Regional replication of association with refractive error on 15q14 and 15q25 in the Age-Related Eye Disease Study cohort.
OBJECTIVE
Refractive error is a complex trait with multiple genetic and environmental risk factors, and is the most common cause of preventable blindness worldwide. The common nature of the trait suggests the presence of many genetic factors that individually may have modest effects. To achieve an adequate sample size to detect these common variants, large, international collaborations have formed. These consortia typically use meta-analysis to combine multiple studies from many different populations. This approach is robust to differences between populations; however, it does not compensate for the different haplotypes in each genetic background evidenced by different alleles in linkage disequilibrium with the causative variant. We used the Age-Related Eye Disease Study (AREDS) cohort to replicate published significant associations at two loci on chromosome 15 from two genome-wide association studies (GWASs). The single nucleotide polymorphisms (SNPs) that exhibited association on chromosome 15 in the original studies did not show evidence of association with refractive error in the AREDS cohort. This paper seeks to determine whether the non-replication in this AREDS sample may be due to the limited number of SNPs chosen for replication.


METHODS
We selected all SNPs genotyped on the Illumina Omni2.5v1_B array or custom TaqMan assays or imputed from the GWAS data, in the region surrounding the SNPs from the Consortium for Refractive Error and Myopia study. We analyzed the SNPs for association with refractive error using standard regression methods in PLINK. The effective number of tests was calculated using the Genetic Type I Error Calculator.


RESULTS
Although use of the same SNPs used in the Consortium for Refractive Error and Myopia study did not show any evidence of association with refractive error in this AREDS sample, other SNPs within the candidate regions demonstrated an association with refractive error. Significant evidence of association was found using the hyperopia categorical trait, with the most significant SNPs rs1357179 on 15q14 (p=1.69×10⁻³) and rs7164400 on 15q25 (p=8.39×10⁻⁴), which passed the replication thresholds.


CONCLUSIONS
This study adds to the growing body of evidence that attempting to replicate the most significant SNPs found in one population may not be significant in another population due to differences in the linkage disequilibrium structure and/or allele frequency. This suggests that replication studies should include less significant SNPs in an associated region rather than only a few selected SNPs chosen by a significance threshold.
Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD.
Claire L
CL
Simpson
Robert
R
Wojciechowski
Stephanie S
SS
Yee
Poorva
P
Soni
Joan E
JE
Bailey-Wilson
Dwight
D
Stambolian
D000375:Aging / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006956:Hyperopia / Q000235:genetics; D009216:Myopia / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019655:Quantitative Trait, Heritable; D012030:Refractive Errors / Q000235:genetics*; D015203:Reproducibility of Results