Cell type-specific epigenetic links to schizophrenia risk in the brain

Background The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. Results The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. Conclusions Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.GK is a Jon Heighten Scholar in Autism Research at UT Southwestern. This work was supported by the Uehara Memorial Foundation to NU; JSPS Grant-in-Aid for Early-Career Scientists (18 K14814) to NU; Scientific Research (C) (18K06977) to KT; Takeda Science Foundation to NU; the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603) to SB, NU, KT, and GK; the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition – Scholar Award to GK; National Science Foundation (SBE-131719) to SVY; the National Chimpanzee Brain Resource, NIH R24NS092988, the NIH National Center for Research Resources P51RR165 (superseded by the Office of Research Infrastructure Programs/OD P51OD11132) to TMP; and the NIMH (MH103517) to TMP, GK, and SVY. Human tissue samples were obtained from the NIH NeuroBioBank (The Harvard Brain Tissue Resource Center, funded through HHSN-271-2013-00030C; the Human Brain and Spinal Fluid Mendizabal et al. Genome Biology (2019) 20:135 Page 18 of 21 Resource Center, VA West Los Angeles Healthcare Center; and the University of Miami Brain Endowment Bank) and the UT Psychiatry Psychosis Research Program (Dallas Brain Collection)

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Spontaneous Variability of QTc Interval in Patients with Congenital Long QT Syndrome

Background: QTc interval assessment is an essential tool to diagnose and stratify the risk of adverse cardiac events in patients with congenital long QT syndromes (LQTS). QTc intervals can markedly vary in shape and be intermittently prolonged only before, during and after an arrhythmic event. Objectives: The aim of this study was to assess whether QTc intervals measured on different occasions vary significantly in patients with congenital LQTS. Methods: QTc intervals were measured from three ECG recorded every 7 days, in 25 patients and 15 healthy controls. Results: Both groups evidenced significant QTc interval variability. In patients with LQTS, minimum and maximum QTc were 492 ms (25-75 interquartile range (IQR) 463.5-501.5) and 522 ms (IQR 503.5-543), respectively (p<0.0001). In healthy individuals, these values were 409 ms (IQR 395-418) and 423 ms (IQR 413-431) (p<0.001). In 56% of patients, QTc intervals varied above and below 500 ms, in 24%, they were always below 500 ms and in 20% they were always above this value. QTc interval was always above 500 ms in 50% of symptomatic patients and in 10.5% of asymptomatic ones. Conclusions: QTc intervals vary significantly in patients with LQTS. A single assessment is not enough to stratify risk.Introducción: La medición del intervalo QTc es una herramienta indispensable para diagnosticar y estratificar el riesgo de eventos cardíacos adversos en los pacientes (p) con los síndromes de QT largo (SQTL) hereditarios. Los intervalos QTc pueden variar en forma ostensible y prolongarse de manera intermitente solo antes, durante o después de un evento arrítmico. Objetivos: Determinar si, en los pacientes con SQTL, existen variaciones significativas de los intervalos QTc cuando se los mide en varias oportunidades. Material y métodos: Se midieron la duración de los intervalos QTc en tres ECG registrados cada 7 días, en 25 pacientes con SQTL y 15 controles sanos. Resultados: Los intervalos QTc variaron de manera significativa en ambos grupos. Los valores mínimos y máximos de QTc fueron de 492 mseg (rango intercuartil [RIC] 25-75: 463,5-501,5) y 522 mseg (RIC: 503,5-543) en pacientes con SQTL (p < 0,0001), respectivamente. En los individuos sanos, dichos valores fueron de 409 mseg(RIC: 395-418) y 423 mseg (RIC: 413431) (p < 0,001). En el 56% de los pacientes, las mediciones de los intervalos QTc oscilaron por encima y por debajo de 500 mseg. El 24% tuvo un intervalo QTc siempre por debajo de 500 mseg y el 20% siempre por encima. El intervalo QTc siempre fue mayor de 500 mseg en el 50% de los sintomáticos y en el 10,5% de los asintomáticos. Conclusiones: En los pacientes con SQTL, los intervalos QTc varían significativamente. Una única determinación no es suficiente para estratificar el riesgo

Utilidad del Doppler pulsado tisular en la detección precoz de anormalidades diastólicas en familiares de primer grado de pacientes con miocardiopatía hipertrófica familiar

Introducción y objetivos. El Doppler pulsado tisular (DPT) permite analizar la función miocárdica regional independientemente de la precarga. Se realizó DPT a los familiares de primer grado de pacientes con miocardiopatía hipertrófica familiar (MHF) para detectar anormalidades precoces. Pacientes y método. Se estudió a 47 familiares de primer grado de pacientes con MHF (grupo GI) y se los comparó con un grupo control de 47 sujetos normales (grupo GII). Se realizó ecocardiografía 2D y Doppler pulsado de los flujos mitral y tricuspídeo. Mediante DPT en la pared lateral del ventrículo izquierdo, el ventrículo derecho y el septo interventricular se midieron las velocidades pico S', E' y A' y los períodos de relajación y contracción isovolumétricos. Se consideró función diastólica regional normal a una relación E'/A' > 1 y disfunción diastólica a una relación E'A'< 1. Resultados. No hubo alteraciones de la relajación ventricular en el GII (E'A' derecho, 1,78 ± 0,58; septo, 2,03 ± 0,53; izquierdo, 2,55 ± 0,80), mientras que en el GI la relación E'/A' permitió diferenciar 2 subgrupos: GIa de 37 familiares de primer grado que presentaron patrón de relajación normal (E'/A' derecho, 1,8 ± 0,44; septo, 2,07 ± 0,41; izquierdo, 2,35 ± 0,6, sin diferencias significativas con el grupo control) y GIb de 10 familiares de primer grado con relajación prolongada en el ventrículo derecho (E'/A', 0,70 ± 0,28; p < 0,001), con menor tendencia significativa en el septo (1,57 ± 0,49; p < 0,01) y el lateral izquierdo (1,85 ± 0,53; p < 0,01). Conclusiones. En familiares de primer grado de pacientes con MHF, el DPT permitió diferenciar anormalidades de la relajación ventricular en 10 de los 47 casos (21,3%), más manifiestas en el ventrículo derecho, que podrían ser un marcador preclínico de la enfermedad