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

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

Nitrogen use efficiency in selected rice (Oryza sativa L.) genotypes under different water regimes and nitrogen levels

Water and nutrient availability are two major constraints in most rice-based rainfed shallow lowland systems of Asia. Both stresses interact and contribute to the low productivity and widespread poverty in this environment. The objective of this study was to improve the understanding of interaction between the two factors and to identify varietal characteristics beneficial for productivity in a water- and nutrient-limited rice environment. For this purpose, we screened 19 rice genotypes adapted to different rice environments under two water and two nutrient treatments during the wet season of 2004 and 2005 in southern Luzon, Philippines. Across all genotypes tested and in comparison with the irrigated control, rainfed conditions reduced grain yield of the treatment without N application by 69% in 2004 and by 59% in 2005. The mean nitrogen fertilizer response was highest in the dryer season of 2004 and the rainfed treatment, indicating that water stress had no effect on fertilizer response. Nitrogen application reduced the relative yield loss to 49% of the irrigated treatment in 2004 and to 52% of the irrigated treatment in 2005. Internal efficiency of N (IEN) and recovery efficiency of applied N (REN) were significantly different between genotypes, but were not affected by water availability (REN) or by water and nutrient availability (IEN). In contrast, grain yield and total N uptake were affected by cultivar, N and water availability. Therefore, germplasm for rainfed environments should be screened under conditions of limited and good nitrogen and water supplies. The four best cultivars, CT6510-24-1-2, IR55423-01, IR72, and IR57514-PMI5-B-1-2, performed well across all treatments and both years. Except for IR72, they were all characterized by medium height, medium duration, high early vigor, and a moderate level of drought tolerance. This combination of characteristics seems to enable the optimal use of limited water and nutrient resources occurring in many shallow rainfed lowlands. We also concluded that moderate drought stress does not necessarily affect the response to moderate N rates, provided that drought does not induce high spikelet sterility and that fertilizer N is properly managed.S.M. Haefele, S.M.A. Jabbar, J.D.L.C. Siopongco, A. Tirol-Padre, S.T. Amarante, P.C. Sta Cruz, W.C. Cosic