Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with kno

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

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

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

The influence of pre-weaning nutrition on biochemical and myofibre characteristics of bovine semitendinosus muscle

This study investigates pre-weaning growth of cattle and its effect on biochemical and histochemical markers of muscle development and subsequent biophysical attributes of eating quality. Combinations of cow (late pregnancy to mid-lactation) and pre-weaning (varying duration of access to a high-energy ration) supplementation were used to vary calf growth to weaning in 6 treatment groups. After weaning, calves were grazed together on pasture (backgrounding) and then grown rapidly on a feedlot ration (finishing) until slaughter. Biochemical and myofibre characteristics were determined in semitendinosus muscle samples collected just prior to weaning (7 months), at the end of backgrounding (13 months), and at slaughter (17 months). The concentration of sarcoplasmic protein and the activity of lactate dehydrogenase in the muscle at weaning were associated with differences in pre-weaning growth and both variables correlated positively with liveweight at weaning. Isocitrate dehydrogenase activity varied with sex, not treatment, at weaning and at the end of backgrounding. The size of myofibres at weaning related to differences in growth path and correlated positively with liveweight. Pre-weaning growth effects on these characteristics were not evident at slaughter. Biophysical properties of the meat were not affected by earlier growth path treatment, and were not correlated with biochemical characteristics or myofibre type profile. Variation in both shear peak force and adhesion was related to sex. We conclude that the effects of divergent early life growth do not persist 10 months after weaning, at least in meat quality characteristics

Effects of sire genotype and plane of nutrition on fascicular structure of M. longissimus thoracis et lumborum and its effect on eating quality

The purpose of this study was to determine if estimated breeding value (EBV) of an animal’s sire and or the animal’s nutrition affected the structure of its M. longissimus thoracis et lumborum (LL) and, hence, the eating quality of meat derived from its carcass. Lambs were chosen based on the EBV of their sires in terms of post-weaning live weight (PWWT), post weaning fat at the C-site (PFAT), and post-weaning eye muscle depth (PEMD). Morphometric techniques were used to characterise muscle structure in terms of the distribution of intramuscular connective tissue; the variables together are called fascicular structure. Perimysial seam thickness and fascicular width were both influenced by sire estimated breeding values for PWWT, PFAT, and PEMD. Variation in fascicular structure was associated with an interaction between PEMD-EBV and PFAT-EBV of the sire. Fascicular width decreased with increased PEMD-EBV and increased with PFAT-EBV, but was not affected by PWWT-EBV. When the total seam thickness was adjusted to a common fascicular width, the lambs on a low plane of nutrition had relatively more intramuscular connective tissue than those on a high plane. The total seam thickness was negatively associated with PFAT-EBV and positively associated with PEMD-EBV. Warner Bratzler shear (WBS) peak force (PF) and initial yield were not associated with differences in sire EBV. The residual WBS shear force, peak force minus initial yield (PFIY), and compression values were negatively associated with nutrition but were positively associated with PWWT-EBV and PEMD-EBV of the sires. These latter 2 effects were moderated by nutrition. The data support the hypothesis that morphological characteristics of perimysium are genetically determined and nutritionally responsive. Variance in morphology accounted for some variance in the biophysical attributes of meat and may help explain why sheep with high muscling potential have tougher meat