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1.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
2.
Neurobiol Dis ; 124: 479-488, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30590179

RESUMO

Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Espinhas Dendríticas/patologia , Histona Acetiltransferases/genética , Esquizofrenia , Animais , Feminino , Camundongos , Proteoma , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia
3.
Nat Genet ; 50(5): 668-681, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29700475

RESUMO

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

4.
Eur J Pediatr ; 177(9): 1399-1405, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29594432

RESUMO

Congenital nephrogenic diabetes insipidus (CNDI) is characterized by the reduced ability of renal collecting duct cells to reabsorb water in response to the antidiuretic effect of vasopressin. Chronic polyuria and polydipsia are the hallmarks of the disease. Approximately 90% of all patients with CNDI have X-linked inherited disease caused by variants in the arginine vasopressin receptor 2 (AVPR2) gene. We present genetic findings in 34 individuals from 19 kindreds including one or more family members with CNDI. Coding regions of AVPR2 were sequenced bi-directionally. We identified eight novel disease-causing variants in AVPR2, p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro in nine kindreds. In all three families with more than one affected individual, the novel variants segregated with the disease. We also identified eight recurrent disease-causing variants, p.Val88Met, p.Leu111Valfs*80, p.Arg113Trp, p.Tyr124*, p.Ser167Leu, p.Thr207Asn, p.Arg247Alafs*12, and p.Arg337* in ten kindreds. Our findings contribute to the growing list of AVPR2 variants causing X-linked CNDI. CONCLUSION: Being a rapid diagnostic tool for CNDI, direct sequencing of AVPR2 should be encouraged in newborns with familial predisposition to CNDI. What is Known: • Disease-causing variants in AVPR2 cause X-linked congenital nephrogenic diabetes insipidus (CNDI). • DNA sequencing of AVPR2 is rapid, facilitates differential diagnosis, early intervention, and genetic diagnosis thus reducing morbidity in CNDI. What is New: • We identified eight novel disease-causing variants in AVPR2: p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro, thereby adding to the growing list of AVPR2 disease-causing variants and emphasizing the importance of genetic testing in CNDI.


Assuntos
Diabetes Insípido Nefrogênico/genética , Receptores de Vasopressinas/genética , Criança , Pré-Escolar , Família , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Análise de Sequência de DNA/métodos
5.
J Neurosci Methods ; 296: 93-98, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29287746

RESUMO

BACKGROUND: Dendritic spine morphology is heterogeneous and highly dynamic. To study the changing or aberrant morphology in test setups, often spines from several neurons from a few experimental units e.g. mice or primary neuronal cultures are measured. This strategy results in a multilevel data structure, which, when not properly addressed, has a high risk of producing false positive and false negative findings. METHODS: We used mixed-effects models to deal with data with a multilevel data structure and compared this method to analyses at each level. We apply these statistical tests to a dataset of dendritic spine morphology parameters to illustrate advantages of multilevel mixed-effects model, and disadvantages of other models. RESULTS: We present an application of mixed-effects models for analyzing dendritic spine morphology datasets while correcting for the data structure. COMPARISON WITH EXISTING METHODS: We further show that analyses at spine level and aggregated levels do not adequately account for the data structure, and that they may lead to erroneous results. CONCLUSION: We highlight the importance of data structure in dendritic spine morphology analyses and highly recommend the use of mixed-effects models or other appropriate statistical methods to deal with multilevel datasets. Mixed-effects models are easy to use and superior to commonly used methods by including the data structure and the addition of other explanatory variables, for example sex, and age, etc., as well as interactions between variables or between variables and level identifiers.

6.
Case Rep Nephrol Dial ; 7(3): 130-137, 2017 Sep-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29177155

RESUMO

Early diagnosis and treatment of congenital nephrogenic diabetes insipidus (CNDI) are essential due to the risk of intellectual disability caused by repeated episodes of dehydration and rapid rehydration. Timely genetic testing for disease-causing variants in the arginine vasopressin receptor 2 (AVPR2) gene is possible in at-risk newborns with a known family history of X-linked CNDI. In this study, a Swedish male with no family history was diagnosed with CNDI at 6 months of age during an episode of gastroenteritis. We analyzed the coding regions of AVPR2 by PCR and direct DNA sequencing and identified an 80-bp duplication in exon 2 (GenBank NM_000054.4; c.800_879dup) in the proband. This variant leads to a frameshift and introduces a stop codon four codons downstream (p.Ala294Profs*4). The variant gene product either succumbs to nonsense-mediated decay or is translated to a truncated nonfunctional vasopressin V2 receptor. This variant was absent in four unaffected family members, including his parents, as well as in 100 alleles from healthy controls, and is thus considered a novel de novo disease-causing variant. Identification of the disease-causing variant facilitated precise diagnosis of CNDI in the proband. Furthermore, it allows future genetic counseling in the family. This case study highlights the importance of genetic testing in sporadic infant cases with CNDI that can occur due to de novo variants in AVPR2 or several generations of female transmission of the disease-causing variant.

7.
Biol Psychiatry ; 82(1): 62-76, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27837920

RESUMO

BACKGROUND: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative. METHODS: This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1+/- mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters. RESULTS: Brd1+/- mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1+/- and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D2 [Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]). CONCLUSIONS: Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.


Assuntos
Comportamento Animal/fisiologia , Expressão Gênica/genética , Histona Acetiltransferases/fisiologia , Esquizofrenia/genética , Transmissão Sináptica/genética , Acetilação , Animais , Animais Geneticamente Modificados/genética , Corpo Estriado/metabolismo , Dopamina/metabolismo , Histona Acetiltransferases/genética , Histonas/metabolismo , Interneurônios/fisiologia , Camundongos , Serotonina/metabolismo
8.
Proteomics ; 16(14): 2059-63, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27080621

RESUMO

Histone modifications play an important role in regulating chromatin stability and gene expression, but to date, investigating them remains challenging. In order to obtain peptides suitable for MS-based analysis, chemical derivatization of N-terminus and lysine residues by propionic anhydride is commonly performed. Several side reactions (methyl-esterification, amidation, solvolysis, overpropionylation, and missed propionylation) during propionylation protocols have been described, yet their relative abundances remain vague. Because methyl-esterification could interfere with correct interpretation of the modification pattern, it is essential to take measures to avoid it. Here we present in-depth quantitative analyses of methyl-esterification and the other side reactions in a standard propionylation protocol containing methanol, and when replacing methanol with isopropanol or acetonitrile. We show that the use of alternative solvents can eliminate methyl-esterification and that even though other side reactions are not prevented, their contribution can be kept relatively small. We also show that replacing methanol can be of importance also in other proteomics methods, such as mixed cation exchange, using methanol under acidic conditions.


Assuntos
Anidridos/química , Código das Histonas , Histonas/análise , Fragmentos de Peptídeos/análise , Propionatos/química , Processamento de Proteína Pós-Traducional , Solventes/química , 2-Propanol/química , Acetonitrilos/química , Amidas/química , Sequência de Aminoácidos , Aminoácidos/química , Aminoácidos/metabolismo , Anidridos/metabolismo , Artefatos , Esterificação , Histonas/química , Histonas/metabolismo , Humanos , Metanol/química , Metilação , Mapeamento de Peptídeos , Propionatos/metabolismo , Proteômica/métodos , Espectrometria de Massas em Tandem/normas , Tripsina/química
9.
Scand J Urol Nephrol ; 46(2): 91-6, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22150692

RESUMO

OBJECTIVE: In search of potential urinary biomarkers of obstructive nephropathy, this study examined whether a potential change in the concentration of urinary cytokines [interferon-γ(IFN-γ), interleukin-1ß (IL-1ß), IL-2, IL-6, IL-10 and tumour necrosis factor-α (TNF-α)] reliably reflects changes in renal parenchymal levels of the same cytokines following the release of acute and chronic unilateral ureteral obstruction, respectively. MATERIAL AND METHODS: Acute obstruction was performed in 12 adult rats. After 48 h, six rats were used for selective urine collection and six rats had their kidneys removed and dissected into inner medulla and cortex. Chronic obstruction was performed in newborn rats. After 10 weeks, a similar set-up to that of the acute study was implemented. Sham-operated rats were prepared in parallel. Urine and tissue cytokines were measured with a bead-based multiplex sandwich immunoassay and analysed on a Luminex 100 IS instrument. RESULTS: In the acute study, there were significantly increased concentrations of IL-1ß and IL-6 in inner medulla and in urine from the obstructed kidney, significantly increased concentrations of TNF-α in urine from the obstructed kidney and, importantly, significantly increased levels of IL-10 in cortex and in urine from the non-obstructed kidney. In the chronic study, there were similar changes in IL-1ß and IL-6 (not significant) but no changes in TNF-α and IL-10. CONCLUSIONS: This study showed that inflammatory cytokines can be detected both in renal parenchyma and in urine from rats with experimental unilateral ureteral obstruction. Further studies are needed to confirm the diagnostic accuracy of IL-1ß, IL-6, IL-10 and TNF-α in urine.


Assuntos
Citocinas/urina , Hidronefrose/urina , Rim/metabolismo , Obstrução Ureteral/urina , Doença Aguda , Animais , Biomarcadores/urina , Doença Crônica , Citocinas/metabolismo , Hidronefrose/etiologia , Hidronefrose/metabolismo , Interferon gama/urina , Interleucina-1beta/urina , Interleucina-2/urina , Interleucina-6/urina , Masculino , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/urina , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo
10.
J Biol Chem ; 283(23): 15694-700, 2008 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-18400758

RESUMO

We have previously reported the association of a mutation (c.292G > A/p.V98I) in the human HSPD1 gene that encodes the mitochondrial Hsp60 chaperonin with a dominantly inherited form of hereditary spastic paraplegia. Here, we show that the purified Hsp60-(p.V98I) chaperonin displays decreased ATPase activity and exhibits a strongly reduced capacity to promote folding of denatured malate dehydrogenase in vitro. To test its in vivo functions, we engineered a bacterial model system that lacks the endogenous chaperonin genes and harbors two plasmids carrying differentially inducible operons with human Hsp10 and wild-type Hsp60 or Hsp10 and Hsp60-(p.V98I), respectively. Ten hours after shutdown of the wild-type chaperonin operon and induction of the Hsp60-(p.V98I)/Hsp10 mutant operon, bacterial cell growth was strongly inhibited. No globally increased protein aggregation was observed, and microarray analyses showed that a number of genes involved in metabolic pathways, some of which are essential for robust aerobic growth, were strongly up-regulated in Hsp60-(p.V98I)-expressing bacteria, suggesting that the growth arrest was caused by defective folding of some essential proteins. Co-expression of Hsp60-(p.V98I) and wild-type Hsp60 exerted a dominant negative effect only when the chaperonin genes were expressed at relatively low levels. Based on our in vivo and in vitro data, we propose that the major effect of heterozygosity for the Hsp60-(p.V98I) mutation is a moderately decreased activity of chaperonin complexes composed of mixed wild-type and Hsp60-(p.V98I) mutant subunits.


Assuntos
Adenosina Trifosfatases/metabolismo , Substituição de Aminoácidos , Chaperoninas/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Paraplegia Espástica Hereditária/metabolismo , Adenosina Trifosfatases/genética , Chaperonina 10/genética , Chaperonina 10/metabolismo , Chaperonina 60 , Chaperoninas/genética , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Heterozigoto , Humanos , Malato Desidrogenase/genética , Malato Desidrogenase/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Mitocondriais , Modelos Biológicos , Óperon/genética , Dobramento de Proteína , Paraplegia Espástica Hereditária/genética
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