Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness

Central corneal thickness (CCT), one of the most highly heritable human traits (h2 typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6×10−10. The locus on chromosome 16 was associated with CCT with p = 8.95×10−11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population

Ethnic and mouse strain differences in central corneal thickness and association with pigmentation phenotype

The cornea is a transparent structure that permits the refraction of light into the eye. Evidence from a range of studies indicates that central corneal thickness (CCT) is strongly genetically determined. Support for a genetic component comes from data showing significant variation in CCT between different human ethnic groups. Interestingly, these studies also appear to show that skin pigmentation may influence CCT. To validate these observations, we undertook the first analysis of CCT in an oculocutaneous albinism (OCA) and Ugandan cohort, populations with distinct skin pigmentation phenotypes. There was a significant difference in the mean CCT of the OCA, Ugandan and Australian-Caucasian cohorts (Ugandan: 517.3±37 µm; Caucasian: 539.7±32.8 µm, OCA: 563.3±37.2 µm; p<0.001). A meta-analysis of 53 studies investigating the CCT of different ethnic groups was then performed and demonstrated that darker skin pigmentation is associated with a thinner CCT (p<0.001). To further verify these observations, we measured CCT in 13 different inbred mouse strains and found a significant difference between the albino and pigmented strains (p = 0.008). Specific mutations within the melanin synthesis pathway were then investigated in mice for an association with CCT. Significant differences between mutant and wild type strains were seen with the nonagouti (p<0.001), myosin VA (p<0.001), tyrosinase (p = 0.025) and tyrosinase related protein (p = 0.001) genes. These findings provide support for our hypothesis that pigmentation is associated with CCT and identifies pigment-related genes as candidates for developmental determination of a non-pigmented structure.David P. Dimasi, Alex W. Hewitt, Kenneth Kagame, Sam Ruvama, Ludovica Tindyebwa, Bastien Llamas, Kirsty A. Kirk, Paul Mitchell, Kathryn P. Burdon and Jamie E. Crai

The babel of drugs: On the consequences of evidential pluralism in pharmaceutical regulation and regulatory data journeys

This is the final version. Available on open access from Springer via the DOI in this recordThroughout the last century, pharmaceutical regulators all over the world have used various methods to test medical treatments. From 1962 until 2016, the Randomized Clinical Trial (RCT) was the reference test for most regulatory agencies. Today, the standards are about to change, and in this chapter we draw on the idea of the data journey to illuminate the trade-offs involved. The 21st Century Cures Act (21CCA) allows for the use of Electronic Health Records (EHRs) for the assessment of different treatment indications for already approved drugs. This might arguably shorten the testing period, bringing treatments to patients faster. Yet, EHR are not generated for testing purposes and no amount of standardization and curation can fully make up for their potential flaws as evidence of safety and efficacy. The more noise in the data, the more mistakes regulators are likely to make in granting market access to new drugs. In this paper we will discuss the different dimensions of this journey: the different sources and levels of curation involved, the speed at which they can travel, and the level of risk of regulatory error involved as compared with the RCT standard. We are going to defend that what counts as evidence, at the end of the journey, depends on the risk definition and threshold regulators work with.European Research Council (ERC)Engineering and Physical Sciences Research Council (EPSRC

Abnormal iris processes may be a marker of glaucoma gene carrier status in some cases of primary infantile glaucoma

Purpose: To report the presence of dense and abnormal iris processes in the unaffected parents and sibling of a non consanguineous family where 3 children out of 4 suffer from primary infantile glaucoma (PIG). Methods: A descriptive case report. All family members were clinically characterized. Candidate gene screening and chromosome analysis were also performed. Results: The 3 children with PIG displayed a spectrum of anterior chamber angle anomalies with the absence of posterior embryotoxon and iridotrabeculodysgenesis abnormalities. Unaffected family members had dense and abnormal iris processes but no features of glaucoma. Candidate gene screening and chromosome analysis were normal. Conclusion: Iris processes indicate angle maldevelopment and may signify carrier status of an autosomal recessive glaucoma gene. Identification of iris processes in relatives of PIG children is a useful clinical sign that may be of benefit for genetic counseling and risk stratification purposes