Assumption-free estimation of the genetic contribution to refractive error across childhood

作者：Guggenheim Jeremy A; St Pourcain Beate; McMahon George; Timpson Nicholas J; Evans David M; Williams Cathy

来源：Molecular Vision, 2015, 21: 621-632.

Purpose: Studies in relatives have generally yielded high heritability estimates for refractive error: twins 75-90%, families 15-70%. However, because related individuals often share a common environment, these estimates are inflated (via misallocation of unique/common environment variance). We calculated a lower-bound heritability estimate for refractive error free from such bias.
Methods: Between the ages 7 and 15 years, participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent non-cycloplegic autorefraction at regular research clinics. At each age, an estimate of the variance in refractive error explained by single nucleotide polymorphism (SNP) genetic variants was calculated using genome-wide complex trait analysis (GCTA) using high-density genome-wide SNP genotype information (minimum N at each age=3,404).
Results: The variance in refractive error explained by the SNPs ("SNP heritability") was stable over childhood: Across age 7-15 years, SNP heritability averaged 0.28 (SE=0.08, p<0.001). The genetic correlation for refractive error between visits varied from 0.77 to 1.00 (all p<0.001) demonstrating that a common set of SNPs was responsible for the genetic contribution to refractive error across this period of childhood. Simulations suggested lack of cycloplegia during autorefraction led to a small underestimation of SNP heritability (adjusted SNP heritability=0.35; SE=0.09). To put these results in context, the variance in refractive error explained (or predicted) by the time participants spent outdoors was <0.005 and by the time spent reading was <0.01, based on a parental questionnaire completed when the child was aged 8-9 years old.
Conclusions: Genetic variation captured by common SNPs explained approximately 35% of the variation in refractive error between unrelated subjects. This value sets an upper limit for predicting refractive error using existing SNP genotyping arrays, although higher-density genotyping in larger samples and inclusion of interaction effects is expected to raise this figure toward twin-and family-based heritability estimates. The same SNPs influenced refractive error across much of childhood. Notwithstanding the strong evidence of association between time outdoors and myopia, and time reading and myopia, less than 1% of the variance in myopia at age 15 was explained by crude measures of these two risk factors, indicating that their effects may be limited, at least when averaged over the whole population.

• 出版日期2015-5-26