin, J (Jan) Lam, E Yonova-Doing, C Venturini, SM Hosseini, HS Wong, T Lehtimaki, M Kahonen, O Raitakari, NJ Timpson, DM Evans, CC Khor, T Aung, TL Young, P Mitchell, B Klein, Cornelia Duijn, T Meitinger, JB Jonas, PN Baird, DA Mackey, TY Wong, SM Saw, O Parssinen, D Stambolian, CJ Hammond, Caroline Klaver, C Williams, AD Paterson, JE Bailey-Wilson, JA Guggenheim

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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	Undefined/Unknown
Pages (from-to)	131-146
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 - 2015

Research programs

EMC MGC-02-96-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC OR-01-60-01

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Li, Q., Wojciechowski, R., Simpson, CL., Hysi, PG., Verhoeven, V., Ikram, MK., Hohn, R., Vitart, V., Hewitt, AW., Oexle, K., Makela, KM., Macgregor, S., Pirastu, M., Fan, Q., Cheng, CY., St Pourcain, B., McMahon, G., Kemp, JP., Northstone, K., ... Guggenheim, JA. (2015). Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium. Human Genetics, 134(2), 131-146. https://doi.org/10.1007/s00439-014-1500-y

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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 = "Q Li and R Wojciechowski and CL Simpson and PG Hysi and Virginie Verhoeven and MK Ikram and R Hohn and V Vitart and AW Hewitt and K Oexle and KM Makela and S Macgregor and M Pirastu and Q Fan and Cheng, {CY (Ching-Yu)} and {St Pourcain}, B and G McMahon and JP Kemp and K Northstone and JS Rahi and PM Cumberland and NG Martin and PG Sanfilippo and Lu, {Y (Yi)} and YX Wang and C Hayward and O Polasek and H Campbell and G Bencic and AF Wright and J Wedenoja and T Zeller and A Schillert and A Mirshahi and K Lackner and SP Yip and MKH Yap and JS Ried and C Gieger and F Murgia and JF Wilson and B Fleck and S Yazar and Hans Vingerling and Bert Hofman and Andr{\'e} Uitterlinden and Fernando Rivadeneira and Najaf Amin and L Karssen and Ben Oostra and X Zhou and YY Teo and ES Tai and E Vithana and V Barathi and YF Zheng and RG Siantar and K Neelam and YC Shin and Lam, {J (Jan)} and E Yonova-Doing and C Venturini and SM Hosseini and HS Wong and T Lehtimaki and M Kahonen and O Raitakari and NJ Timpson and DM Evans and CC Khor and T Aung and TL Young and P Mitchell and B Klein and Cornelia Duijn and T Meitinger and JB Jonas and PN Baird and DA Mackey and TY Wong and SM Saw and O Parssinen and D Stambolian and CJ Hammond and Caroline Klaver and C Williams and AD Paterson and JE Bailey-Wilson and JA Guggenheim",

year = "2015",

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

language = "Undefined/Unknown",

volume = "134",

pages = "131--146",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Science+Business Media",

number = "2",

}

Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, V, Ikram, MK, Hohn, R, Vitart, V, Hewitt, AW, Oexle, K, Makela, 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, Polasek, 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, H , Hofman, B , Uitterlinden, A , Rivadeneira, F , Amin, N, Karssen, L, Oostra, B, Zhou, X, Teo, YY, Tai, ES, Vithana, E, Barathi, V, Zheng, YF, Siantar, RG, Neelam, K, Shin, YC, Lam, J, Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, HS, Lehtimaki, T, Kahonen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, CC, Aung, T, Young, TL, Mitchell, P, Klein, B, Duijn, C, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, SM, Parssinen, O, Stambolian, D, Hammond, CJ, Klaver, C, 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

TY - JOUR

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

AU - Li, Q

AU - Wojciechowski, R

AU - Simpson, CL

AU - Hysi, PG

AU - Verhoeven, Virginie

AU - Ikram, MK

AU - Hohn, R

AU - Vitart, V

AU - Hewitt, AW

AU - Oexle, K

AU - Makela, KM

AU - Macgregor, S

AU - Pirastu, M

AU - Fan, Q

AU - Cheng, CY (Ching-Yu)

AU - St Pourcain, B

AU - McMahon, G

AU - Kemp, JP

AU - Northstone, K

AU - Rahi, JS

AU - Cumberland, PM

AU - Martin, NG

AU - Sanfilippo, PG

AU - Lu, Y (Yi)

AU - Wang, YX

AU - Hayward, C

AU - Polasek, O

AU - Campbell, H

AU - Bencic, G

AU - Wright, AF

AU - Wedenoja, J

AU - Zeller, T

AU - Schillert, A

AU - Mirshahi, A

AU - Lackner, K

AU - Yip, SP

AU - Yap, MKH

AU - Ried, JS

AU - Gieger, C

AU - Murgia, F

AU - Wilson, JF

AU - Fleck, B

AU - Yazar, S

AU - Vingerling, Hans

AU - Hofman, Bert

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - Amin, Najaf

AU - Karssen, L

AU - Oostra, Ben

AU - Zhou, X

AU - Teo, YY

AU - Tai, ES

AU - Vithana, E

AU - Barathi, V

AU - Zheng, YF

AU - Siantar, RG

AU - Neelam, K

AU - Shin, YC

AU - Lam, J (Jan)

AU - Yonova-Doing, E

AU - Venturini, C

AU - Hosseini, SM

AU - Wong, HS

AU - Lehtimaki, T

AU - Kahonen, M

AU - Raitakari, O

AU - Timpson, NJ

AU - Evans, DM

AU - Khor, CC

AU - Aung, T

AU - Young, TL

AU - Mitchell, P

AU - Klein, B

AU - Duijn, Cornelia

AU - Meitinger, T

AU - Jonas, JB

AU - Baird, PN

AU - Mackey, DA

AU - Wong, TY

AU - Saw, SM

AU - Parssinen, O

AU - Stambolian, D

AU - Hammond, CJ

AU - Klaver, Caroline

AU - Williams, C

AU - Paterson, AD

AU - Bailey-Wilson, JE

AU - Guggenheim, JA

PY - 2015

Y1 - 2015

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.

U2 - 10.1007/s00439-014-1500-y

DO - 10.1007/s00439-014-1500-y

M3 - Article

C2 - 25367360

SN - 0340-6717

VL - 134

SP - 131

EP - 146

JO - Human Genetics

JF - Human Genetics

IS - 2

ER -