title: Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent.
abstract: Ocular refraction is measured in spherical equivalent as the power of the external lens required to focus images on the retina. Myopia (nearsightedness) and hyperopia (farsightedness) are the most common refractive errors, and the leading causes of visual impairment and blindness in the world. The goal of this study is to identify rare and low-frequency variants that influence spherical equivalent.
  
  
  
  We conducted variant-level and gene-level quantitative trait association analyses for mean spherical equivalent, using data from 1,560 individuals in the Beaver Dam Eye Study. Genotyping was conducted using the Illumina exome array. We analyzed 34,976 single nucleotide variants and 11,571 autosomal genes across the genome, using single-variant tests as well as gene-based tests.
  
  
  
  Spherical equivalent was significantly associated with five genes in gene-based analysis: PTCHD2 at 1p36.22 (p = 3.6 × 10(-7)), CRISP3 at 6p12.3 (p = 4.3 × 10(-6)), NAP1L4 at 11p15.5 (p = 3.6 × 10(-6)), FSCB at 14q21.2 (p = 1.5 × 10(-7)), and AP3B2 at 15q25.2 (p = 1.6 × 10(-7)). The variant-based tests identified evidence suggestive of association with two novel variants in linkage disequilibrium (pairwise r(2) = 0.80) in the TCTE1 gene region at 6p21.1 (rs2297336, minor allele frequency (MAF) = 14.1%, β = -0.62 p = 3.7 × 10(-6); rs324146, MAF = 16.9%, β = -0.55, p = 1.4 × 10(-5)). In addition to these novel findings, we successfully replicated a previously reported association with rs634990 near GJD2 at 15q14 (MAF = 47%, β = -0.29, p=1.8 × 10(-3)). We also found evidence of association with spherical equivalent on 2q37.1 in PRSS56 at rs1550094 (MAF = 31%, β = -0.33, p = 1.7 × 10(-3)), a region previously associated with myopia.
  
  
  
  We identified several novel candidate genes that may play a role in the control of spherical equivalent. However, further studies are needed to replicate these findings. In addition, our results contribute to the increasing evidence that variation in the GJD2 and PRSS56 genes influence the development of refractive errors. Identifying that variation in these genes is associated with spherical equivalent may provide further insight into the etiology of myopia and consequent vision loss.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Barbara E K
authors.initials: BE
authors.lastname: Klein
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH.
authors.forename: Barbara
authors.initials: B
authors.lastname: Truitt
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH.
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics*; D033966:Adaptor Protein Complex beta Subunits / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009216:Myopia / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012471:Salivary Proteins and Peptides / Q000235:genetics*; D029589:Seminal Plasma Proteins / Q000235:genetics*
chemical_list: C095597:AP3B2 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; C489926:CRISP3 protein, human; D002135:Calcium-Binding Proteins; C502279:DISP3 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; C104356:NAP1L4 protein, human; D009687:Nuclear Proteins; D012471:Salivary Proteins and Peptides; D029589:Seminal Plasma Proteins