Pieter W.M. Bonnemaijer

Evaluation of the Myocilin Mutation Gln368Stop Demonstrates Reduced Penetrance for Glaucoma in European Populations

PURPOSE Sequence variations in the myocilin (MYOC) gene account for approximately 2% to 4% of glaucoma cases. One particular MYOC mutation, Gln368Stop (dbSNP accession number: rs74315329), is the most common genetic mutation causing glaucoma by increasing intraocular pressure (IOP). The objective of this study was to evaluate the effect of this MYOC mutation on IOP using data from large-scale European population panels (directly sequenced and imputation based). DESIGN Cross-sectional, cohort study. PARTICIPANTS For this study, the penetrance of the variant rs74315329 was estimated in 2 population-based cohorts, the TwinsUK (N = 6092) and the Rotterdam Study (RS) (N =11 189). METHODS Carriers of the risk allele for rs74315329 were identified using whole-genome sequencing and imputation data (based on 1000 Genomes Project and Haplotype Reference Consortium panels). The penetrance of this variant was evaluated using IOP measurements and data on visual field testing/a diagnosis of glaucoma (if available). MAIN OUTCOME MEASURES The penetrance of the variant rs74315329 was estimated from the percentage of the carriers of the risk allele of the variant who had high IOP (ocular hypertension) or glaucoma. RESULTS In our study, the observed penetrance of the variant rs74315329 in relation to increased IOP was 12.5% and 19.4% in the TwinsUK and the RS, respectively. Thus, our study suggests a much lower penetrance for rs74315329 for ocular hypertension (and thus glaucoma), in comparison with that reported previously. CONCLUSIONS The significance of this finding is that higher numbers of healthy individuals in the population are expected to be carriers of this mutation, which in turn reduces the utility of identifying carriers of this mutation as a screening tool for glaucoma.

Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low‐frequency variants. Furthermore, we performed a genome‐wide association meta‐analysis of vertical cup‐disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta‐analysis using 1000GP to the meta‐analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10−61), particularly for suggestive variants. Both meta‐analyses were performed in the same sample size, yet we found eight genome‐wide significant loci in the HRC‐based meta‐analysis versus seven genome‐wide significant loci in the 1000GP‐based meta‐analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.

Genetic African Ancestry Is Associated With Central Corneal Thickness and Intraocular Pressure in Primary Open-Angle Glaucoma

Purpose To unravel the relationship between African ancestry, central corneal thickness (CCT), and intraocular pressure (IOP) by estimating the genetic African ancestry (GAA) proportion in primary open-angle glaucoma (POAG) patients and controls from an admixed South African Colored (SAC) and a South African Black (SAB) population. Methods In this case-control study, 268 POAG patients and 137 controls were recruited from a university clinic in Cape Town, South Africa. All participants were genotyped on the Illumina HumanOmniExpress beadchip or HumanOmni2.5Exome beadchip. ADMIXTURE was used to infer participants GAA among 86,632 SNPs. Linear and logistic regression models were used to assess the relation between GAA, POAG, CCT, and IOP. Results The median proportion of GAA was 60% in the study population. GAA was significantly associated with thinner CCT (P < 0.001) and IOP (P = 0.034) in POAG patients. The effect of GAA on CCT was marginally different among POAG patients versus controls (P = 0.066). In POAG patients, the CCT was significantly thinner compared to controls after adjusting for age and sex (P = 0.016). In a stratified analysis in participants with >60% GAA, CCT was not associated with POAG (P = 0.550). Conclusions This study demonstrated that a higher proportion of GAA was associated with a thinner CCT and a higher IOP in POAG patients. Remarkably, at higher proportions of GAA, the difference in CCT between POAG and controls was reduced. This suggests that thinner CCT is not associated with POAG in Africans.

Association of Retinal Neurodegeneration on Optical Coherence Tomography With Dementia: A Population-Based Study

Importance Retinal structures may serve as a biomarker for dementia, but longitudinal studies examining this link are lacking. Objective To investigate the association of inner retinal layer thickness with prevalent and incident dementia in a general population of Dutch adults. Design, Setting, and Participants From September 2007 to June 2012, participants from the prospective population-based Rotterdam Study who were 45 years and older and had gradable retinal optical coherence tomography images and at baseline were free from stroke, Parkinson disease, multiple sclerosis, glaucoma, macular degeneration, retinopathy, myopia, hyperopia, and optic disc pathology were included. They were followed up until January 1, 2015, for the onset of dementia. Exposures Inner retinal layer thicknesses (ie, retinal nerve fiber layer [RNFL]) and ganglion cell–inner plexiform layer (GC-IPL) thicknesses measured on optical coherence tomography images. Main Outcomes and Measures Odds ratios and hazard ratios for incident dementia per SD decrease in retinal layer thickness adjusted for age, sex, education, and cardiovascular risk factors. Results Of 5065 individuals eligible for optical coherence tomography scanning, 3289 (64.9%) (mean [SD] age 68.9 [9.9] years, 1879 [57%] women) were included in the analysis. Of these 3289 individuals, 41 (1.2%) already had dementia. Thinner GC-IPL was associated with prevalent dementia (odds ratio per SD decrease in GC-IPL, 1.37 [95% CI, 0.99-1.90]). No association was found of RNFL with prevalent dementia. During 14 674 person-years of follow-up (mean [SD], 4.5 [1.6] years), 86 individuals (2.6%) developed dementia of whom 68 (2.1%) had Alzheimer disease. Thinner RNFL at baseline was associated with an increased risk of developing dementia (hazard ratio per SD decrease in RNFL, 1.44 [95% CI, 1.19-1.75]), which was similar for Alzheimer disease (hazard ratio, 1.43 [95% CI, 1.15-1.78]). No association was found between GC-IPL thickness and incident dementia (hazard ratio, 1.13 [95% CI, 0.90-1.43]). Conclusions and Relevance Thinner RNFL is associated with an increased risk of dementia, including Alzheimer disease, suggesting that retinal neurodegeneration may serve as a preclinical biomarker for dementia.

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26–1.93; P = 4.79 × 10−5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10−8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

RETINAL NEURODEGENERATION ON OPTICAL COHERENCE TOMOGRAPHY AND RISK OF DEMENTIA AND STROKE

APL1b28 peptide in plasma. The concentration of APL1b28 is w0.4pM, which is much less than that in CSF (w500pM). Currently, we are analyzing the APL1b28 ratio in CSF and plasma paired samples. We are also investigating correlation between plasma APL1b28 ratio and CSF Ab42 ratio. Conclusions:We have tried to develop an Ab42 surrogate marker in peripheral blood. We intend to show how and to what degree the plasma APL1b28 ratio correlates with CSF Ab42 ratio.