Dataset Information

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

ABSTRACT: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N?=?10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P?=?6.6E-08) and 2.3% (P?=?6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N?=?5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P?=?6.3E-04).

SUBMITTER: Fan Q

PROVIDER: S-EPMC4865831 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

Fan Qiao Q Guo Xiaobo X Tideman J Willem L JW Williams Katie M KM Yazar Seyhan S Hosseini S Mohsen SM Howe Laura D LD Pourcain Beaté St BS Evans David M DM Timpson Nicholas J NJ McMahon George G Hysi Pirro G PG Krapohl Eva E Wang Ya Xing YX Jonas Jost B JB Baird Paul Nigel PN Wang Jie Jin JJ Cheng Ching-Yu CY Teo Yik-Ying YY Wong Tien-Yin TY Ding Xiaohu X Wojciechowski Robert R Young Terri L TL Pärssinen Olavi O Oexle Konrad K Pfeiffer Norbert N Bailey-Wilson Joan E JE Paterson Andrew D AD Klaver Caroline C W CC Plomin Robert R Hammond Christopher J CJ Mackey David A DA He Mingguang M Saw Seang-Mei SM Williams Cathy C Guggenheim Jeremy A JA

Scientific reports 20160513

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwo ...[more]

PMID: 27174397

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Project description:PurposeA previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted.DesignCandidate gene genetic association study.ParticipantsTwo thousand participants drawn from the Age-Related Eye Disease Study (AREDS) were chosen for genotyping. After quality-control filtering, 1912 individuals were available for analysis.MethodsMicroarray genotyping was performed using the HumanOmni 2.5 bead array (Illumina, Inc., San Diego, CA). Single nucleotide polymorphisms originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction were performed on 30 markers using linear regression models and an additive genetic risk model while adjusting for age, sex, education, and population substructure. Post hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P(emp)) and multiple-test study-wise (P(multi)) significance levels were calculated empirically through permutation.Main outcome measuresMean spherical equivalent refraction was used as a quantitative measure of ocular refraction.ResultsThe mean age and ocular refraction were 68 years (standard deviation [SD], 4.7 years) and +0.55 diopters (D; SD, 2.14 D), respectively. Pointwise statistical significance was obtained for rs1939008 (P(emp) = 0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The 2 highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P(emp)<0.01 in the lower-education stratum of AREDS participants.ConclusionsThis study showed suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. Evidence of a gene-environment interaction between previously reported markers and education on refractive error also was shown. Variants in MMP1 through MMP10 and MMP2 regions seem to affect population variation in ocular refraction in environmental conditions less favorable for myopia development.

Dataset Information

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

Publications

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

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