Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Epigenetics and epilepsy

Introduction: Epigenetics is the study of heritable modifications in gene expression that do not change the DNA nucleotide sequence. Some of the most thoroughly studied epigenetic mechanisms at present are DNA methylation, post-transcriptional modifications of histones, and the effect of non-coding RNA molecules. Gene expression is regulated by means of these mechanisms and disruption of these molecular pathways may elicit development of diseases. Development: We describe the main epigenetic regulatory mechanisms and review the most recent literature about epigenetic mechanisms and how those mechanisms are involved in different epileptic syndromes. Conclusion: Identifying the epigenetic mechanisms involved in epilepsy is a promising line of research that will deliver more in-depth knowledge of epilepsy pathophysiology and treatments. Resumen: Introducción: La epigenética es el estudio de los cambios heredables en el ADN sin afectar a las secuencia de nucleótidos. Entre los mecanismos de regulación epigenética, los más estudiados y conocidos hasta la fecha son la metilación del ADN, la modificación de las histonas y los ARN no codificantes. Mediante estos mecanismos se regula la expresividad génica y la alteración de los mismos puede llevar al desarrollo de patologías. Desarrollo: Describimos los principales mecanismos de regulación epigenética y realizamos una revisión de la bibliografía reciente sobre los mecanismos de regulación epigenética y su implicación en distintos síndromes epilépticos. Conclusión: La identificación de los mecanismos epigenéticos implicados en la epilepsia constituye una prometedora vía de investigación para profundizar en el conocimiento de la fisiopatología y terapéutica de esta enfermedad. Keywords: Epigenetics, Neurodevelopment, Epileptogenesis, Epilepsy, Palabras clave: Epigenética, Neurodesarrollo, Epileptogénesis, Epilepsi

Epigenética y epilepsia

Resumen: Introducción: La epigenética es el estudio de los cambios heredables en el ADN sin afectar a las secuencia de nucleótidos. Entre los mecanismos de regulación epigenética, los más estudiados y conocidos hasta la fecha son la metilación del ADN, la modificación de las histonas y los ARN no codificantes. Mediante estos mecanismos se regula la expresividad génica y la alteración de los mismos puede llevar al desarrollo de patologías. Desarrollo: Describimos los principales mecanismos de regulación epigenética y realizamos una revisión de la bibliografía reciente sobre los mecanismos de regulación epigenética y su implicación en distintos síndromes epilépticos. Conclusión: La identificación de los mecanismos epigenéticos implicados en la epilepsia constituye una prometedora vía de investigación para profundizar en el conocimiento de la fisiopatología y terapéutica de esta enfermedad. Abstract: Introduction: Epigenetics is the study of heritable modifications in gene expression that do not change the DNA nucleotide sequence. Some of the most thoroughly studied epigenetic mechanisms at present are DNA methylation, post-transcriptional modifications of histones, and the effect of non-coding RNA molecules. Gene expression is regulated by means of these mechanisms and disruption of these molecular pathways may elicit development of diseases. Development: We describe the main epigenetic regulatory mechanisms and review the most recent literature about epigenetic mechanisms and how those mechanisms are involved in different epileptic syndromes. Conclusion: Identifying the epigenetic mechanisms involved in epilepsy is a promising line of research that will deliver more in-depth knowledge of epilepsy pathophysiology and treatments. Palabras clave: Epigenética, Neurodesarrollo, Epileptogénesis, Epilepsia, Keywords: Epigenetics, Neurodevelopment, Epileptogenesis, Epileps

Epigenetic changes in neurology: DNA methylation in multiple sclerosis

Introduction: Epigenetics is defined as the study of the mechanisms that regulate gene expression without altering the underlying DNA sequence. The best known is DNA methylation. Multiple sclerosis (MS) is a disease with no entirely known aetiology, in which it is stated that the involvement of environmental factors on people with a genetic predisposition, may be key to the development of the disease. It is at this intersection between genetic predisposition and environmental factors where DNA methylation may play a pathogenic role. Development: A literature review of the effects of environmental risk factors for the development of MS can have on the different epigenetic mechanisms as well as the implication that such changes have on the development of the disease. Conclusion: Knowledge of epigenetic modifications involved in the pathogenesis of MS, opens a new avenue of research for identification of potential biomarkers, as well as finding new therapeutic targets. Resumen: Introducción: La epigenética se define como el estudio de los mecanismos que regulan la expresión génica sin modificar la secuencia de ADN, siendo entre ellos el más conocido la metilación del ADN. La esclerosis múltiple (EM) es una enfermedad de etiología no del todo conocida, en la que se plantea que la participación de factores ambientales sobre individuos con una determinada predisposición genética, pueden resultar claves para el desarrollo de la enfermedad. Es en esta intersección entre la predisposición genética y los factores ambientales donde la metilación del ADN puede desempeñar un papel patogénico. Desarrollo: Realizamos una revisión bibliográfica de los efectos que los factores de riesgo ambiental para el desarrollo de EM pueden ejercer sobre los distintos mecanismos epigenéticos, así como la implicación que presentan dichas modificaciones en el desarrollo de la enfermedad. Conclusión: El conocimiento de las modificaciones epigenéticas involucradas en la patogenia de la EM abre una nueva vía de investigación para la identificación de potenciales biomarcadores, así como para la búsqueda de nuevas dianas terapéuticas. Keywords: Multiple sclerosis, Epigenetics, DNA methylation, Vitamin D, Smoking, Epstein Barr virus, Palabras clave: Esclerosis múltiple, Epigenética, Metilación del ADN, Vitamina D, Tabaco, Virus Epstein Bar

Estudio comparativo de los niveles plasmáticos de homocisteína, vitamina B12 y ácido fólico en pacientes epilépticos frente a controles

Resumen: Introducción: El aumento de homocisteína en sangre constituye un conocido factor de riesgo cardiovascular. Los pacientes epilépticos en tratamiento crónico con fármacos antiepilépticos pueden presentar niveles más elevados de homocisteína y, en consecuencia, un potencial aumento del riesgo cardiovascular. Material y métodos: Estudio observacional de casos y controles para la comparación de los niveles plasmáticos de homocisteína, ácido fólico y vitamina B12. Resultados: Se reclutó a un total de 88 sujetos, 52 de ellos epilépticos y 36 controles. Se observó una tendencia a niveles de homocisteína más elevados (p = 0,084) en los pacientes epilépticos y unos valores de ácido fólico más bajos (p < 0,05). Conclusiones: Por su potencial efecto como factor de riesgo cardiovascular, es importante prestar atención a los niveles de homocisteína en los pacientes epilépticos en tratamiento crónico con fármacos antiepilépticos y en caso de encontrar niveles elevados sugerimos la instauración de tratamiento específico. Abstract: Introduction: Increased blood homocysteine levels are a known cardiovascular risk factor. Epileptic patients on long-term treatment with antiepileptic drugs may present higher homocysteine levels and, consequently, a potential increase in cardiovascular risk. Material and methods: We conducted an observational case-control study to compare plasma levels of homocysteine, folic acid, and vitamin B12. Results: Our study included a total of 88 subjects: 52 patients with epilepsy and 36 controls. Epileptic patients showed higher homocysteine levels (P=.084) and lower levels of folic acid (P<.05). Conclusion: Homocysteine levels should be monitored in epileptic patients on long-term treatment with antiepileptic drugs. We suggest starting specific treatment in patients with high homocysteine levels. Palabras clave: Hiperhomocisteinemia, Ácido fólico, Vitamina B12, Epilepsia, Fármacos antiepilépticos, Riesgo cardiovascular, Keywords: Hyperhomocysteinaemia, Folic acid, Vitamin B12, Epilepsy, Antiepileptic drugs, Cardiovascular ris

Comparative case-control study of homocysteine, vitamin B12, and folic acid levels in patients with epilepsy

Introduction: Increased blood homocysteine levels are a known cardiovascular risk factor. Epileptic patients on long-term treatment with antiepileptic drugs may present higher homocysteine levels and, consequently, a potential increase in cardiovascular risk. Material and methods: We conducted an observational case-control study to compare plasma levels of homocysteine, folic acid, and vitamin B12. Results: Our study included a total of 88 subjects: 52 patients with epilepsy and 36 controls. Epileptic patients showed higher homocysteine levels (P = .084) and lower levels of folic acid (P < .05). Conclusion: Homocysteine levels should be monitored in epileptic patients on long-term treatment with antiepileptic drugs. We suggest starting specific treatment in patients with high homocysteine levels. Resumen: Introducción: El aumento de homocisteína en sangre constituye un conocido factor de riesgo cardiovascular. Los pacientes epilépticos en tratamiento crónico con fármacos antiepilépticos pueden presentar niveles más elevados de homocisteína y, en consecuencia, un potencial aumento del riesgo cardiovascular. Material y métodos: Estudio observacional de casos y controles para la comparación de los niveles plasmáticos de homocisteína, ácido fólico y vitamina B12. Resultados: Se reclutó a un total de 88 sujetos, 52 de ellos epilépticos y 36 controles. Se observó una tendencia a niveles de homocisteína más elevados (p = 0,084) en los pacientes epilépticos y unos valores de ácido fólico más bajos (p < 0,05). Conclusiones: Por su potencial efecto como factor de riesgo cardiovascular, es importante prestar atención a los niveles de homocisteína en los pacientes epilépticos en tratamiento crónico con fármacos antiepilépticos y en caso de encontrar niveles elevados sugerimos la instauración de tratamiento específico. Keywords: Hyperhomocysteinaemia, Folic acid, Vitamin B12, Epilepsy, Antiepileptic drugs, Cardiovascular risk, Palabras clave: Hiperhomocisteinemia, Ácido fólico, Vitamina B12, Epilepsia, Fármacos antiepilépticos, Riesgo cardiovascula