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1.
BMC Infect Dis ; 24(1): 557, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834971

RESUMO

BACKGROUND: Evidence continues to accumulate regarding the potential long-term health consequences of COVID-19 in the population. To distinguish between COVID-19-related symptoms and health limitations from those caused by other conditions, it is essential to compare cases with community controls using prospective data ensuring case-control status. The RESPIRA study addresses this need by investigating the lasting impact of COVID-19 on Health-related Quality of Life (HRQoL) and symptomatology in a population-based cohort in Costa Rica, thereby providing a robust framework for controlling HRQoL and symptoms. METHODS: The study comprised 641 PCR-confirmed, unvaccinated cases of COVID-19 and 947 matched population-based controls. Infection was confirmed using antibody tests on enrollment serum samples and symptoms were monitored monthly for 6 months post-enrolment. Administered at the 6-month visit (occurring between 6- and 2-months post-diagnosis for cases and 6 months after enrollment for controls), HRQoL and Self-Perceived Health Change were assessed using the SF-36, while brain fog, using three items from the Mental Health Inventory (MHI). Regression models were utilized to analyze SF-36, MHI scores, and Self-Perceived Health Change, adjusted for case/control status, severity (mild case, moderate case, hospitalized) and additional independent variables. Sensitivity analyses confirmed the robustness of the findings. RESULTS: Cases showed significantly higher prevalences of joint pain, chest tightness, and skin manifestations, that stabilized at higher frequencies from the fourth month post-diagnosis onwards (2.0%, 1.2%, and 0.8% respectively) compared to controls (0.9%, 0.4%, 0.2% respectively). Cases also exhibited significantly lower HRQoL than controls across all dimensions in the fully adjusted model, with a 12.4 percentage-point difference [95%CI: 9.4-14.6], in self-reported health compared to one year prior. Cases reported 8.0% [95%CI: 4.2, 11.5] more physical limitations, 7.3% [95%CI: 3.5, 10.5] increased lack of vitality, and 6.0% [95%CI: 2.4, 9.0] more brain fog compared to controls with similar characteristics. Undiagnosed cases detected with antibody tests among controls had HRQoL comparable to antibody negative controls. Differences were more pronounced in individuals with moderate or severe disease and among women. CONCLUSIONS: PCR-confirmed unvaccinated cases experienced prolonged HRQoL reductions 6 months to 2 years after diagnosis, this was particularly the case in severe cases and among women. Mildly symptomatic cases showed no significant long-term sequelae.


Assuntos
COVID-19 , Qualidade de Vida , Humanos , Costa Rica/epidemiologia , COVID-19/epidemiologia , COVID-19/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos de Casos e Controles , SARS-CoV-2 , Estudos de Coortes , Idoso , Estudos Prospectivos , Adulto Jovem
2.
Am J Med Genet B Neuropsychiatr Genet ; 195(3): e32960, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37860990

RESUMO

Psychiatric disorders have a great impact in terms of mortality, morbidity, and disability across the lifespan. Considerable effort has been devoted to understanding their complex and heterogeneous genetic architecture, including diverse ancestry populations. Our aim was to review the psychiatric genetics research published with Latin American populations from 2010 to 2019, and classify it according to country of origin, type of analysis, source of funding, and other variables. We found that most publications came from Brazil, Mexico, and Colombia. Also, local funds are generally not large enough for genome-wide studies in Latin America, with the exception of Brazil and Mexico; larger studies are often done in collaboration with international partners, mostly funded by US agencies. In most of the larger studies, the participants are individuals of Latin American ancestry living in the United States, which limits the potential for exploring the complex gene-environment interaction. Family studies, traditionally strong in Latin America, represent about 30% of the total research publications. Scarce local resources for research in Latin America have probably been an important limitation for conducting bigger and more complex studies, contributing to the reduced representation of these populations in global psychiatric genetics studies. Increasing diversity must be a goal to improve generalizability and applicability in clinical settings.


Assuntos
Hispânico ou Latino , Transtornos Mentais , Humanos , América Latina , Transtornos Mentais/genética , México , Projetos de Pesquisa
3.
Mol Psychiatry ; 27(12): 5020-5027, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224258

RESUMO

Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data.


Assuntos
Neurogênese , Síndrome de Tourette , Pré-Escolar , Humanos , Costa Rica , Haplótipos , Linhagem , Transdução de Sinais , Síndrome de Tourette/genética , Neurogênese/genética , Polimorfismo Genético , Sequenciamento Completo do Genoma , Fator 2 de Liberação do Nucleotídeo Guanina/genética
4.
Mol Psychiatry ; 24(4): 523-535, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29955165

RESUMO

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.


Assuntos
Família/psicologia , Transtornos Mentais/genética , Alelos , Frequência do Gene/genética , Variação Genética/genética , Genótipo , Humanos , Saúde Mental , Linhagem , Fenótipo , Projetos de Pesquisa , Tamanho da Amostra , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos
5.
Neurol Psychiatry Brain Res ; 35: 38-41, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32863597

RESUMO

BACKGROUND: Imprecision of the psychiatric phenotype might partially explain the failure of genetic research to identify genes that contribute to susceptibility of anxiety disorders. Previous research concluded two underlying constructs, worry and rumination, might explain anxiety sub-syndromic symptoms in Costa Rican patients with history of mania. The goal of the current study is to explore the presence of latent constructs for quantitative anxiety in a group of subjects with a wide diagnostic phenotype and non-affected individuals. METHODS: We conducted an exploratory factor analysis of anxiety trait in 709 subjects. Our sample was comprised by 419 subjects with psychiatric disorders and 290 non-affected individuals. We used principal factors extraction method with squared multiple correlations of the STAI (trait subscale). RESULTS: We found the following preliminary results: a three-factor solution with a good simple structure and statistical adequacy was obtained with a KMO of 0.92 (>0.6) and Bartlett's Test of Sphericity of 5644,44 (p<0.05). The STAI items were grouped into three factors: anxiety-absent, worry and rumination based on the characteristics of the symptoms. CONCLUSION: Two underlying constructs, worry and rumination may explain anxiety sub-syndromic symptoms in Costa Rican subjects. Our proposed underlying structure of subsyndromal anxiety in individuals should be considered as an important factor in defining better phenotypic characterizations on a broader diagnostic concept. Worry and rumination as a phenotypic characterization may assist in genotyping; however, its predictive value on actual illness outcome still requires more research. The Genome-Wide QTL analysis for anxiety trait in the same sample is ongoing.

6.
Am J Med Genet B Neuropsychiatr Genet ; 180(3): 213-222, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30779416

RESUMO

We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E - 5) and associated single marker (rs2280915, p = 2.70E - 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E - 5) and associated single marker (rs11887088, p = 2.90E - 6) were located in intragenic regions near ACTR3 and DPP10. None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 2/genética , Transtornos Psicóticos/genética , Proteína 3 Relacionada a Actina/genética , Proteína 3 Relacionada a Actina/metabolismo , Adulto , Transtorno Bipolar/psicologia , Mapeamento Cromossômico/métodos , Costa Rica , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Feminino , Ligação Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Guatemala , Hispânico ou Latino/genética , Humanos , Escore Lod , Masculino , México , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/psicologia , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Estados Unidos
7.
Am J Med Genet B Neuropsychiatr Genet ; 174(7): 683-690, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28556497

RESUMO

Personality traits have been suggested as potential endophenotypes for Bipolar Disorder (BP), as they can be quantitatively measured and show correlations with BP. The present study utilized data from 2,745 individuals from 686 extended pedigrees originally ascertained for having multiplex cases of BP (963 cases of BPI or schizoaffective BP). Subjects were assessed with the NEO Personality Inventory, Revised (NEO PI-R) and genotyped using the Illumina HumanLinkage-24 Bead Chip, with an average genetic coverage of 0.67 cM. Two point linkage scores were calculated for each trait as a quantitative variable using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Suggestive evidence for linkage was found for neuroticism at 1q32.1 (LOD = 2.52), 6q23.3 (2.32), 16p12 (2.79), extraversion at 4p15.3 (2.33), agreeableness at 4q31.1 (2.37), 5q34 (2.80), 7q31.1 (2.56), 16q22 (2.52), and conscientiousness at 4q31.1 (2.50). Each of the above traits have been shown to be correlated with the broad BP phenotype in this same sample. In addition, for the trait of openness, we found significant evidence of linkage to chromosome 3p24.3 (rs336610, LOD = 4.75) and suggestive evidence at 1q43 (2.74), 5q35.1 (3.03), 11q14.3 (2.61), 11q21 (2.30), and 19q13.1 (2.52). These findings support previous linkage findings of the openness trait to chromosome 19q13 and the agreeableness trait to 4q31 and identify a number of new loci for personality endophenotypes related to bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos/genética , Ligação Genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Inventário de Personalidade , Locos de Características Quantitativas , Genótipo , Humanos , Fenótipo
8.
J Cross Cult Gerontol ; 31(2): 129-41, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26883764

RESUMO

To find associations of age, sex, and education with neuropsychological test performance in cognitively normal Spanish-speaking Costa Rican nonagenarians with little education; to provide norms; and to compare their performance with similar Puerto Ricans. For 95 Costa Ricans (90-102 years old, 0-6 years of education), multiple regression assessed associations with demographics of performance on six neuropsychological tests. Analyses of covariance compared them with 23 Puerto Ricans (90-99 years old). Younger age and being female-but not education-were associated with better performance on some neuropsychological tests, in particular episodic memory. The Puerto Ricans performed better on learning and memory tasks. In cognitively intact Spanish-speaking nonagenarians with little or no education, education did not affect test performance. Additional studies of the effect of education on cognitive performance are warranted in other samples with extremely low education or old age. National differences in performance highlight the importance of group-specific norms.


Assuntos
Envelhecimento/psicologia , Cognição/fisiologia , Comparação Transcultural , Escolaridade , Hispânico ou Latino/psicologia , Hispânico ou Latino/estatística & dados numéricos , Testes Neuropsicológicos/estatística & dados numéricos , Fatores Etários , Idoso de 80 Anos ou mais , Costa Rica , Educação , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Porto Rico , Fatores Sexuais
9.
J Neural Transm (Vienna) ; 121(5): 479-90, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24380930

RESUMO

Aberrant neuregulin 1-ErbB4 signaling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation, we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non-carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N = 6, Val/Leu N = 5, T test, FDR (1 %), α = 0.05, -log10 p value >1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signaling as the top pathways altered. Within NRG1 signaling, protein kinase C (PKC)-eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (serine/threonine) was performed after stimulating cells (V/V N = 6, V/L N = 6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (six peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signaling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology.


Assuntos
Mutação de Sentido Incorreto , Neuregulina-1/genética , Proteínas Quinases/metabolismo , Esquizofrenia/genética , Linhagem Celular , Feminino , Expressão Gênica , Genoma Humano , Genômica/métodos , Humanos , Leucócitos/fisiologia , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Neuregulina-1/química , Neuregulina-1/metabolismo , Neuritos/fisiologia , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-4/metabolismo , Esquizofrenia/metabolismo , Transdução de Sinais , Transcriptoma
10.
Am J Geriatr Psychiatry ; 22(10): 957-60, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24731780

RESUMO

OBJECTIVE: To study the association of dementia with apolipoprotein E-e4 (APOE-e4) and its interaction with age in a nonagenarian Costa Rican group (N-sample) and a general elderly contrast group (GE-sample). METHODS: In both case-control studies, participants were cognitively intact or diagnosed with dementia. The N-sample (N = 112) was at least age 90 years; the GE-sample (N = 98) was at least age 65 years. RESULTS: Dementia and APOE-e4 were not significantly associated in the N-sample, but were in the GE-sample. There was a significant interaction of age with APOE-e4 in the N-sample, but not in the GE-sample. Descriptively dividing the N-sample at the median (age 93 years) showed a group interaction: APOE-e4 was more associated with dementia in the younger N-sample than in the older N-sample, where six of seven APOE-e4 carriers were cognitively intact. CONCLUSIONS: The results support the reduction in association of APOE-e4 with dementia in extreme old age, consistent with a survivor effect model for successful cognitive aging.


Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Apolipoproteína E4/genética , Demência/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Costa Rica , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino
11.
Rev Panam Salud Publica ; 36(4): 266-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25563152

RESUMO

The World Health Organization (WHO) Mental Health Action Plan 2013-2020 urges its Member States to strengthen leadership in mental health, ensure mental and social health interventions in community-based settings, promote mental health and strengthen information systems, and increase evidence and research for mental health. Although Costa Rica has strongly invested in public health and successfully reduced the burden of nutritional and infectious diseases, its transitional epidemiological pattern, population growth, and immigration from unstable neighboring countries has shifted the burden to chronic disorders. Although policies for chronic disorders have been in place for several decades, mental disorders have not been included. Recently, as the Ministry of Health of Costa Rica developed a Mental Health Policy for 2013-2020, it became evident that the country needs epidemiological data to prioritize evidence-based intervention areas. This article stresses the importance of conducting local epidemiological studies on mental health, and calls for changes in research funding priorities by public and private national and international funding agencies in order to follow the WHO Mental Health Action Plan.


Assuntos
Saúde Mental , Apoio à Pesquisa como Assunto , Pesquisa/economia , Costa Rica , Países em Desenvolvimento , Financiamento Governamental , Organização do Financiamento , Promoção da Saúde , Necessidades e Demandas de Serviços de Saúde , Financiamento da Assistência à Saúde , Humanos , Transtornos Mentais/epidemiologia , Transtornos Mentais/prevenção & controle , Transtornos Mentais/reabilitação , Transtornos Mentais/terapia , Serviços de Saúde Mental/provisão & distribuição , Formulação de Políticas , Psiquiatria , Pesquisa/tendências , Apoio à Pesquisa como Assunto/tendências , Previdência Social/economia , Recursos Humanos , Organização Mundial da Saúde
12.
Am J Med Genet B Neuropsychiatr Genet ; 165B(2): 122-30, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24464604

RESUMO

Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high-throughput ways of assessing, and ranking potential endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of endophenotypes in the psychiatric genetics community.


Assuntos
Encéfalo/metabolismo , Endofenótipos , Proteômica , Psiquiatria , Animais , Biomarcadores , Encéfalo/anatomia & histologia , Endofenótipos/metabolismo , Predisposição Genética para Doença , Humanos , Proteômica/métodos
13.
Am J Med Genet B Neuropsychiatr Genet ; 165B(6): 479-91, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25044503

RESUMO

A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 8/genética , Ligação Genética , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Família , Humanos , Modelos Genéticos , Fenótipo , Análise de Sequência de DNA , Estatísticas não Paramétricas
14.
Bipolar Disord ; 15(2): 206-14, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23437964

RESUMO

OBJECTIVES: Through recent genome-wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage-dependent, L-type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European-American cohorts. We performed a family-based association study to determine whether CACNA1C is associated with BP in the Latino population. METHODS: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single-nucleotide polymorphisms (SNPs) that spanned a 602.9-kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family-Based Association Test (version 2.0.3) and Haploview (version 4.2) software. RESULTS: An eight-locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). CONCLUSIONS: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.


Assuntos
Transtorno Bipolar/genética , Canais de Cálcio/genética , Saúde da Família , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Costa Rica , Feminino , Frequência do Gene , Estudos de Associação Genética , Guatemala , Haplótipos , Hispânico ou Latino/genética , Humanos , Masculino , México , Estados Unidos
15.
Hum Biol ; 85(5): 721-40, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25078957

RESUMO

The genetic structure of Costa Rica's population is complex, both by region and by individual, due to the admixture process that started during the 15th century and historical events thereafter. Previous studies have been done mostly on Amerindian populations and the Central Valley inhabitants using various microsatellites and mitochondrial DNA markers. Here, we study for the first time a random sample from all regions of the country with ancestry informative markers (AIMs) to address the individual and regional admixture proportions. A sample of 160 male individuals was screened for 78 AIMs customized in a GoldenGate platform from Illumina. We observed that this small set of AIMs has the same power of hundreds of microsatellites and thousands of single-nucleotide polymorphisms to evaluate admixture, with the benefit of reducing genotyping costs. This type of investigation is necessary to explore new genetic markers useful for forensic and genetic investigation. Our data showed a mean admixture proportion of 49.2% European (EUR), 37.8% Native American (NAM), and 12.9% African (AFR), with a disproportionate admixture composition by region. In addition, when Chinese (CHB) was included as a fourth component, the proportions changed to 45.6% EUR, 33.5% NAM, 11.7% AFR, and 9.2% CHB. The admixture trend is consistent among all regions (EUR > NAM > AFR), and individual admixture estimates vary broadly in each region. Though we did not find stratification in Costa Rica's population, gene admixture should be evaluated in future genetic studies of Costa Rica, especially for the Caribbean region, as it contains the largest proportion of African ancestry (30.9%).


Assuntos
Variação Genética/genética , Linhagem , Povo Asiático/genética , População Negra/genética , Costa Rica/epidemiologia , DNA Mitocondrial/genética , Marcadores Genéticos/genética , Genótipo , Geografia , Humanos , Indígenas Centro-Americanos/genética , Masculino , Repetições de Microssatélites/genética , População Branca/genética
16.
Am J Hum Biol ; 23(2): 225-7, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21319252

RESUMO

OBJECTIVE: To determine if individuals who carry mitochondrial markers which have been previously shown to affect longevity also have differential lifetime reproductive success (LRS). METHODS: We extracted the mtDNA from living subjects residing in Atenas, Costa Rica. Since mtDNA does not recombine, and its probability of mutation is low, we assume that all maternal ancestors of the living subjects have the same mtDNA. We reconstructed the maternal genealogy of the living subjects, so that we have information on the LRS and longevity of the maternal ancestors of the living subjects. We compared the LRS of women who carried the 5178A marker in haplogroup D (associated with decreased longevity) and who carried the 150T polymorphism (associated with increased longevity) with the LRS of controls born in the same half century time period from 1750 to 1939. RESULTS: We found that the LRS of neither group of women with a longevity-associated polymorphism (LAP) differed from the LRS of controls, even if these women differed significantly from the controls in their longevity. CONCLUSIONS: Although LAPS significantly affect longevity, such differential longevity does not result in differential lifetime reproductive success. From an evolutionary perspective, these longevity-associated polymorphisms do not affect the carriers' Darwinian fitness.


Assuntos
DNA Mitocondrial/genética , Aptidão Genética , Longevidade/genética , Linhagem , Polimorfismo Genético , Costa Rica , Feminino , Haplótipos , História do Século XVIII , História do Século XIX , História do Século XX , Humanos
17.
Per Med ; 18(2): 141-152, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33576268

RESUMO

Aim: We explore attitudes from the public in Costa Rica regarding willingness to donate DNA data for research. Materials & methods: A total of 224 Costa Rican individuals answered the anonymous online survey 'Your DNA, Your Say'. It covers attitudes toward DNA and medical data donation, trust in research professionals and concerns about consequences of reidentification. Results & conclusion: Most individuals (89%) are willing to donate their information for research purposes. When confronted with different potential uses of their data, participants are significantly less likely to donate data to for-profit researchers (34% willingness to donate). The most frequently cited concerns regarding donation of genetic data relate to possible discrimination by health/life insurance companies and employers. For the participants in the survey, the most trusted professionals are their own medical doctor and nonprofit researchers from their country. This is the first study regarding attitudes toward genetic data donation in Costa Rica.


Assuntos
Atitude/etnologia , Bancos de Espécimes Biológicos , DNA/análise , Adulto , Confidencialidade , Costa Rica , Feminino , Humanos , Disseminação de Informação , Masculino , Pessoa de Meia-Idade , Fatores Sociodemográficos
18.
Neuropsychopharmacology ; 46(3): 673-682, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33288841

RESUMO

Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient's genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate < 0.3), in patients compared to controls. We identified 454 differentially expressed genes in hiPSC-derived neurons, enriched in pathways including phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling, with serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3ß, as part of this pathway. We further found that pharmacological inhibition of downstream effectors of the PI3K/GSK3 pathway, SGK1 and GSK3, induced alterations in levels of neurite markers ßIII tubulin and fibroblast growth factor 12, with differential effects in patients compared to controls. While demonstrating the utility of hiPSCs derived from multiplex families to identify significant cell-specific gene network alterations in SCZ, these studies support a role for disruption of PI3K/GSK3 signaling as a risk factor for SCZ.


Assuntos
Células-Tronco Neurais , Esquizofrenia , Genômica , Quinase 3 da Glicogênio Sintase/genética , Humanos , Neurônios , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Esquizofrenia/genética
19.
Biol Psychiatry ; 90(6): 373-384, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-33975707

RESUMO

BACKGROUND: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. METHODS: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. RESULTS: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. CONCLUSIONS: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery.


Assuntos
Transtorno Depressivo Maior , Transtornos Mentais , Transtornos Psicóticos , Cognição , Humanos , Memória de Curto Prazo , Testes Neuropsicológicos , Linhagem , Transtornos Psicóticos/genética
20.
Ann Hum Genet ; 74(6): 516-24, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20946256

RESUMO

The population of Costa Rica has been considered valuable for locating susceptibility genes of complex disorders because of historical events and a gradual admixture process. We present an assessment of 426 unrelated individuals with a familial history of mental disorder and with ancestors born in the Central Valley, genotyped at 730 microsatellites to evaluate genetic diversity, ancestry, and substructure at the general and regional population levels using quantitative methods. Low population substructure was found. Estimated mean ancestry proportions were 54%, 32%, and 13% for European, Amerindian, and African components, respectively, with some regional variation. The F(ST) values obtained confirm the largest genetic similarity to Europeans. Subdivision of the Amerindians into individual populations revealed strong similarity to Chibchan groups. Analysis of the African ancestry showed high similarity to West and Central African populations. Gene ancestries from other African areas were also detected, probably resulting from ancestral admixture within Africa prior to colonial times. Our analyses show, in an ethnohistorical-genetic context, that gene flow and admixture are important components of Costa Rican population history. The results confirm the need to consider the particular regional genetic structure, the effects of genetic drift and the ancestry when designing and interpreting investigations of genetic traits in this population.


Assuntos
Indígena Americano ou Nativo do Alasca/genética , População Negra/genética , Genética Populacional , Transtornos Mentais/genética , População Branca/genética , África , Costa Rica , Etnicidade/genética , Feminino , Fluxo Gênico , Frequência do Gene , Variação Genética , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Análise de Componente Principal , Reprodução
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