Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent

Fei Chen, Priya Duggal, Barbara E K Klein, Kristine E. Lee, Barbara Truitt, Ronald Klein, Sudha K. Iyengar, Alison Klein

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Methods: 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. Results: 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 r2 = 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)783-796
Number of pages14
JournalMolecular Vision
Volume22
StatePublished - Jul 14 2016

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Myopia
Genes
Gene Frequency
Hyperopia
Refractive Errors
Ocular Refraction
Exome
Vision Disorders
Linkage Disequilibrium
Blindness
Lenses
Retina
Rodentia
Nucleotides
Genome

ASJC Scopus subject areas

  • Ophthalmology

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Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent. / Chen, Fei; Duggal, Priya; Klein, Barbara E K; Lee, Kristine E.; Truitt, Barbara; Klein, Ronald; Iyengar, Sudha K.; Klein, Alison.

In: Molecular Vision, Vol. 22, 14.07.2016, p. 783-796.

Research output: Contribution to journalArticle

Chen, F, Duggal, P, Klein, BEK, Lee, KE, Truitt, B, Klein, R, Iyengar, SK & Klein, A 2016, 'Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent', Molecular Vision, vol. 22, pp. 783-796.
Chen F, Duggal P, Klein BEK, Lee KE, Truitt B, Klein R et al. Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent. Molecular Vision. 2016 Jul 14;22:783-796.
Chen, Fei ; Duggal, Priya ; Klein, Barbara E K ; Lee, Kristine E. ; Truitt, Barbara ; Klein, Ronald ; Iyengar, Sudha K. ; Klein, Alison. / Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent. In: Molecular Vision. 2016 ; Vol. 22. pp. 783-796.
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abstract = "Purpose: 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. Methods: 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. Results: 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 r2 = 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. Conclusions: 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.",
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T1 - Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent

AU - Chen, Fei

AU - Duggal, Priya

AU - Klein, Barbara E K

AU - Lee, Kristine E.

AU - Truitt, Barbara

AU - Klein, Ronald

AU - Iyengar, Sudha K.

AU - Klein, Alison

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N2 - Purpose: 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. Methods: 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. Results: 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 r2 = 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. Conclusions: 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.

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