ALSPAC myopia GWAS methodology

The YP phenotypes analysed were those collected at the TF3 clinic (refractive error, myopia case/control status, astigmatism case/control status, eye axial length, and corneal curvature).

The only mother's phenotype we have analysed to date has been myopia case/control status (inferred from questionnaire responses). We also plan to analyse the mother's quantitative refractive error (data on a subset of mothers collected from opticians or from assessments at the TF3 clinic). [Note that Exec approval for analysis of the mother's data was kindly granted recently to allow us to check for replication of our YP GWAS results].

Outliers, defined as values 4 standard deviations from the mean, were excluded. Quantitative traits were transformed to normal deviates prior to analysis. Autosomes: quantitative traits and case/control status were analysed with mach2qtl and mach2dat, respectively, using sex as a covariate (for datasets of imputed genotypes previously prepared by John Kemp). Chromosome X: analyses were run in PLINK. SNPs with an imputation quality Rsqless than 0.3 or MAFless than 0.01 were excluded.

We have not yet attempted joint analyses of YP + mother's data. If this is done, we will take account of the non-independence of the genotypes and phenotypes in parents/offspring (e.g. perform analysis in GenABEL using the mmscore function).

ALSPAC myopia GWAS results

We found no evidence of population stratification (l~1.00; ditto QQ plots). In YPs, we replicated a locus within the PDGFRA gene associated with corneal curvature in Asians [6]. In mothers, we replicated a locus associated with refractive error and myopia at 15q14 [4]. However, only a single SNP had a P-value below 5x10E-8 (an imputed SNP on the X chromosome with a MAF =0.06....and we note our X-chromosome analysis did not properly account for genotype imputation uncertainty).

Plans for meta-analysis

Most members of the CREAM consortium, including ALSPAC, have already participated in a replication of the 15q14 and 15q25 myopia loci [as approved by the Exec; manuscript currently in revision].

Meta-analysis will be carried out using standard procedures [10]. An Executive Committee will set specific objectives, consider applications for consortium membership, and resolve conflicts. To accelerate progress, analyses/manuscript writing will be distributed to three Working Groups (Refractive Error/Ocular Biometry/Astigmatism). Each working group will be co-chaired by individuals with expertise in statistical genetics and/or the phenotype of interest. Working Groups will be expected to organise conference calls at approximately monthly intervals to monitor progress. CW and/or JG will represent the ALSPAC myopia team in each working group (this option will also be open to GM & BSP if other demands on their time permit).

As well contributing directly to the meta-analysis, the ALSPAC cohort is ideal for examining the effects of genetic variants across childhood (e.g. following the strategy of Sovio et al. [11]) and their interaction with environmental exposures (e.g. following the strategy of Kilpelainen et al. [12]).

As mentioned above, a draft MOU has been prepared to cover the operation of the consortium (attached).

We would be grateful for the Exec's opinion on the MOU and any amendments that would be required before it could be given approval.

If the MOU were to be approved, we would also be grateful for advice on how it should be processed through the University, e.g. via RED?

References

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3. Sanfilippo PG, Hewitt AW, Hammond CJ, Mackey DA. The heritability of ocular traits. Surv Ophthalmol 2010; 55:561-583.

4. Solouki AM, Verhoeven VJ, van Duijn CM, et al. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. Nature Genet 2010; 42:897-901.

5. Fan Q, Zhou X, Khor CC, et al. Genome-wide meta-analysis of five Asian cohorts identifies PDGFRA as a susceptibility locus for corneal astigmatism. PLoS Genet 2011; 7:e1002402.

6. Han S, Chen P, Fan Q, et al. Association of variants in FRAP1 and PDGFRA with corneal curvature in three Asian populations from Singapore. Hum Mol Genet 2011; 20:3693-698.

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10. Thompson JR, Attia J, Minelli C. The meta-analysis of genome-wide association studies. Briefings Bioinformat 2011; 12:259-269.

11. Sovio U, Mook-Kanamori DO, Warrington NM, et al. Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development. PLoS Genet 2011; 7.

12. Kilpelainen TO, Qi L, Brage S, et al. Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children. PLoS Medicine 2011; 8.