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

Hum Genet. 2015 Feb;134(2):131-46. doi: 10.1007/s00439-014-1500-y. Epub 2014 Nov 4.

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.

Publication types

  • Meta-Analysis

MeSH terms

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

Substances

  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal
  • Genetic Markers
  • High Mobility Group Proteins
  • NRXN1 protein, human
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules
  • TOX protein, human