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BACKGROUND: Ageing, disease and malignant transformation of the skin are associated with changes in DNA methylation. So far, mostly invasive methodologies such as biopsies have been applied in collecting DNA methylation signatures. Tape stripping offers a noninvasive option for skin diagnostics. It enables the easy but robust capture of biologic material in large numbers of participants without the need for specialized medical personnel. OBJECTIVES: To design and validate a methodology for noninvasive skin sample collection using tape stripping for subsequent DNA -methylation analysis. METHODS: A total of 175 participants were recruited and provided tape-stripping samples from a sun-exposed area; 92 provided matched tape-stripping samples from a sun-protected area, and an additional 5 provided matched skin-shave biopsies from the same area. Using -enzymatic conversion and whole-genome Illumina sequencing, we generated genome-wide DNA methylation profiles that were used to evaluate the feasibility of noninvasive data acquisition, to compare with established sampling approaches and to investigate biomarker identification for age and ultraviolet (UV) exposure. RESULTS: We found that tape-stripping samples showed strong concordance in their global DNA methylation landscapes to those of conventional invasive biopsies. Moreover, we showed sample reproducibility and consistent global methylation profiles in skin tape-stripping samples collected from different areas of the body. Using matched samples from sun-protected and sun-exposed areas of the body we were able to validate the capacity of our method to capture the effects of environmental changes and ageing in a cohort covering various ages, ethnicities and skin types. We found DNA methylation changes on the skin resulting from UV exposure and identified significant age-related hypermethylation of CpG islands, with a pronounced peak effect at 50-55 years of age, including methylation changes in well-described markers of ageing. CONCLUSIONS: These data demonstrate the feasibility of using tape stripping combined with whole-genome sequencing as a noninvasive approach to measuring DNA methylation changes in the skin. In addition, they outline a viable experimental framework for the use of skin tape stripping, particularly when it is performed in large cohorts of patients to identify biomarkers of skin ageing, UV damage and, possibly, to track treatment response to therapeutic interventions.

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Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

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ABSTRACT Frailty and sarcopenia are geriatric syndromes highly prevalent, complex, and hard to diagnose and treat. The literature still lacks a consensus on which resistance training program is better for older people, especially when considering frailty status and sarcopenia. We aimed to evaluate the effectiveness of a progressive resistance training program on muscle mass and frailty status in older sarcopenic women. This study included 18 community-dwelling sarcopenic women aged 65 or older enrolled in the progressive resistance training program. The intervention was based on 75% of each subject's maximum repetition test (3 times/week, for 12 weeks). Before the intervention, 16.7% were frail, and 61.1% were pre-frail; after the intervention, 5.6% were frail, and 50% were pre-frail. The result shows that the intervention reduced frailty status and increased muscle mass (p=0.01). Hence, after the intervention, we observed both a decrease in frailty and a positive change in function, since the percentage of robust women increased twice (p=0.01). We conclude that the progressive resistance training program might be the best strategy to prevent frailty and sarcopenia. Therefore, we suggest using weight resistance training in daily clinical practice to improve muscle mass and decrease frailty status in sarcopenic women.

RESUMO Fragilidade e sarcopenia são consideradas síndromes geriátricas que apresentam grande prevalência e complexidade e são de difícil diagnóstico e tratamento. Ainda não existe consenso quanto ao melhor programa de exercícios resistidos, especialmente quando se considera a fragilidade e a sarcopenia. O objetivo deste estudo foi avaliar a efetividade de um programa de carga na massa muscular e na classificação de fragilidade em idosas sarcopênicas. Participaram 18 idosas sarcopênicas, com idade a partir de 65 anos, que completaram um programa de carga progressiva. A intervenção utilizou o cálculo de 75% de uma repetição máxima (1RM) para cada participante (3 vezes/semana, por 12 semanas). Antes da intervenção, 16,7% foram consideradas frágeis e 61,1% pré-frágeis; após, 5,6% passaram a ser consideradas frágeis e 50% pré-frágeis. Os resultados mostraram que a intervenção alterou a classificação de fragilidade e aumentou a massa muscular das idosas (p=0,01). Observou-se diminuição nos itens de classificação da fragilidade e consequente melhora no perfil funcional, havendo o aumento da porcentagem daquelas consideradas não frágeis após a intervenção (p=0,01). Conclui-se que o programa de exercício resistido progressivo é provavelmente uma das melhores estratégias para prevenir a fragilidade e a sarcopenia. Desta forma, recomenda-se o seu uso na prática clínica diária para melhorar a massa muscular e diminuir o status de fragilidade em mulheres sarcopênicas.

RESUMEN La fragilidad y la sarcopenia son síndromes geriátricos de alta prevalencia y complejidad, además de ser de difícil diagnóstico y tratamiento. Todavía no hay un consenso sobre el programa de ejercicios de fuerza más indicado, especialmente teniendo en cuenta la fragilidad y la sarcopenia. El objetivo de este estudio fue evaluar la efectividad de un programa de carga sobre la masa muscular y la clasificación de la fragilidad en ancianas con sarcopenia. Participaron 18 ancianas con sarcopenia, de más de 65 años y que completaron un programa de carga progresiva. La intervención utilizó el cálculo del 75% de repetición máxima (1RM) para cada participante (3 veces/semana, durante 12 semanas). Antes de la intervención, el 16,7% de las participantes se consideraban frágiles y el 61,1% prefrágiles; después de la intervención, el 5,6% se consideraban frágiles y el 50% prefrágiles. Los resultados mostraron que la intervención produjo cambios en la clasificación de la fragilidad y aumentó la masa muscular de las ancianas (p=0,01). Hubo una reducción en los ítems de clasificación de la fragilidad y una mejora en el perfil funcional, con un aumento del porcentaje de aquellas consideradas no frágiles después de la intervención (p=0,01). Se concluye que el programa de ejercicios de fuerza progresiva se mostró una de las mejores estrategias para prevenir la fragilidad y la sarcopenia. Por tanto, se recomienda aplicarlo en la práctica clínica cotidiana para mejorar la masa muscular y disminuir el estado de fragilidad de mujeres con sarcopenia.

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BACKGROUND AND PURPOSE: Physical functioning refers to the ability to independently perform activities that require physical ability, and may be an important tool for predicting a higher risk of hospitalization. The objective of this study was to verify whether aspects of physical functioning are independently associated with the risk for new hospitalization in older adults seen in primary health care. METHODS: This prospective cohort study consisted of 473 older adults 60 years and older who had not been hospitalized in the prior year. Hospitalization records were obtained with authorization from the hospital admission. Depending on physical functioning, the probability of a new hospital admission within the next 5 years was determined based on survival analysis and the Kaplan-Meier curve. Physical functioning was evaluated using 5 easy-to-administer tests: handgrip strength using a Jamar dynamometer, functional performance using the Short Physical Performance Battery, balance using the step test, mobility using the Timed Up and Go (TUG) test, and gait speed using the 4-m walk test. The association between poor physical functioning and new hospitalization was verified using a Cox regression model, adjusted for sex, age, number of comorbidities, number of medications, and BMI. Models were implemented separately for each physical functioning test. RESULTS: In the sample, 32% had been hospitalized at least once in 5 years. The Kaplan-Meier curve showed a decrease in the probability of nonhospitalization within the next 5 years. Cox regression analysis showed an association between hospitalization within the next 5 years and mobility on the TUG test of more than 12.4 seconds in the crude (hazard ratio [HR] = 1.33, 95% CI = 1.10-1.60) and adjusted models (HR = 1.26, 95% CI = 1.02-1.56), and balance using the step test of more than 7.5 seconds in the crude (HR = 1.27, 95% CI = 1.03-1.56) model. CONCLUSIONS: Physical functioning tests demonstrated that poor physical performance predicts new hospitalization, and reinforced the importance of their application in physical therapy practice in primary health care settings.

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Controlling aggression is a crucial skill in social species like rodents and humans and has been associated with anterior cingulate cortex (ACC). Here, we directly link the failed regulation of aggression in BALB/cJ mice to ACC hypofunction. We first show that ACC in BALB/cJ mice is structurally degraded: neuron density is decreased, with pervasive neuron death and reactive astroglia. Gene-set enrichment analysis suggested that this process is driven by neuronal degeneration, which then triggers toxic astrogliosis. cFos expression across ACC indicated functional consequences: during aggressive encounters, ACC was engaged in control mice, but not BALB/cJ mice. Chemogenetically activating ACC during aggressive encounters drastically suppressed pathological aggression but left species-typical aggression intact. The network effects of our chemogenetic perturbation suggest that this behavioral rescue is mediated by suppression of amygdala and hypothalamus and activation of mediodorsal thalamus. Together, these findings highlight the central role of ACC in curbing pathological aggression.

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BACKGROUND: Low back pain (LBP) has emerging as an epidemic, multifactorial and multidimensional condition in older age. Assessment of attitudes and beliefs of patients with back pain is necessary for understanding the impact of psychosocial factors on pain perception and management. OBJECTIVES: To cross-culturally adapt and examine the validity and reproducibility (intra and interrater reliability and agreement) of the Back Beliefs Questionnaire (BBQ) in older Brazilians with acute LBP. DESIGN AND SETTING: Cross-sectional methodological report conducted at the Department of Physical Therapy of the Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. METHODS: The present study was conducted for translating, adapting, and examining the psychometric properties of a questionnaire. Participants aged ≥ 60 years experiencing an acute episode of LBP were recruited. Coefficients of internal consistency, reliability and agreement were obtained using Cronbach's α, intraclass correlations, and standard error of measurement and the smallest detectable change, respectively. RESULTS: Twenty-six participants aged between 60-84 years and reporting a mean of 9.8 (4.3) years of schooling completed the study. The Brazilian Portuguese-language version of the BBQ (BBQ-Brazil) was proposed and presented with adequate conceptual, semantic, operational, and measurement equivalence from the original version. Intra and interrater evaluations showed moderate (0.74) and excellent (0.91) intraclass correlation coefficients, respectively, with small standard error of measurement for both evaluations. Internal consistency was considered adequate (0.70). CONCLUSION: BBQ-Brazil had consistent measurements of validity and reproducibility, and proved to be a valuable tool in clinical practice for addressing attitudes and beliefs of older patients with acute LBP.

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Clozapine is an atypical antipsychotic medication that is used to treat schizophrenia patients who are resistant to other antipsychotic drugs. The molecular mechanisms mediating the effects of clozapine are not well understood and its use is often associated with severe side-effects. In this study, we exposed groups of wild-type zebrafish to two doses of clozapine ('low' (20 µg/L) and 'high' (70 µg/L)) over a 72-h period, observing dose-dependent effects on behaviour. Using RNA sequencing (RNA-seq) we identified multiple genes differentially expressed in the zebrafish brain following exposure to clozapine. Network analysis identified co-expression modules characterised by striking changes in module connectivity in response to clozapine, and these were enriched for regulatory pathways relevant to the etiology of schizophrenia. Our study highlights the utility of zebrafish as a model for assessing the molecular consequences of antipsychotic medications and identifies genomic networks potentially involved in schizophrenia.

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Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality.

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BACKGROUND: Frailty and sarcopenia are highly prevalent, as a part of geriatric syndrome, among elderly individuals. However, little is known about how these syndromes can affect elderly individuals who continue to work. OBJECTIVE: To estimate the prevalence of sarcopenia and frailty, and their individual and occupational factors among elderly individuals. METHODS: This cross-sectional study included elderly individuals working in a public university in Brazil, who were classified according to their sarcopenia and frailty profiles. They answered a structured questionnaire comprising potential explanatory variables: individual sociodemographic factors, work related factors, and health behaviors. Additionally, they performed a physical performance test. Multinomial logistic regression was used to estimate odds ratios and respective 95% confidence intervals (95% CIs). All analyses were conducted using the Stata 13.0 software, considering a significance of 5%. RESULTS: Respectively, 55.8% and 6.3% of the elderly participants were classified in the Sarcopenia and Severe Sarcopenia groups. Frailty prevalence was 9.4%, with 62.5% classified as Pre-frail. Sarcopenia prevalence was significantly higher among men, and among those living with a partner, with a university degree, exhibiting poor lower limb function, and with multiple work demands. Frailty prevalence was significantly higher among women, and among those living without a partner, having a low educational level, with less work experience, working in an unhealthy/dangerous environment, and whose job was predominantly physical. CONCLUSION: This study identified different potential trigger factors for the development of sarcopenia and frailty. These findings confirm that individual and work factors could explain the incidence of sarcopenia and frailty syndrome.

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RESUMO Estabeleceram-se pontos de corte alternativos para o cálculo da massa muscular apendicular (MMA) em idosos brasileiros para classificar a sarcopenia. Foram analisados dados de 562 idosos participantes do estudo Fibra (Fragilidade em Idosos Brasileiros), no polo Belo Horizonte. Por meio da equação de Lee, determinaram-se pontos de corte para MMA baseado na percentil 20 de sua distribuição na população estudada. Em seguida, os sujeitos foram classificados para sarcopenia de acordo com os critérios do Consenso Europeu sobre Definição e Diagnóstico da Sarcopenia em Idosos, além de avaliadas as possíveis associações desta com a capacidade funcional e comorbidades. A maioria da amostra foi composta por mulheres (65,5%) com idade média de 74,1 (±6,4) e média de 1,5 (±1,4) comorbidades. Os pontos de corte para MMA foram <6.47kg/m2 para mulheres e <8.76kg/m2 para homens. A prevalência de sarcopenia foi de 14,9%, sendo 13,5% da população parcialmente dependente para atividades básicas de vida diária (ABVD), 30,6% para atividades instrumentais de vida diária (AIVD) e 66,7% para atividades avançadas de aida diária (AAVD). A sarcopenia se correlacionou apenas com AIVD (r=0,081, p= 0.05), e encontrou-se uma correlação negativa entre sarcopenia e comorbidades (r= −0,103, p=0,014). Foram propostos pontos de corte específicos para MMA para a população de idosos brasileiros e não foram encontradas correlações entre as variáveis do estudo, exceto para AIVD e comorbidades.

RESUMEN Se establecieron puntos de corte alternativos para el cálculo de la masa muscular apendicular (MMA) en ancianos brasileños para clasificar la sarcopenia. Fueron analizados datos de 562 ancianos participantes del estudio Fibra (Debilidad en Ancianos Brasileños), en el polo Belo Horizonte. Por medio de la ecuación de Lee, se determinaron puntos de corte para MMA basado en la percentil 20 de su distribución en la población estudiada. Luego, los sujetos fueron clasificados para sarcopenia de acuerdo con los criterios del Consenso Europeo sobre Definición y Diagnóstico de la Sarcopenia en Ancianos, además de evaluadas las posibles asociaciones de esta con la capacidad funcional y comorbidades. La gran parte de la muestra fue compuesta por mujeres (el 65,5%) con edad media de 74,1 (±6,4) y promedio de 1,5 (±1,4) comorbidades. Los puntos de corte para MMA fueron <6.47kg/m2 para mujeres y <8.76kg/m2 para hombres. La prevalencia de sarcopenia fue del 14,9%, siendo el 13,5% de la población parcialmente dependiente para actividades básicas de vida diaria (ABVD), el 30,6% para actividades instrumentales de vida diaria (AIVD) y el 66,7% para actividades avanzadas de vida diaria (AAVD). La sarcopenia se correlacionó solamente con AIVD (r=0,081, p= 0.05), y se encontró una correlación negativa entre sarcopenia y comorbidades (r= −0,103, p=0,014). Fueron propuestos los puntos de corte específicos para MMA para la población de ancianos brasileños y no fueron encontradas correlaciones entre las variables del estudio, excepto para AIVD y comorbidades.

ABSTRACT Alternative cut-off points for the calculation of appendicular muscle mass (AMM) in older Brazilians were established to classify sarcopenia. Data from 562 older adults from Belo Horizonte who participated in the Fibra study (Fragilidade em Idosos Brasileiros [Fragility in Older Brazilians) were analyzed. Through Lee's equation, cut-off points for AMM were determined based on the 20th percentile of their distribution in the studied population. Then, the subjects were classified for sarcopenia according to the criteria of the European Consensus on Definition and Diagnosis of Sarcopenia in Older Adults, and its possible associations with functional capacity and comorbidities were evaluated. Most of the sample was composed by women (65.5%) with 74.1 years of age (±6.4) and 1.5 (±1.4) comorbidities on average. The cut-off points for AMM were <6.47kg/m2 for women and <8.76kg/m2 for men. The prevalence of sarcopenia was 14.9%, 13.5% of the population being partially dependent for basic activities of daily living (BADL), 30.6% for instrumental activities of daily living (IADL) and 66.7% for advanced activities of daily living (AADL). Sarcopenia was correlated with IADL only (r=0.081, p=0.05), and a negative correlation was found between sarcopenia and comorbidities (r=−0.103, p=0.014). Cut-off points specific to AAM for the population of older Brazilians were proposed, and no correlations between the variables of the study were found, except for IADL and comorbidities.

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OBJECTIVES: To investigate the correlates of a recent history of disabling low back pain (LBP) in older persons. MATERIALS AND METHODS: The Pain in the Elderly (PAINEL) Study was derived from the Frailty among Brazilian Older Adults (FIBRA) Network Study. Data were collected through face-to-face/telephone interviews and clinical examination. A series of logistic regressions assessed associations between a recent history of disabling LBP and sociodemographic, physical/lifestyle, and psychological factors. RESULTS: Of the 378 community-dwelling elders included in the study (age±SD, 75.5±6.1), 9.3% experienced LBP that was bad enough to limit or change their daily activities during the past year. Those reporting a recent history of disabling LBP were more likely to be women and under financial strain, to present poor self-rated health, overweight, multimorbidity, low physical activity level, fatigue, depressive symptomatology/diagnosis and fear beliefs, and to report decreased sleep time, prolonged sitting time, chronic pain (in location other than lower back), and frequently recurring LBP. The multivariate logistic regression analysis indicated that overweight (odds ratio [OR], 29.6; 95% confidence interval [CI], 2.3-391.0), low physical activity level (OR, 4.4; 95% CI, 1.3-15.4), fatigue (OR, 10.3; 95% CI, 2.4-43.4), depression diagnosis (OR, 4.9; 95% CI, 1.3-18.4), and frequently recurring LBP (OR, 4.6; 95% CI, 1.0-20.1) were independently associated with a recent history of disabling LBP. DISCUSSION: Our study supports the link between disabling LBP and other age-related chronic conditions in a middle-income country with a rapidly aging population.

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Abstract Introduction: Resistance training is quoted as one of the best pathways to manage sarcopenia and progressive resistance training is supposed to improve muscle mass, strength and performance in older adults. Objective: The aim was to examine the impact of a progressive resistance exercise program (PREP) on muscle and function performance in sarcopenic community-dwelling elder women. Methods: Quasi-experimental study (pre - post intervention). Participated 18 sarcopenic community-dwelling elder women (65 years or older). PREP based on 75% of the participant's maximum load (12/wk, 3 times/wk). Main outcome measures: muscle strength of knee extensors (isokinetic dynamometry), muscle mass (dual-x ray absorptiometry - DXA), functional performance (Short Physical Performance Battery - SPPB). Paired t-test was used to evaluate differences pre and post intervention. Results: Improvements on power (p = 0.01) and peak torque (p = 0.01) were observed when measured by the isokinetic dynamometer at low speed (60º/s). Improvements on DXA (pre PREP: 5.49 kg/m2 vs. post PREP: 6.01 kg/m2; p = 0.03) and SPPB scores (pre PREP: 9.06 vs. post PREP: 10.28; p = 0.01) were also observed. Conclusion: The PREP was able to improve muscle and functional performance in sarcopenic community-dwelling elder women. This program should be considered in clinical practice.

Resumo Introdução: Exercícios com carga são uma das boas indicações de tratamento no caso da sarcopenia e o treinamento com carga progressiva pode aumentar a massa muscular, força e desempenho em idosos. Objetivo: Avaliar o impacto de um programa de exercícios com carga progressiva (PECP) no desempenho muscular e funcional de idosas sarcopênicas da comunidade. Métodos: Estudo quasi-experimental (pré-pós intervenção). Participaram 18 idosas sarcopênicas, da comunidade (65 anos e mais). PECP foi baseado em 75% de uma resistência máxima (12/semanas, 3 x/ semana). Medidas de desfecho: força muscular dos extensores de joelho (dinamômetro isocinético), massa muscular (dual-x ray absorptiometry - DXA), desempenho funcional (Short Physical Performance Battery - SPPB). Comparações pré-pós intervenção foi por meio do teste t-test pareado. Resultados: Houve aumento na potência (p = 0,01) e no torque (p = 0,01), observados nas medidas do isocinético em baixa velocidade (60º/s). Observou-se também aumento no DXA (5,49 kg/m2 vs. 6,01 kg/m2; p = 0,03) e melhora nos escores do SPPB (9,06 vs. 10,28; p = 0,01). Conclusão: O PECP aumentou o desempenho funcional e muscular das idosas sarcopênicas comunitárias. Este programa deve ser considerado para a prática clínica.

Resumen Introducción: Ejercicios con carga es una de las buenas indicaciones de tratamiento en el caso de la sarcopenia y el entrenamiento con carga progresiva puede aumentar la masa muscular, fuerza y desempeño en ancianos. Objetivo: Evaluar el impacto de un programa de ejercicios con carga progresiva (PECP) en el desempeño muscular y funcional de ancianas sarcopénicas de la comunidad. Métodos: Estudio cuasiexperimental (pre-pos intervención). Participaron 18 ancianas sarcopénicas, de La comunidad (65 años y más). PECP se basó en 75% de una resistencia máxima (12/semanas, 3 x/semana). Las medidas de desenlace: fuerza muscular de los extensores de rodilla (dinamómetro isocinético), masa muscular (dual-x ray absorptiometry - DXA), desempeño funcional (Short Physical Performance Battery - SPPB). Las comparaciones pre-post-intervención fueron a través de La prueba t-test pareado. Resultados: Hubo aumento en la potencia (p = 0,01) y en el par de apriete - torque (p= 0,01), observados en las medidas del isocinético a baja velocidad (60º/s). Se observo también un aumento en el DXA (5,49 kg/m² vs. 6,01 kg/m², p = 0,03) y mejora en los escores del SPPB (9,06 vs. 10,28, p = 0,01. Conclusión: El PECP aumento el desempeño funcional y muscular de las ancianas sarcopénicas comunitarias. Este programa debe ser considerado para la práctica clínica.

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Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with aetiological variation in complex disease.

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BACKGROUND: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. RESULTS: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. CONCLUSIONS: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.

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Malnutrition is a risk factor for noncommunicable diseases related to ageing, and it can also contribute to musculoskeletal health. This study investigated whether nutritional risk is associated with chronic musculoskeletal pain in community-dwelling older persons. Nutritional risk was assessed by the DETERMINE Checklist. Chronic musculoskeletal pain was defined as the presence of pain in the past six months that did not disappear for at least 30 consecutive days. Multivariate logistic regression including confounding variables was used for the analysis. The sample was comprised of 383 participants (age 75.6 ± SD 6.1); the majority were at moderate-to-high nutritional risk (69%) and approximately one third presented chronic musculoskeletal pain (30%). The nutritional risk score was independently associated with chronic musculoskeletal pain: adding one unit in the risk score produces an 11% increment in the odds of presenting pain (OR 1.109, 95% CI 1.022-1.204). Individuals classified into moderate- or high-risk categories also had substantially higher odds (∼90%) of presenting chronic musculoskeletal pain when compared to those in the low-risk category, although our findings were only marginally significant. This is the first study to demonstrate the association between nutritional risk and chronic musculoskeletal pain above and beyond the contributed effects from relevant confounders.

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We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.

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Childhood psychotic symptoms are associated with increased rates of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood; thus, elucidating early risk indicators is crucial to target prevention efforts. There is considerable discordance for psychotic symptoms between monozygotic twins, indicating that child-specific non-genetic factors must be involved. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to childhood psychotic symptoms. Therefore, this study explored whether differences in DNA methylation at age 10 were associated with monozygotic twin discordance for psychotic symptoms at age 12. The Environmental Risk (E-Risk) Longitudinal Twin Study cohort of 2,232 children (1,116 twin pairs) was assessed for age-12 psychotic symptoms and 24 monozygotic twin pairs discordant for symptoms were identified for methylomic comparison. Children provided buccal samples at ages 5 and 10. DNA was bisulfite modified and DNA methylation was quantified using the Infinium HumanMethylation450 array. Differentially methylated positions (DMPs) associated with psychotic symptoms were subsequently tested in post-mortem prefrontal cortex tissue from adult schizophrenia patients and age-matched controls. Site-specific DNA methylation differences were observed at age 10 between monozygotic twins discordant for age-12 psychotic symptoms. Similar DMPs were not found at age 5. The top-ranked psychosis-associated DMP (cg23933044), located in the promoter of the C5ORF42 gene, was also hypomethylated in post-mortem prefrontal cortex brain tissue from schizophrenia patients compared to unaffected controls. These data tentatively suggest that epigenetic variation in peripheral tissue is associated with childhood psychotic symptoms and may indicate susceptibility to schizophrenia and other mental health problems.

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BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances ine arly brain development. There is mounting evidence to support a role for developmentally regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. RESULTS: We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci,particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples.Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that schizophrenia-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. CONCLUSIONS: Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects.

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Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy in humans. Most affected individuals carry one extra X-chromosome (47,XXY karyotype) and the condition presents with a heterogeneous mix of reproductive, physical and psychiatric phenotypes. Although the mechanism(s) by which the supernumerary X-chromosome determines these features of KS are poorly understood, skewed X-chromosome inactivation (XCI), gene-dosage dysregulation, and the parental origin of the extra X-chromosome have all been implicated, suggesting an important role for epigenetic processes. We assessed genomic, methylomic and transcriptomic variation in matched prefrontal cortex and cerebellum samples identifying an individual with a 47,XXY karyotype who was comorbid for schizophrenia and had a notably reduced cerebellum mass compared with other individuals in the study (n = 49). We examined methylomic and transcriptomic differences in this individual relative to female and male samples with 46,XX or 46,XY karyotypes, respectively, and identified numerous locus-specific differences in DNA methylation and gene expression, with many differences being autosomal and tissue-specific. Furthermore, global DNA methylation, assessed via the interrogation of LINE-1 and Alu repetitive elements, was significantly altered in the 47,XXY patient in a tissue-specific manner with extreme hypomethylation detected in the prefrontal cortex and extreme hypermethylation in the cerebellum. This study provides the first detailed molecular characterization of the prefrontal cortex and cerebellum from an individual with a 47,XXY karyotype, identifying widespread tissue-specific epigenomic and transcriptomic alterations in the brain.

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BACKGROUND: Frailty and sarcopenia are frequent conditions in the elderly and are related to inactivity and functionality. However, little is known about the influence of the sarcopenia indicators on the frailty profile or their functional implications. OBJECTIVE: To evaluate whether the indirect indicators of sarcopenia and functionality influence the frailty profile in elderly subjects. METHOD: This was a cross-sectional study with 53 elderly subjects recruited by an active search in a secondary health care service. The indirect indicators of sarcopenia were body mass index (BMI), gait speed, Mini-Nutritional Assessment (MNA), Human Activity Profile (HAP), and handgrip strength. Frailty was characterized according to Fried's Frailty Phenotype. Functional capacity was assessed according to the Short Physical Performance Battery (SPPB). Physical activity level was assessed by HAP. Data were analyzed by analysis of variance (ANOVA) and multiple regression. RESULTS: Overall, 75.5% of the subjects were women, with a mean age of 76.72 (±5.89) years; 15.1% were frail and 54.7% pre-frail; and the level of physical activity was the most prevalent indicator of sarcopenia. Significant differences (p<0.05) were observed in both the physical activity level and gait speed between the non-frail and pre-frail groups and between the non-frail and frail groups. In addition, some sarcopenia indicators were associated with functional capacity and geriatric depression score. CONCLUSION: The level of physical activity and gait speed appeared to be the most relevant factors in the development of frailty in the study sample, which may have functional implications.

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