Quantifying interactions between accommodation and vergence in a binocularly normal population

AbstractStimulation of the accommodation system results in a response in the vergence system via accommodative vergence cross-link interactions, and stimulation of the vergence system results in an accommodation response via vergence accommodation cross-link interactions. Cross-link interactions are necessary in order to ensure simultaneous responses in the accommodation and vergence systems. The crosslink interactions are represented most comprehensively by the response AC/A (accommodative vergence) and CA/C (vergence accommodation) ratios, although the stimulus AC/A ratio is measured clinically, and the stimulus CA/C ratio is seldom measured in clinical practice. The present study aims to quantify both stimulus and response AC/A and CA/C ratios in a binocularly normal population, and determine the relationship between them. 25 Subjects (mean±SD age 21.0±1.9years) were recruited from the university population. A significant linear relationship was found between the stimulus and response ratios, for both AC/A (r2=0.96, p<0.001) and CA/C ratios (r2=0.40, p<0.05). Good agreement was found between the stimulus and response AC/A ratios (95% CI −0.06 to 0.24MA/D). Stimulus and response CA/C ratios are linearly related. Stimulus CA/C ratios were higher than response ratios at low values, and lower than response ratios at high values (95% CI −0.46 to 0.42D/MA). Agreement between stimulus and response CA/C ratios is poorer than that found for AC/A ratios due to increased variability in vergence responses when viewing the Gaussian blurred target. This study has shown that more work is needed to refine the methodology of CA/C ratio measurement

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Protective effect of a peptide derived from the endogenous PKC inhibitor PKI55 on the neurosecretory function in ischemic brain slices

We have recently identified the PKI55 protein, coding for 55 amino acids, that is normally poorly translated in vivo and acts as a specific modulator of either cPKC-α and nPKC-δ isozymes. PKI55 remains relatively inactive until PKC attains an active conformation and reaches a critical concentration in the cell; it is not modified by the enzyme but irreversibly associates with its target, thus behaving as a suicidal inhibitor. The inhibition and degradation of over-activated PKC isozymes may prevent unfavorable changes in cellular phenotypes, resulting from PKC overexpression (Selvatici, J Mol Evol 2003 57:131). In the present work we compared the in vitro biochemical activity of the PKI55 protein, of its 39-amino acids N-terminal fragment (G39) and of its 16 amino acids C-terminal fragment (G16) on specific PKC recombinant isozymes, by measuring the initial rate of phosphate incorporation from 32P-ATP into saturating amounts of histone IIIS. PKI55 concentration-dependently inhibited PKC activity, provided that calcium ions were present in the assay medium (IC50=6μM). The inhibitory activity was retained by G16 (IC50=50μM), but not by G39. The active fragment G16 was tested in an in vitro model of brain ischemia: superfused guinea pig cerebral cortex slices, continuously electrically (10 Hz) stimulated, were exposed to 20 min of oxygen-glucose deprivation (OGD, Badini, Neurochem Int 1997 31:817), and then reperfused for 1 hour (REP). PKC activity was increased to 244±36% at the end of OGD, while acetylcholine (ACh) release, taken as an index of the neurosecretory function, was reduced to 35±2% of the controls. Following REP, a reduction in PKC activity to 54±7% was displayed, indicating a down regulation of previously activated PKC (Selvatici, J Neurosci Res 2003 71:64). ACh release only partially recovered (REP=69±6% of the controls), suggesting persistence of neuronal suffering. PKC activation during OGD was attenuated by 50µM G16 and the consequent down regulation following REP was prevented. Moreover, ACh release fully recovered to normal values (REP+G16=91±4% of the controls). These data suggest a neuroprotective action for G16, the active fragment of the endogenous PKC inhibitor PKI55

Polygenic burden in focal and generalized epilepsies

© The Author(s) (2019).Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japaneseancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy