HOMERO PINTO VALLADA FILHO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Psiquiatria, Faculdade de Medicina - Docente
LIM/23 - Laboratório de Psicopatologia e Terapêutica Psiquiátrica, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/23 - Laboratório de Psicopatologia e Terapêutica Psiquiátrica, Hospital das Clínicas, Faculdade de Medicina - Líder
6 resultados
Resultados de Busca
Agora exibindo 1 - 6 de 6
conferenceObject GAD1 POLYMORPHISMS ARE ASSOCIATED WITH GLUTAMATERGIC ACTIVITY IN THE ANTERIOR CINGULATE IN BIPOLAR I DISORDER(2017) SOEIRO-DE-SOUZA, Marcio; MACHADO-VIEIRA, Rodrigo; MORENO, Ricardo; CHILE, Thais; GOUVEIA, Gisele; PASTORELLO, Bruno; LEITE, Claudia; HENNING, Anke; OTADUY, Maria Concepcion; VALLADA, Homero- Genome-wide association study of obsessive-compulsive disorder(2013) STEWART, S. E.; YU, D.; SCHARF, J. M.; NEALE, B. M.; FAGERNESS, J. A.; MATHEWS, C. A.; ARNOLD, P. D.; EVANS, P. D.; GAMAZON, E. R.; OSIECKI, L.; MCGRATH, L.; HADDAD, S.; CRANE, J.; HEZEL, D.; ILLMAN, C.; MAYERFELD, C.; KONKASHBAEV, A.; LIU, C.; PLUZHNIKOV, A.; TIKHOMIROV, A.; EDLUND, C. K.; RAUCH, S. L.; MOESSNER, R.; FALKAI, P.; MAIER, W.; RUHRMANN, S.; GRABE, H-J; LENNERTZ, L.; WAGNER, M.; BELLODI, L.; CAVALLINI, M. C.; RICHTER, M. A.; COOK JR., E. H.; KENNEDY, J. L.; ROSENBERG, D.; STEIN, D. J.; HEMMINGS, S. M. J.; LOCHNER, C.; AZZAM, A.; CHAVIRA, D. A.; FOURNIER, E.; GARRIDO, H.; SHEPPARD, B.; UMANA, P.; MURPHY, D. L.; WENDLAND, J. R.; VEENSTRA-VANDERWEELE, J.; DENYS, D.; BLOM, R.; DEFORCE, D.; NIEUWERBURGH, F. Van; WESTENBERG, H. G. M.; WALITZA, S.; EGBERTS, K.; RENNER, T.; MIGUEL, E. C.; CAPPI, C.; HOUNIE, A. G.; ROSARIO, M. Conceicao do; SAMPAIO, A. S.; VALLADA, H.; NICOLINI, H.; LANZAGORTA, N.; CAMARENA, B.; DELORME, R.; LEBOYER, M.; PATO, C. N.; PATO, M. T.; VOYIAZIAKIS, E.; HEUTINK, P.; CATH, D. C.; POSTHUMA, D.; SMIT, J. H.; SAMUELS, J.; BIENVENU, O. J.; CULLEN, B.; FYER, A. J.; GRADOS, M. A.; GREENBERG, B. D.; MCCRACKEN, J. T.; RIDDLE, M. A.; WANG, Y.; CORIC, V.; LECKMAN, J. F.; BLOCH, M.; PITTENGER, C.; EAPEN, V.; BLACK, D. W.; OPHOFF, R. A.; STRENGMAN, E.; CUSI, D.; TURIEL, M.; FRAU, F.; MACCIARDI, F.; GIBBS, J. R.; COOKSON, M. R.; SINGLETON, A.; HARDY, J.; CRENSHAW, A. T.; PARKIN, M. A.; MIREL, D. B.; CONTI, D. V.; PURCELL, S.; NESTADT, G.; HANNA, G. L.; JENIKE, M. A.; KNOWLES, J. A.; COX, N.; PAULS, D. L.Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469 410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P = 2.49 x 10(-6) and P = 3.44 x 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value = 3.84 x 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 x 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P < 0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P = 0.001) was observed within the top-ranked SNPs (P < 0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
- ACC Glu/GABA ratio is decreased in euthymic bipolar disorder I patients: possible in vivo neurometabolite explanation for mood stabilization(2021) SCOTTI-MUZZI, Estevao; CHILE, Thais; MORENO, Ricardo; PASTORELLO, Bruno Fraccini; LEITE, Claudia da Costa; HENNING, Anke; OTADUY, Maria Concepcion Garcia; VALLADA, Homero; SOEIRO-DE-SOUZA, Marcio GerhardtBipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (H-1-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T H-1-MRS in the dACC (2 x 2 x 4.5 cm(3)) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood states. ClincalTrials.gov registration: NCT01237158.
- alpha CaMKII controls the establishment of cocaine's reinforcing effects in mice and humans(2014) EASTON, A. C.; LOURDUSAMY, A.; HAVRANEK, M.; MIZUNO, K.; SOLATI, J.; GOLUB, Y.; CLARKE, T-K; VALLADA, H.; LARANJEIRA, R.; DESRIVIERES, S.; MOLL, G. H.; MOESSNER, R.; KORNHUBER, J.; SCHUMANN, G.; GIESE, K. P.; FERNANDES, C.; QUEDNOW, B. B.; MUELLER, C. P.Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca2+/calmodulin-dependent protein kinase-II (alpha CaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. The autophosphorylation of aCaMKII was shown to accelerate learning. Thus, we investigated the role of aCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that alpha CaMKII autophosphorylation-deficient alpha CaMKIIT286A mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg(-1), intraperitoneal). In vivo microdialysis revealed that alpha CaMKIIT286A mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg(-1), intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in alpha CaMKIIT286A mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n = 688) and Switzerland (n = 141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that alpha CaMKII controls the speed for the establishment of cocaine's reinforcing effects.
- Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture(2013) DAVIS, Lea K.; YU, Dongmei; KEENAN, Clare L.; GAMAZON, Eric R.; KONKASHBAEV, Anuar I.; DERKS, Eske M.; NEALE, Benjamin M.; YANG, Jian; LEE, S. Hong; EVANS, Patrick; BARR, Cathy L.; BELLODI, Laura; BENARROCH, Fortu; BERRIO, Gabriel Bedoya; BIENVENU, Oscar J.; BLOCH, Michael H.; BLOM, Rianne M.; BRUUN, Ruth D.; BUDMAN, Cathy L.; CAMARENA, Beatriz; CAMPBELL, Desmond; CAPPI, Carolina; SILGADO, Julio C. Cardona; CATH, Danielle C.; CAVALLINI, Maria C.; CHAVIRA, Denise A.; CHOUINARD, Sylvain; CONTI, David V.; COOK, Edwin H.; CORIC, Vladimir; CULLEN, Bernadette A.; DEFORCE, Dieter; DELORME, Richard; DION, Yves; EDLUND, Christopher K.; EGBERTS, Karin; FALKAI, Peter; FERNANDEZ, Thomas V.; GALLAGHER, Patience J.; GARRIDO, Helena; GELLER, Daniel; GIRARD, Simon L.; GRABE, Hans J.; GRADOS, Marco A.; GREENBERG, Benjamin D.; GROSS-TSUR, Varda; HADDAD, Stephen; HEIMAN, Gary A.; HEMMINGS, Sian M. J.; HOUNIE, Ana G.; ILLMANN, Cornelia; JANKOVIC, Joseph; JENIKE, Michael A.; KENNEDY, James L.; KING, Robert A.; KREMEYER, Barbara; KURLAN, Roger; LANZAGORTA, Nuria; LEBOYER, Marion; LECKMAN, James F.; LENNERTZ, Leonhard; LIU, Chunyu; LOCHNER, Christine; LOWE, Thomas L.; MACCIARDI, Fabio; MCCRACKEN, James T.; MCGRATH, Lauren M.; RESTREPO, Sandra C. Mesa; MOESSNER, Rainald; MORGAN, Jubel; MULLER, Heike; MURPHY, Dennis L.; NAARDEN, Allan L.; OCHOA, William Cornejo; OPHOFF, Roel A.; OSIECKI, Lisa; PAKSTIS, Andrew J.; PATO, Michele T.; PATO, Carlos N.; PIACENTINI, John; PITTENGER, Christopher; POLLAK, Yehuda; RAUCH, Scott L.; RENNER, Tobias J.; REUS, Victor I.; RICHTER, Margaret A.; RIDDLE, Mark A.; ROBERTSON, Mary M.; ROMERO, Roxana; ROSARIO, Maria C.; ROSENBERG, David; ROULEAU, Guy A.; RUHRMANN, Stephan; RUIZ-LINARES, Andres; SAMPAIO, Aline S.; SAMUELS, Jack; SANDOR, Paul; SHEPPARD, Brooke; SINGER, Harvey S.; SMIT, Jan H.; STEIN, Dan J.; STRENGMAN, E.; TISCHFIELD, Jay A.; DUARTE, Ana V. Valencia; VALLADA, Homero; NIEUWERBURGH, Filip Van; VEENSTRA-VANDERWEELE, Jeremy; WALITZA, Susanne; WANG, Ying; WENDLAND, Jens R.; WESTENBERG, Herman G. M.; SHUGART, Yin Yao; MIGUEL, Euripedes C.; MCMAHON, William; WAGNER, Michael; NICOLINI, Humberto; POSTHUMA, Danielle; HANNA, Gregory L.; HEUTINK, Peter; DENYS, Damiaan; ARNOLD, Paul D.; OOSTRA, Ben A.; NESTADT, Gerald; FREIMER, Nelson B.; PAULS, David L.; WRAY, Naomi R.; STEWART, S. Evelyn; MATHEWS, Carol A.; KNOWLES, James A.; COX, Nancy J.; SCHARF, Jeremiah M.The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
- Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study(2014) MCGRATH, Lauren M.; YU, Dongmei; MARSHALL, Christian; DAVIS, Lea K.; THIRUVAHINDRAPURAM, Bhooma; LI, Bingbin; CAPPI, Carolina; GERBER, Gloria; WOLF, Aaron; SCHROEDER, Frederick A.; OSIECKI, Lisa; O'DUSHLAINE, Colm; KIRBY, Andrew; ILLMANN, Cornelia; HADDAD, Stephen; GALLAGHER, Patience; FAGERNESS, Jesen A.; BARR, Cathy L.; BELLODI, Laura; BENARROCH, Fortu; BIENVENU, O. Joseph; BLACK, Donald W.; BLOCH, Michael H.; BRUUN, Ruth D.; BUDMAN, Cathy L.; CAMARENA, Beatriz; CATH, Danielle C.; CAVALLINI, Maria C.; CHOUINARD, Sylvain; CORIC, Vladimir; CULLEN, Bernadette; DELORME, Richard; DENYS, Damiaan; DERKS, Eske M.; DION, Yves; ROSARIO, Maria C.; EAPEN, Valsama; EVANS, Patrick; FALKAI, Peter; FERNANDEZ, Thomas V.; GARRIDO, Helena; GELLER, Daniel; GRABE, Hans J.; GRADOS, Marco A.; GREENBERG, Benjamin D.; GROSS-TSUR, Varda; GRUENBLATT, Edna; HEIMAN, Gary A.; HEMMINGS, Sian M. J.; HERRERA, Luis D.; HOUNIE, Ana G.; JANKOVIC, Joseph; KENNEDY, James L.; KING, Robert A.; KURLAN, Roger; LANZAGORTA, Nuria; LEBOYER, Marion; LECKMAN, James F.; LENNERTZ, Leonhard; LOCHNER, Christine; LOWE, Thomas L.; LYON, Gholson J.; MACCIARDI, Fabio; MAIER, Wolfgang; MCCRACKEN, James T.; MCMAHON, William; MURPHY, Dennis L.; NAARDEN, Allan L.; NEALE, Benjamin M.; NURMI, Erika; PAKSTIS, Andrew J.; PATO, Michele T.; PATO, Carlos N.; PIACENTINI, John; PITTENGER, Christopher; POLLAK, Yehuda; REUS, Victor I.; RICHTER, Margaret A.; RIDDLE, Mark; ROBERTSON, Mary M.; ROSENBERG, David; ROULEAU, Guy A.; RUHRMANN, Stephan; SAMPAIO, Aline S.; SAMUELS, Jack; SANDOR, Paul; SHEPPARD, Brooke; SINGER, Harvey S.; SMIT, Jan H.; STEIN, Dan J.; TISCHRIELD, Jay A.; VALLADA, Homero; VEENSTRA-VANDERWEELE, Jeremy; WALITZA, Susanne; WANG, Ying; WENDFAND, Jens R.; SHUGART, Yin Yao; MIGUEL, Euripedes C.; NICOLINI, Humberto; OOSTRA, Ben A.; MOESSNER, Rainald; WAGNER, Michael; RUIZ-LINARES, Andres; HEUTINK, Peter; NESTADT, Gerald; FREIMER, Nelson; PETRYSHEN, Tracey; POSTHUMA, Danielle; JENIKE, Michael A.; COX, Nancy J.; HANNA, Gregory L.; BRENTANI, Helena; SCHERER, Stephen W.; ARNOLD, Paul D.; STEWART, S. Evelyn; MATHEWS, Carol A.; KNOWLES, James A.; COOK, Edwin H.; PAULS, David L.; WANG, Kai; SCHARF, Jeremiah M.Objective: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. Method: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Results: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). Conclusion: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.