19 research outputs found
Multi-trait genome-wide association study identifies new loci associated with optic disc parameters
A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH
Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.
Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia
Cycles of dim red light capable of entraining circadian rhythms of rats after long‐term exposure to constant white light
A comparative study of SQP-type algorithms for nonlinear and nonconvex mixed-integer optimization
Environmental, societal, and genetic contributions to the epidemic of hypertension in African Americans
Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma
Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the
BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk
of developing POAG. The BXD RI strain set was used to define mammalian genomic loci
modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between
60–100 days of age). The mice were anesthetized and the eyes were positioned in front of
the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system.
CCT data for each strain was averaged and used to QTLs modulating this phenotype using
the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes
and genomic loci identified in the mouse were then directly compared with the summary
data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This
analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region
(Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2,
two resulted in changes in the amino acid proline which could result in altered secondary
structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were
examined in the NEIGHBORHOOD database to determine if they are potential risk factors for
human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided
within one gene (POU6F2), with the highest significance level of p = 10−6 for SNP rs76319873.
POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of
POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/
2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified
a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a
subset of retinal ganglion cells an
Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma
Ophthalmic researc