Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population

Mutations in . TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of . TMEM230 in PD etiology

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Modelagem hidrológica em microbacia hidrográfica parte I: aprimoramento do modelo HidroBacia Hydrologic modeling in a small watershed part I: improvement of the HidroBacia model

Testes preliminares realizados com o modelo hidrológico HidroBacia, indicaram desequilíbrio no seu balanço de massa, despertando a necessidade de estudos visando ao seu aperfeiçoamento; assim, o presente trabalho consistiu no aprimoramento do modelo HidroBacia a partir da localização e correção de falhas no código-fonte do seu programa computacional, essas falhas foram identificadas através da depuração do modelo durante simulações do hidrograma de escoamento superficial, utilizando-se dados de uma microbacia hidrográfica experimental. A principal causa relacionada com o desequilíbrio do balanço de massa do modelo, tinha referência com a solução das equações do modelo de ondas cinemáticas usado na propagação dos hidrogramas de escoamento superficial, cujo problema foi contornado pela substituição do algoritmo linear utilizado, Bras (1990), pelo algoritmo não-linear apresentado por Li et al. (1975). A partir desta modificação, considerada principal, e outras modificações implementadas, o balanço de massa do modelo HidroBacia foi ajustado e suas simulações passaram a gerar estimativas coerentes. Em virtude das alterações efetuadas, o HidroBacia evoluiu da versão 1.0 para a versão 1.1.<br>In previous tests conducted by the HidroBacia hydrologic model, desequilibria in its mass balance was detected, thus showing the need for further studies for its improvement. This work consisted of improvement of the HidroBacia model by means of identification and correction of mistakes in its software source code. The mistakes were identified through adjustment during runoff hydrograph simulations using an experimental watershed data bank. The main factor, related to the mass balance desequilibria in the model, was correlated with the solution of the equations for the kinematic wave model used for propagation of the runoff hydrographs. This problem was corrected by the substitution of the linear algorithm used (Bras, 1990), by the non-linear algorithm proposed by Li et al. (1975). Starting from this modification, considered as the principal one, and other modifications made in the program, mass balance of the HidroBacia model was fitted and its simulations started to generate coherent estimates. Due to the modifications made in HidroBacia the software evolved from version 1.0 to version 1.1

Synaptonemal complex assembly and H3K4Me3 demethylation determine DIDO3 localization in meiosis

Synapsis of homologous chromosomes is a key meiotic event, mediated by a large proteinaceous structure termed the synaptonemal complex. Here we describe a role in meiosis for the murine Death inducer obliterator (Dido) gene. The Dido gene codes for three proteins that recognize trimethylated histone H3 lysine 4 through their aminoterminal PHD domain. DIDO3, the largest of the three isoforms, localizes to the central region of the synaptonemal complex in germ cells. DIDO3 follows the distribution of the central region protein SYCP1 in Sycp3-/- spermatocytes, which lack the axial elements of the synaptonemal complex. This indicates that synapsis is a requirement for DIDO3 incoporation. Interestingly, DIDO3 is missing from the synaptonemal complex in Atm mutant spermatocytes, which form synapses but show persistent trimethylation of histone H3 lysine 4. In order to further address a role of epigenetic modifications in DIDO3 localization, we made a mutant of the Dido gene that produces a truncated DIDO3 protein. This truncated protein, which lacks the histone-binding domain, is incorporated in the synaptonemal complex irrespective of histone trimethylation status. DIDO3 protein truncation in Dido mutant mice causes mild meiotic defects, visible as gaps in the synaptonemal complex, but allows for normal meiotic progression. Our results indicate that histone H3 lysine 4 demethylation modulates DIDO3 localization in meiosis, and suggest epigenetic regulation of the synaptonemal complex.Ministerio de Salud (FIS PI051965) Comunidad de Madrid (S-BIO-0189-2006, P-GEN-0166-2006) Ministerio de Ciencia (RyC004-1886)Peer reviewe