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

Evaluation of factors underlying sex-based disparities in cardiovascular care in adults with self-reported premature atherosclerotic cardiovascular disease

Importance: There are limited data regarding sex-based differences in physical and mental health domains and health care access in adults with premature atherosclerotic cardiovascular disease (ASCVD).Objective: To study the association of sex with physical and mental health domains as well as health care access-related factors among adults with self-reported premature ASCVD.Design, setting, and participants: Retrospective cohort analysis of 748 090 adults aged 18 to 55 years in the Behavioral Risk Factor Surveillance System 2016 to 2019 in the US. Data were analyzed from June to July 2021.Exposures: Self-reported ASCVD, defined as having a history of coronary artery disease, myocardial infarction, or stroke.Main outcomes and measures: Self-reported physical and mental health and measures of health care access, including self-reported cost-related medication nonadherence and inability to see a physician due to cost.Results: Between 2016 and 2019, 748 090 adults aged 18-55 years were identified, of whom 28 522 (3.3%) had self-reported premature ASCVD. Of these, 14 358 (47.0%) were women. Compared with men, women with premature ASCVD were more likely to report being clinically depressed (odds ratio [OR], 1.73; 95% CI, 1.41-2.14; P \u3c .001), have cost-related medication nonadherence (OR, 1.42; 95% CI, 1.11-1.82; P = .005), have not seen a physician due to cost-related issues (OR, 4.52; 95% CI, 2.24-9.13; P \u3c .001), and were more likely to report overall poor physical health (OR, 1.39; 95% CI, 1.09-1.78; P = .008) despite being more likely to have health care coverage (85.3% vs 80.8%; P = .04) and a primary care physician (84.2% vs 75.7%; P \u3c .001).Conclusions and relevance: Results from this study indicate that women with premature ASCVD were more likely to report worse overall physical and mental health, inability to see a physician due to cost, and cost-related medical nonadherence. Interventions addressing mental health and out-of-pocket costs are needed in adults with premature ASCVD

Evaluation of factors underlying sex-based disparities in cardiovascular care in adults with self-reported premature atherosclerotic cardiovascular disease

Importance: There are limited data regarding sex-based differences in physical and mental health domains and health care access in adults with premature atherosclerotic cardiovascular disease (ASCVD).Objective: To study the association of sex with physical and mental health domains as well as health care access-related factors among adults with self-reported premature ASCVD.Design, setting, and participants: Retrospective cohort analysis of 748 090 adults aged 18 to 55 years in the Behavioral Risk Factor Surveillance System 2016 to 2019 in the US. Data were analyzed from June to July 2021.Exposures: Self-reported ASCVD, defined as having a history of coronary artery disease, myocardial infarction, or stroke.Main outcomes and measures: Self-reported physical and mental health and measures of health care access, including self-reported cost-related medication nonadherence and inability to see a physician due to cost.Results: Between 2016 and 2019, 748 090 adults aged 18-55 years were identified, of whom 28 522 (3.3%) had self-reported premature ASCVD. Of these, 14 358 (47.0%) were women. Compared with men, women with premature ASCVD were more likely to report being clinically depressed (odds ratio [OR], 1.73; 95% CI, 1.41-2.14; P \u3c .001), have cost-related medication nonadherence (OR, 1.42; 95% CI, 1.11-1.82; P = .005), have not seen a physician due to cost-related issues (OR, 4.52; 95% CI, 2.24-9.13; P \u3c .001), and were more likely to report overall poor physical health (OR, 1.39; 95% CI, 1.09-1.78; P = .008) despite being more likely to have health care coverage (85.3% vs 80.8%; P = .04) and a primary care physician (84.2% vs 75.7%; P \u3c .001).Conclusions and relevance: Results from this study indicate that women with premature ASCVD were more likely to report worse overall physical and mental health, inability to see a physician due to cost, and cost-related medical nonadherence. Interventions addressing mental health and out-of-pocket costs are needed in adults with premature ASCVD

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