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

TY - JOUR

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

AU - Li, Qing

AU - Wojciechowski, Robert

AU - Simpson, Claire L

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

AU - 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/genetics

KW - Calcium-Binding Proteins

KW - Cell Adhesion Molecules, Neuronal/genetics

KW - Cohort Studies

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Markers

KW - Genome-Wide Association Study

KW - High Mobility Group Proteins/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Nerve Tissue Proteins/genetics

KW - Neural Cell Adhesion Molecules

U2 - 10.1007/s00439-014-1500-y

DO - 10.1007/s00439-014-1500-y

M3 - SCORING: Journal article

C2 - 25367360

VL - 134

SP - 131

EP - 146

JO - HUM GENET

JF - HUM GENET

SN - 0340-6717

IS - 2

ER -