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Jelle Vehof, Christopher J Hammond, Pirro G Hysi; A GWAS investigation of dry eye disease in two European populations. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1962.
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© ARVO (1962-2015); The Authors (2016-present)
Twin studies have shown that dry eye disease (DED) is heritable, but to date, the genetic bases for this disease remain unknown. Here we report our attempt to explore the genetics of DED by performing genome wide association studies (GWAS) in two population-based cohorts of European descent.
DED cases were defined, in accordance with the validated Women’s Health Study (WHS) dry eye questionnaire criteria, by the presence of either a clinical diagnosis of DED and/or report of symptoms of both irritation and dryness “often” or “constantly”. The primary discovery cohort, the Lifelines Cohort Study from the Netherlands, included 922 cases and 8564 controls (median age 53 years, age range 23-93, 59% female). The second cohort included 336 cases and 1452 controls, all unrelated subjects from the TwinsUK cohort (median age 62 years, age range 16-91, 92% female). Genotypes were obtained using standard platforms and were, for both cohorts, imputed using the 1000 Genomes Project. Heritability analyses were performed using the REML algorithm and association analyses were conducted using PLINK.
A total of 10.2 million SNPs passed the quality controls and were used for a GWAS in the discovery cohort. The heritability explained by the SNPs in the Lifelines cohort was 0.39 (SE=0.15), similar to previously reported twin model estimates. No SNP reached genome wide significance (p<5x10-08) in the Lifelines cohort, but several suggestive association signals were found for SNPs on a region on Chromosome 18q22.3. After meta-analysis with the TwinsUK however, one of the SNPs on that region (rs4479346) achieved statistical significance for association with DED (OR=0.70, 95%CI=0.66-0.75, p=4.8x10-08 for allele A). This region is located within a gene-poor part of the genome, but overlaps with numerous DNase I hypersensitive and other putatively regulatory genomic regions.
This first ever reported GWAS of DED showed significant SNP-based heritability, confirming the potential for gene finding in DED using questionnaire based definitions. It also identified a potential genomic region associated with DED, although independent replication and additional work in larger sample sizes will be needed in the future to confirm these findings.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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