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

Multi-trophic native and non-native prey naïveté shape marine invasion success.

Invasive predators have caused rapid declines in many native prey species across the globe. Predator invasion success may be attributed to prey naïveté, or the absence of anti-predator behavior between native and non-native species. An understanding of the effects of naïveté at different timescales since introduction and across multiple trophic levels is lacking, however, particularly in marine systems. Given the central role of trophic interactions in invasion dynamics, this knowledge gap limits the ability to predict high impact predator invasions. Naïveté was examined across three trophic levels of marine invertebrates: a native basal prey (hard clam), two non-native intermediate predators (the recently-introduced Asian shore crab and the long-established European green crab), a native intermediate predator (juvenile blue crabs), and a native top predator (adult blue crab). We hypothesized that naïveté would be more pronounced in trophic interactions involving the recently-introduced non-native predator in comparison to the long-established non-native and native intermediate predators. We further hypothesized that the recently-introduced intermediate predator would both benefit from naïveté of the native basal prey and be hindered by higher mortality through its own naïveté to the native top predator. To test these hypotheses, three laboratory experiments and a field experiment were used. Consistent with our hypotheses, basal prey naïveté was most pronounced with the recently-introduced intermediate predator, and this increased the predator's foraging success. This recently-introduced intermediate predator, however, exhibited an ineffective anti-predator response to the native top predator, and was also preyed upon more in the field than its long-established and native counterparts. Therefore, despite direct benefits from basal prey naïveté, the recently-introduced intermediate predator's naïveté to its own predators may limit its invasion success. These results highlight the importance of a multi-trophic perspective on predator-prey dynamics to more fully understand the consequences of naïveté in invasion biology

Navigating the seascape of ocean management: waypoints on the voyage toward sustainable use

Some societies have sustainably managed their local marine resources for centuries using traditional methods, but we are only beginning to learn how to do it at larger scales, including globally. A broad, deep and constantly growing body of ocean knowledge has developed, adding many new concepts, perspectives, management models and analytical tools into the knowledge base in a relatively short period. Such rapid growth has created a potentially confusing mash-up of ideas, acronyms, techniques, tools and regulations, demonstrated by recent titles such as, ‘Marine planning: tragedy of the acronyms’ (Ardron 2010), ‘Integrated marine science and management: wading through the morass’ (Elliott 2014), ‘Beyond rhetoric: navigating the conceptual tangle towards effective implementation of the ecosystem approach to oceans management ‘ (Engler 2015) and ‘Marine legislation – the ultimate ‘horrendogram’’ (Boyes and Elliott 2014, undated and 2016). The purpose of this paper is to assist policy makers, marine managers and those considering careers in this area by providing a short history of ocean management, its conceptual foundation, frameworks for modern management and examples of its application at different scales. Extensive literature exists to supplement the summarized information we present. We highlight the following terms as navigational markers through the ‘seascape’1 of marine management rhetoric: sustainability, ecosystem approach, ecosystem-based management, natural capital, ecosystem services, integrated ecosystem assessment, the causal framework DPSIR (Drivers, Pressures, States, Impacts, Responses) and its variants, indicators and reference points, marine area planning, marine spatial management (including decision support tools), adaptive ocean management and dynamic ocean management. We also point out the important roles of marine initiatives such as Blue Economy, the Ocean Health Index, Large Marine Ecosystems, Seascapes, Protected Areas and others. Understanding the similarities, differences, relationships and synergies among these activities increases the likelihood of achieving successful management processes or solutions. Further knowledge and additional methods are still needed to safeguard the human-ocean system and the benefits it provides to people particularly with continued global population growth, but better awareness of what we already know will speed collective progress toward healthier oceans and coastlines. Working toward that goal can also be a uniting force in an increasingly divisive world, because it must necessarily breach political, geographic, economic and other differences

Trade‐offs for data‐limited fisheries when using harvest strategies based on catch‐only models

Many of the world's fisheries are unassessed, with little information about population status or risk of overfishing. Unassessed fisheries are particularly predominant in developing countries and in small‐scale fisheries, where they are important for food security. Several catch‐only methods based on time series of fishery catch and commonly available life‐history traits have been developed to estimate stock status (defined as biomass relative to biomass at maximum sustainable yield: B/BMSY). While their stock status performance has been extensively studied, performance of catch‐only models as a management tool is unknown. We evaluated the extent to which a superensemble of three prominent catch‐only models can provide a reliable basis for fisheries management and how performance compares across management strategies that control catch or fishing effort. We used a management strategy evaluation framework to determine whether a superensemble of catch‐only models can reliably inform harvest control rules (HCRs). Across five simulated fish life histories and two harvest‐dynamic types, catch‐only models and HCR combinations reduced the risk of overfishing and increased the proportion of stocks above BMSY compared to business as usual, though often resulted in poor yields. Precautionary HCRs based on fishing effort were robust and insensitive to error in catch‐only models, while catch‐based HCRs caused high probabilities of overfishing and more overfished populations. Catch‐only methods tended to overestimate B/BMSY for our simulated data sets. The catch‐only superensemble combined with precautionary effort‐based HCRs could be part of a stepping stone approach for managing some data‐limited stocks while working towards more data‐moderate assessment methods.JRC.D.2-Water and Marine Resource

Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology

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

Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology

Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. Methods The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. Findings Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. Interpretation Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. Funding DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany)