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

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

Bulk sediment and diatom silica carbon isotope composition from coastal marine sediments off East Antarctica

Organic carbon occluded in diatom silica is assumed to be protected from degradation in the sediment. δ13C from diatom carbon (δ13C(diatom)) therefore potentially provides a signal of conditions during diatom growth. However, there have been few studies based on δ13C(diatom). Numerous variables can influence δ13C of organic matter in the marine environment (e.g., salinity, light, nutrient and CO2 availability). Here we compare δ13C(diatom) and δ13C(TOC) from three sediment records from individual marine inlets (Rauer Group, East Antarctica) to (i) investigate deviations between δ13C(diatom) and δ13C(TOC), to (ii) identify biological and environmental controls on δ13C(diatom) and δ13C(TOC), and to (iii) discuss δ13C(diatom) as a proxy for environmental and climate reconstructions. The records show individual δ13C(diatom) and δ13C(TOC) characteristics, which indicates that δ13C is not primarily controlled by regional climate or atmospheric CO2 concentration. Since the inlets vary in water depths offsets in δ13C are probably related to differences in water column stratification and mixing, which influences redistribution of nutrients and carbon within each inlet. In our dataset changes in δ13C(diatom) and δ13C(TOC) could not unequivocally be ascribed to changes in diatom species composition, either because the variation in δ13C(diatom) between the observed species is too small or because other environmental controls are more dominant. Records from the Southern Ocean show depleted δ13C(diatom) values (1–4 ‰) during glacial times compared to the Holocene. Although climate variability throughout the Holocene is low compared to glacial/interglacial variability, we find variability in δ13C(diatom), which is in the same order of magnitude. δ13C of organic matter produced in the costal marine environment seems to be much more sensitive to environmental changes than open ocean sites and δ13C is of strongly local nature