Borderline personality and attention-deficit hyperactivity traits in childhood are associated with hypomanic features in early adulthood

Background There is limited understanding of the symptomatic development of bipolar disorder from childhood to early adulthood. Aims We assessed whether borderline personality disorder traits, ADHD, and emotional, behavioural and social difficulties during childhood were associated with hypomania assessed in young adulthood. Method We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), to examine associations between measures of childhood psychopathology and lifetime hypomanic features assessed at age 22–23 years using the Hypomania Checklist-32 (HCL-32; n = 3,372). We also conducted a factor analysis of the HCL to identify latent constructs underlying hypomania, and the extent to which childhood psychopathology was associated with these. Results We identified two factors of the HCL corresponding to energy/mood and risk-taking/irritability. There was evidence of association between childhood borderline personality disorder traits and both hypomania factors, with evidence that the association was stronger with the risk-taking/irritability factor. All individual borderline traits, with the exception of fear of abandonment, were associated with hypomania. There was also evidence of association between most other measures of childhood psychopathology (ADHD, hyperactivity, conduct problems, peer relationship problems and reduced prosocial behaviour) and the risk-taking/irritability factor, but much less consistent evidence of association with the energy/mood factor. Limitations The HCL cannot diagnose bipolar disorder and may be subject to reporting bias. Conclusions A broad range of childhood psychopathologies may represent early markers of risk for hypomania. Further studies are required to understand the mechanisms underlying these associations, and to inform earlier detection of bipolar disorder

Genetic risk for bipolar disorder and psychopathology from childhood to early adulthood

Background: Studying the phenotypic manifestations of increased genetic liability for Bipolar Disorder (BD) can increase understanding of this disorder. Aims: We assessed whether genetic risk for BD was associated with childhood psychopathology and features of hypomania in young adulthood within a large population-based birth cohort. Methods: We used data from the second Psychiatric Genetics Consortium Genome Wide Association Study (GWAS) for Bipolar Disorder to construct a polygenic risk score (PRS) for each individual in the Avon Longitudinal Study of Parents and Children (ALSPAC). Linear and logistic regression models were used to assess associations between the BD-PRS and emotional/behavioural difficulties, attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) traits in childhood, as well as hypomania in early adulthood (sample sizes from 2654 to 6111). Results: The BD-PRS was not associated with total hypomania score, but was weakly associated with a binary measure of hypomania (OR = 1.13, 95%CI 0.98,1.32; p = 0.097), and particularly at higher hypomania symptom thresholds (strongest evidence OR = 1.33, 95%CI 1.07, 1.65; p = 0.01). The BD-PRS was also associated with ADHD (OR = 1.31, 95%CI 1.10, 1.57; p = 0.018), but not with other childhood psychopathology. Limitations: The PRS only captures common genetic variation and currently explains a relatively small proportion of the variance for BD. Conclusions: The BD-PRS was associated with ADHD in childhood, and weakly with adult hypomania, but not with other psychopathology examined. Our findings suggest that genetic risk for BD does not appear to manifest in childhood to the same extent as schizophrenia genetic risk has been reported to do

Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.

BackgroundThe causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.MethodsRetrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.ResultsBetween 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011).ConclusionsMolecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence

Investigating associations between genetic risk for bipolar disorder and cognitive functioning in childhood

Introduction Identifying phenotypic manifestations of genetic risk for bipolar disorder (BD) in childhood could increase our understanding of aetiological mechanisms. Aims To examine whether BD genetic risk is associated with childhood (age 8 years) cognitive function. Methods Using data from the Avon Longitudinal Study of Parents and Children, we examined associations between polygenic risk scores for BD (BD-PRS) derived using Psychiatric Genomics Consortium summary data at p-thresholds (PT) ≤0.01 (primary) and ≤0.5 (secondary) and several cognitive domains (sample sizes 5,613 to 5,936). We also examined whether associations were due to SNPs that have shared risk effects on schizophrenia (SZ). Results At PT≤0.01, the BD-PRS was associated with poorer executive functioning (ß= -0.03, 95%CI -0.06, -0.01; p = 0.013), and, more weakly with poorer processing speed (ß = -0.02, 95%CI -0.05, 0.02; p = 0.075). Evidence of association with both poorer processing speed (p = 0.016) and performance IQ (p = 0.018) was stronger at PT≤0.5. Associations with performance IQ and processing speed were primarily driven by genetic effects that are shared with SZ risk, but there was some evidence of bipolar-specific genetic effects on childhood executive functioning. Limitations The BD-PRS still explains only a small proportion of the variance for BD which will have reduced power to detect associations. Conclusions Genetic risk for BD manifests as impaired cognition in childhood, and this is driven by risk SNPs that are also shared with SZ genetic risk. Further elucidation of which cognitive domains are most affected by genetic risk for BD could help understanding of aetiology and improve prediction of BD

為取替申一札之事（助郷人馬請負証文、古山村役人宛）

Background Identifying the phenotypic manifestations of increased genetic liability for depression (MDD) and bipolar disorder (BD) can enhance understanding of their aetiology. The polygenic risk score (PRS) derived using data from genome-wide-association-studies can be used to explore how genetic risk is manifest in different samples. Aims In this systematic review, we review studies that examine associations between the MDD and BD polygenic risk scores and phenotypic outcomes. Methods Following PRISMA guidelines, we searched EMBASE, Medline and PsycINFO (from August 2009 – 14th March 2016) and references of included studies. Study inclusion was based on predetermined criteria and data were extracted independently and in duplicate. Results Twenty-five studies were included. Overall, both polygenic risk scores were associated with other psychiatric disorders (not the discovery sample disorder) such as depression, schizophrenia and bipolar disorder, greater symptom severity of depression, membership of a creative profession and greater educational attainment. Both depression and bipolar polygenic risk scores explained small amounts of variance in most phenotypes (< 2%). Limitations Many studies did not report standardised effect sizes. This prevented us from conducting a meta-analysis. Conclusions Polygenic risk scores for BD and MDD are associated with a range of phenotypes and outcomes. However, they only explain a small amount of the variation in these phenotypes. Larger discovery and adequately powered target samples are required to increase power of the PRS approach. This could elucidate how genetic risk for bipolar disorder and depression is manifest and contribute meaningfully to stratified medicine

Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes

Grado de Satisfacción de los médicos, que son usuarios del Dpto. de Análisis Clínicos del Instituto de Investigaciones en Ciencias de la Salud (UNA) durante el año 2010

El Instituto de Investigaciones en Ciencias de la Salud depende de la Universidad Nacional de Asunción, es un establecimiento público con laboratorios que brinda a la comunidad servicios de rutina y especializados que satisfacen requisitos de calidad; los cuales son accesibles, seguros, confiables y confidenciales. La satisfacción del usuario médico es un indicador reconocido de calidad asistencial, es por ello que el Instituto ha elaborado un estudio de opinión con el objetivo de conocer el grado de satisfacción de los profesionales médicos con respecto al Departamento de Análisis Clínicos (AC) mediante una encuesta dirigida a los mismos y mejorar si fuese necesario el servicio brindado por el laboratorio. Se realizó un estudio observacional descriptivo de corte transverso, la selección de los médicos fue a partir de los pedidos de análisis que llegaron al Dpto. de AC durante el año 2010. Se utilizó como instrumento de medición una encuesta con 11 ítems y sugerencias, relacionadas con la satisfacción de los usuarios médicos. Los pedidos médicos solicitados fueron 68.9% del Hospital de Clínicas y el 31.1% correspondieron a Centros de Salud del Ministerio de Salud Pública, Hospital de Policía, Hospital de las Fuerzas Armadas, entre otros. Del estudio de opinión se concluye que el grado de satisfacción de los médicos con respecto al Departamento de AC es bueno pero que es necesario insistir en aspectos de comunicación y colaboración entre los servicios clínicos y los laboratorios para que la mejora en el trabajo participativo de estos estamentos sea más fructífera

Investigation of the genetic association between quantitative measures of psychosis and schizophrenia:A polygenic risk score analysis

The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p<0.0001). In the case-control sample, the five psychosis dimensions were found to be significantly associated with genetic risk scores; the correlations ranged between.15 and.27 (all p<.001). However, these correlations were not significant in schizophrenia cases or controls separately. While this study confirms the presence of a genetic risk for schizophrenia as categorical diagnostic trait, we did not find evidence for the genetic risk underlying quantitative schizophrenia symptom dimensions. This does not necessarily imply that a genetic basis is nonexistent, but does suggest that it is distinct from the polygenic risk score for schizophrenia

Clinician-centric diagnosis of rare genetic diseases: performance of a gene pertinence metric in decision support for clinicians

Background In diagnosis of rare genetic diseases we face a decision as to the degree to which the sequencing lab offers one or more diagnoses based on clinical input provided by the clinician, or the clinician reaches a diagnosis based on the complete set of variants provided by the lab. We tested a software approach to assist the clinician in making the diagnosis based on clinical findings and an annotated genomic variant table, using cases already solved using less automated processes. Results For the 81 cases studied (involving 216 individuals), 70 had genetic abnormalities with phenotypes previously described in the literature, and 11 were not described in the literature at the time of analysis (“discovery genes”). These included cases beyond a trio, including ones with different variants in the same gene. In 100% of cases the abnormality was recognized. Of the 70, the abnormality was ranked #1 in 94% of cases, with an average rank 1.1 for all cases. Large CNVs could be analyzed in an integrated analysis, performed in 24 of the cases. The process is rapid enough to allow for periodic reanalysis of unsolved cases. Conclusions A clinician-friendly environment for clinical correlation can be provided to clinicians who are best positioned to have the clinical information needed for this interpretation

Frecuencia de dislipidemia y estado nutricional de escolares de áreas rurales paraguayas

Mundialmente la prevalencia de dislipidemias ha crecido en la última década en niños y adultos. En nuestro país las enfermedades circulatorias son la primera causa de muerte. Se determinó la frecuencia de dislipidemia, estado nutricional y factores asociados a dislipidemia en escolares de cuatro escuelas rurales públicas. Estudio observacional descriptivo de corte transverso en una población de escolares de 5 a 13 años de edad, de ambos sexos, con muestreo de casos consecutivos, realizado entre abril de 2008 a setiembre de 2009. Se determinó el estado nutricional por IMC según CDC 2000 y los niveles de colesterol y triglicéridos en sangre por métodos enzimáticos. A través de una encuesta, se consultaron los antecedentes familiares de dislipidemia, actividad física y hábitos alimentarios. El 59% de los 182 escolares incluidos en el estudio presentaron dislipidemia, 33% niveles de colesterol de riesgo moderado o alto, 41% niveles de triglicérido de riesgo moderado o alto. El 8% de los escolares mostró sobrepeso u obesidad. En cuanto a factores de riesgo asociados a dislipidemia, el 60% consumía carnes no magras al menos dos o tres veces por semana y el 56% de los niños que poseían padres con antecedentes de dislipidemia presentaban hipercolesterolemia de riesgo. La prevalencia de dislipidemia en esta población es preocupante y por ello, es necesario introducir estrategias dirigidas a mejorar los hábitos alimenticios en las instituciones educativas