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Ítem Are coastal upwellings affecting the spatial ecology of juvenile hawksbill sea turtles? Insights from a small bay in the eastern tropical pacific(2024-12-03) Valverde Cantillo, Verónica; Espinoza Mendiola, MarioComprender cómo se mueven los animales dentro y entre distintos hábitats y los factores que afectan estos movimientos es crucial para la gestión espacial de las especies en peligro de extinción. Este estudio analizó la abundancia y ecología espacial de las tortugas carey (Eretmochelys imbricata) en el Área Marina de Manejo Bahía Santa Elena (AMMBSE), en el Pacífico norte de Costa Rica. El AMMBSE está compuesta por las bahías Matapalito y Santa Elena, en las cuales existe una gran diversidad de hábitats que han sido identificados como importantes para la alimentación de varias especies de tortugas marinas. Además, el AMMBSE es influenciada por un afloramiento costero estacional, con condiciones ambientales marcadas entre las temporadas de afloramiento (diciembre a mayo) y no afloramiento (junio a noviembre). Este estudio investigó cambios estacionales en la abundancia de tortugas carey en la bahía Matapalito, y además determinó la residencia y conectividad espacial dentro del AMMBSE. Para esto, se realizaron censos de tortugas marinas en la Bahía Matapalito entre el 2012 y el 2023. Además, se monitoreo el movimiento y la residencia de tortugas carey en el AMMBSE utilizando telemetría acústica pasiva. Se calculó el índice de residencia en cada área de monitoreo (Bahía Matapalito, Bahía Santa Elena, y toda el AMMBSE) y se determinaron los movimientos entre los hábitats disponibles en Matapalito y las zonas internas y externas de bahía Santa Elena a partir de las detecciones diarias. Se capturaron en promedio 11.2 ± 11.6 tortugas carey por año, en su mayoría identificadas como juveniles. Hubo diferencias significativas en las capturas entre años, pero no se detectaron diferencias significativas en la abundancia de tortugas Carey entre estaciones (afloramiento y no afloramiento). La residencia fue variable entre individuos, pero similar entre las bahías de Matapalito y Santa Elena. En promedio, las tortugas fueron altamente residentes en el AMMBSE (IR promedio ± DS = 0.6 ± 0.3). La conectividad del hábitat mostró que 85% de los individuos se movieron entre diferentes hábitats. Estos hallazgos resaltan la importancia de esta región para las especies y señalan que la conectividad del hábitat es crucial para el correcto manejo espacial para la conservación de las tortugas marinasÍtem Linkage disequilibrium analyses in the Costa Rican population suggests discrete gene loci for schizophrenia at 8p23.1 and 8q13.3(2006-08) Walss Bass, Consuelo; Montero Vega, Ana Patricia; Armas, Regina; Dassori, Albana Maria; Contreras, Salvador A.; Liu, Wei; Medina, Rolando; Levinson, Douglas F.; Pereira Castro, Mariana; Atmetlla Salazar, Ivannia; NeSmith, Lisa; Leach, Robin Jean; Almasy, Laura; Raventós Vorst, Henriette; Escamilla, Michael A.Linkage studies using multiplex families have repeatedly implicated chromosome 8 as involved in schizophrenia etiology. The reported areas of linkage, however, span a wide chromosomal region. The present study used the founder population of the Central Valley of Costa Rica and phenotyping strategies alternative to DSM-IV classifications in attempts to further delimitate the areas on chromosome 8 that may harbor schizophrenia susceptibility genes. A linkage disequilibrium screen of chromosome 8 was performed using family trios of individuals with a history of psychosis. Four discrete regions showing evidence of association (nominal P values less than 0.05) to the phenotype of schizophrenia were identified: 8p23.1, 8p21.3, 8q13.3 and 8q24.3. The region of 8p23.1 precisely overlaps a region showing strong evidence of linkage disequilibrium for severe bipolar disorder in Costa Rica. The same chromosomal regions were identified when the broader phenotype definition of all individuals with functional psychosis was used for analyses. Stratification of the psychotic sample by history of mania suggests that the 8q13.3 locus may be preferentially associated with non-manic psychosis. These results may be helpful in targeting specific areas to be analyzed in association-based or linkage disequilibrium-based studies, for researchers who have found evidence of linkage to schizophrenia on chromosome 8 within their previous studies.Ítem 24RNA-SEQ analysis in hiPSC-derived neurons from patients with schizophrenia(2019-07-26) Stertz, Laura; Pei, Guangsheng; Jia, Peilin; Li, Shenglan; Raventós Vorst, Henriette; Liu, Ying; Zhao, Zhongming; Walss Bass, ConsueloBackground: Human induced pluripotent stem cells (hiPSC) have provided a new way of studying schizophrenia (SZ), by allowing the establishment of brain cellular models accounting for the patient genetic background. Here we conducted an exploratory RNA-sequencing profiling study of cell lines derived from hiPSCs generated from lymphoblastoid cell lines (LCL) of subjects from the population isolate of the Central Valley of Costa Rica (CVCR). Methods: Five cell lines (LCL, hiPSC, NPC, cortical neurons and astrocytes) derived from 6 healthy controls and 7 SZ patients from the CVCR were generated using standard methodology. RNA from these cells was sequenced using Illumina HiSeqTM2500. Normalization and differential expression (DE) analysis were performed using DESeq2 (|FC| > 1.5 e BH corrected p-value < 0.05). Functional enrichment analysis was performed using DAVID 6.8. Results: hiPSC-derived neurons were responsible for 94.4% of the variance seen on DE analyses. We found 454 genes differently expressed on neurons differentiated from SZ compared to HC. Noteworthy, one of these genes was ZNF804A (FDR = 0.032), a strong candidate gene for schizophrenia susceptibility, with solid evidence of association from GWAS. Discussion: ZNF804A is a zinc finger protein has been shown to regulate neurite outgrowth, dendritic spine maintenance and activity-dependent structural plasticity. It is expressed broadly throughout the brain, especially in the developing hippocampus and the cortex, as well as in the adult cerebellum. A great advantage of using iPS-derived cells is that the effect of outside environmental influences, such as use of medications, is removed and only the effects of genetic composition, which is unchanged by transformation, are left. The DE of ZNF804A only on hiPSC-neurons highlight the crucial role that this protein can have on SZ pathology during neuronal development. Functional studies will help us further characterize this mechanism.Ítem S80NRG1 isoform expression from human derived precursor neuronal cells, astrocytes and neurons from subjects with the NRG1 p.V266l genetic variant(2019-09-27) Ugalde Araya, Karen Daniela; Stertz, Laura; Walss Bass, Consuelo; Raventós Vorst, HenrietteBackground: Neuregulin 1 (NRG1) is an important risk gene in schizophrenia. A previous study found that the variant p.V266L (rs74942016, risk allele: T), in the transmembrane domain of NRG1, is associated with schizophrenia in the Costa Rican population. However, knowledge about the expression of NRG1 isoforms at a cellular level in human central nervous system is still limited. For this reason, we studied the expression of NRG1 isoforms in three human derived neural cell types, to evaluate the effect of the p.V266L variant on neuregulin expression. Methods: We used induced pluripotent stem cells (iPSCs) from lymphoblastoid cell lines (using Episomal-iPSC Reprogramming Kit) of subjects with and without the variant to produce neuronal precursor cells (NPCs), astrocytes and neurons. The variant is heterozygous in five subjects, homozygous in two subjects, and is absent in six subjects. Gene expression of the isoforms was examined using RNAseq. Results: We detected expression of six types of NRG1 isoforms (I to IV) and three additional ARN transcripts that were not grouped in any of those. We found that the expression of NRG1 isoforms varies in different cell types but there were no statistically significant differences between cells of subjects carrying at least one T allele compared to cells of subjects homozygous for the G allele. The type III isoform showed a higher expression in neurons than in the other two cell types, which is agreement with previous reports in human brain tissue. Discussion: Our results suggest that the expression of type I and type III NRG1 isoforms depends on the cell type, therefore, these results are also in agreement with our hypothesis that the variant affects the protein structure (in each cell type), but not the gene expression. Although the difference in isoform expression between genotypes was not significant in the models for isoforms type I and type III, there are slight changes in the isoform expression when the T allele is present. In order to confirm that the presence of the risk allele is not generating a difference in the expression levels of the neuregulin isoforms, it is necessary to replicate the present study with a larger sample. If there is in fact an effect of the variant in the NRG1 gene on isoform expression, our data suggests that this effect could potentially vary in the different cell types.Ítem Assessment of genetic ancestry and population substructure in Costa Rica by analysis of individuals with a familial history of mental disorder(2010-10-06) Segura Wang, Maia; Raventós Vorst, Henriette; Escamilla, Michael; Barrantes Mesén, RamiroThe 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.Ítem Methionine sulfoxide reductase: a novel schizophrenia candidate gene(2008-05-27) Walss Bass, Consuelo; Soto Bernardini, María Clara; Johnson Pais, Teresa L.; Leach, Robin Jean; Ontiveros Sánchez, José Alfonso; Nicolini Sánchez, José Humberto; Mendoza Rodríguez, Ricardo; Jerez Magaña, Álvaro Antonio; Dassori, Albana Maria; Chavarria Siles, Ivan M.; Escamilla, Michael; Raventós Vorst, HenrietteMethionine sulfoxide reductase (MSRA) is an antioxidant enzyme implicated in protection against oxidative stress and protein maintenance. We have previously reported the association of marker D8S542, located within the MSRA gene, with schizophrenia in the Central Valley of Costa Rica (CVCR). By performing fine mapping analysis, we have now identified a potential three-marker at risk haplotype within MSRA in the same CVCR sample, with a global P-value slightly above nominal significance (P = 0.0526). By sequencing the MSRA gene in individuals carrying this haplotype, we identified a novel 4-base pair deletion 1,792 bases upstream of the MSRA transcription start site. This deletion was significantly under-transmitted to schizophrenia patients in the CVCR sample (P = 0.0292) using FBAT, and this was replicated in a large independent sample of 321 schizophrenia families from the Hispanic population (P = 0.0367). These findings suggest a protective effect of the deletion against schizophrenia. Further, MSRA mRNA levels were significantly lower in lymphoblastoid cell lines of individuals homozygous for the deletion compared to carriers of the normal allele (P = 0.0135), although significance was only evident when genotypes were collapsed. This suggests that the deleted sequence may play a role in regulating MSRA expression. In conclusion, this work points towards MSRA as a novel schizophrenia candidate gene. Further studies into the mechanisms by which MSRA is involved in schizophrenia pathophysiology may shed light into the biological underpinnings of this disorder.Ítem Introduction on psychiatric genetics, current findings and advances(2019-03-25) Raventós Vorst, HenrietteBackground. As part of our goal to involve more clinicians from Spanish speaking countries in psychiatric genetics, we have organized this educational session, to review the current findings in the field. In this first lecture, I will introduce the principles of genetic mapping for the following lectures, for a non-specialist audience.Ítem Bioética y derechos humanos en personas con enfermedades mentales Ciudad de Panamá, 5 de agosto 2015(2015-08) Raventós Vorst, HenrietteResumen de la conferencia dictada en el Simposio Latinoamericano de Bioética Ciudad de Panamá, 5 de agosto 2015.Ítem Analysis of single nucleotide polymorphisms in miRNA genes and their role in schizophrenia etiology(2014-02-15) Bolaños Palmieri, Patricia; Raventós Vorst, HenrietteSchizophrenia is a severe neuropsychiatric disease that in spite of having a clear genetic component in its etiology, the genes involved have not yet been unequivocally identified and only explain a small percentage of the cases. Within the complex scenario of gene expression regulation, microRNAs have been implicated in the post-transcriptional regulation of mRNA. This mechanism of protein synthesis regulation has been linked to the correct formation of synapses, which translates in the ability to learn and other higher cognitive functions. Methods: miRNA candidate genes were established according to their genomic location and previous reports of differential expression in schizophrenic brains. Further in silico analysis was carried out in order to establish the targets for miRNA regulation and their relationship to the pathology. SNP genotyping analyses were performed in a sample of schizophrenic probands and their nuclear family members from Costa Rica, in order to establish an association to disease status. Results: A search of the available literature revealed a total of 60 miRNA differentially expressed in brains of schizophrenic patients, of which 12 were located in genomic regions of interest. Amongst the targets of posttranscriptional regulation are the Neurotrophin signaling pathways that have been implicated in important synaptic and neuronal processes. This result strengthens the hypothesis that these miRNA can be involved in disease etiology. Of the 4 SNPs genotyped only rs41283391 on miR-195 was polymorphic in our sample, however the association to Schizophrenia diagnosis was not significant (n = 317, Z = 0.797, p = 0.42). Conclusion: This research project adds further information to the hypothesis of the involvement of the miRNA regulation pathway in neuropsychiatric diseases. Even though the analysis of these particular SNPs gave no evidence of association, it is plausible that further sequence analysis could reveal more information about variants that could influence disease etiology. Another important outcome of this project is the establishment of further hypothesis for future research projects, some of which are already underway.Ítem Kefersteinia nova isthmii Americani australis cum generis synopsi(2024-12) Pupulin, Franco; Salas Hidalgo, Elvira; Bogarín Chaves, Diego GerardoA new species of Kefersteinia (Orchidaceae) from the southern region of the Central American isthmus is described and illustrated, and its affinities with K. elegans are discussed. In Panama, Kefersteinia luteola was previously misidentified as the Colombian K. elegans, but the new species appears to be restricted to the Cordillera de Guanacaste and Talamanca in Costa Rica and Panama. Among Kefersteinia species, K. luteola is distinguished by its small yellowish flowers, broadly extensively excised lip with a depressed laminate, trullate callus, and a column recognized by large, triangular, rounded wings with subciliate margins. The most similar species is Kefersteinia elegans, from which it differs in plant and flower size, with subringent sepals and petals, a sessile entire lip, and minutely glandular-ciliate wings of the column. A synopsis of the genus Kefersteinia is presented, and the species grouped according to their overall similarity.Ítem 507. Association of NRXN3 deletion with schizophrenia and bipolar disorder(2017-05-17) Shavit, Ayal; Gonzalez, Jessica; Chavez, Maricela; Rodriguez, Marco; Camarillo, Cynthia; Ramirez, Mercedez; Zavala, Juan; Contreras Rojas, Javier; Raventós Vorst, Henriette; Flores, Deborah; Jerez, Alvaro; Ontiveros, Alfonso; Nicolini, Humberto; Escamilla, Michael; Gonzalez, SuzanneSchizophrenia (SZ) and bipolar disorder (BD) are the most severe neuropsychiatric disorders affecting 1.2% and 4.4% of Americans, respectively. Certain genes coding for proteins involved in pre-synaptic machinery are thought to play a role in the pathophysiology of the disorder. Deficits in the calcium channel regulator gene NRXN3 have been associated with behaviors of impulsivity and alcohol and drug dependence, which are traits characteristic of BD and SZ.Ítem 846. Human-derived astrocytes from schizophrenia patients express lower levels of GFAP and S100B(2017-04-29) Stertz, Laura; Raventós Vorst, Henriette; Walss Bass, ConsueloSchizophrenia (SZ) is a debilitating psychiatric disorder with a worldwide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 70-85%. Glial cells mediate crucial functions in the CNS and alterations in the function of these cells may be an underlying mechanism for SZ development. Here we use astrocytes derived from induced pluripotent stem cells (iPSCs) from subjects from the population isolate of the Central Valley of Costa Rica (CVCR) to explore a role for astrocytes in SZ pathogenesis.Ítem Ciencia, creencias y políticas: la fertilización in vitro en Costa Rica(2021-02-05) Raventós Vorst, HenrietteLa fertilización in vitro o FIV es una de las técnicas de reproducción asistida llamada de alta complejidad, en que la fertilización ocurre fuera del cuerpo de la mujer. Es la última opción terapéutica para mujeres o parejas con infertilidad, un problema que se presenta en hasta el 15% de la población y que se define como la incapacidad de lograr un embarazo luego de 12 meses de intentarlo. Este artículo aborda las creencias y políticas relacionadas con la legalización de la FIV en Costa Rica.Ítem Genetic research of neuropsychiatric disorders in Latin America(2019) Contreras Rojas, Javier; Raventós Vorst, HenrietteAbstract: Background: Investment in research in middle and low-income countries (LMIC) is generally under 1% of the GNP. According to Saxena et al, only 10% of mental health research is directed to the needs of the 90% of population living in the 153 low and middle-income countries (LMIC) (Saxena et al., 2006). Despite the advances in the identification of genetic variants for neuropsychiatric disorders in European and Asian populations, research of these disorders in Latin American populations remains limited. Methods: We reviewed scientific reports on genetic research of neuropsychiatric disorders from Latin America during the last 10 years (2007-2017). We found 78 published papers in local and international peer-reviewed journals. Results: We divided the publications by geographical regions: South America 41 (52%), Central America 23 (30%), Caribe 6 (8%) and Mexico alone 8 (10%). For the total 41 papers from South America, the countries with the highest number of publications are Brazil: 13 (32%) and Colombia: 12 (30%). For the Mesoamerican Region (Mexico and Central America), we found that only Mexico and Costa Rica have a significant contribution, either alone or in collaboration. Out of the 78 publications, the overall funding source origin is local: 44 (56%). The international agencies that provided support for these researches are: NARSAD, NIH, OCD Foundation and Wellcome Trust. Twenty-four (31%) were family-based versus 54 (69%) case-control studies. Costa Rica has played a leading role in genetic research of neuropsychiatric disorders in our region. The study's results have been published in 102 scientific research papers during the last 25 years. Our research group at the University of Costa Rica (biggest public university with 30,000 students and over 60% of scientific papers from CR) has over 25 years of studying the genetics of neuropsychiatric disorders in Costa Rica, including deafness (first gene for non-syndromic deafness mapped in CR), schizophrenia, bipolar disorder, successful cognitive aging, among others. During the last 13 years, we conducted 12 scientific research projects (2 research training programs funded by Fogarty, 9 research projects to study the genetics of neuropsychiatric disorders and 1 project to form a network that will study resilience and protective factors for neuropsychiatric disorders in LMICs). Because of big pedigrees, good medical and genealogical records, excellent participation of families that also live relatively close together, we have done mostly family studies but also have population-based studies on trios (parents and affected child). Most research is funded by foreign sources such as NIH, ICGEB, other NGOs and limited local sources (Expenditure on research as % of GDP: 0.54%). Conclusions: This shows significant differences in scientific reports among sub regions and a low local investment in genetic research of neuropsychiatric disorders in Latin America.Ítem Genome-wide DNA methylation profiling in nonagenarians suggests an effect of PM20D1 in late onset Alzheimer’s disease(2021) Coto Vílchez, Maria Carolina; Martínez Magaña, José Jaime; Mora Villalobos, Lara; Valerio Aguilar, Daniel; Genis Mendoza, Alma Delia; Silverman, Jeremy M.; Nicolini Sánchez, José Humberto; Raventós Vorst, Henriette; Chavarría Soley, GabrielaBackground. The aim of this study is to identify differentially methylated regions (DMRs) in the genomes of a sample of cognitively healthy individuals and a sample of individuals with LOAD, all of them nonagenarians from Costa Rica. Methods. In this study, we compared whole blood DNA methylation profiles of 32 individuals: 21 cognitively healthy and 11 with LOAD, using the Infinium MethylationEPIC BeadChip. First, we calculated the epigenetic age of the participants based on Horvath’s epigenetic clock. DMRcate and Bumphunter were used to identify DMRs. After in silico and knowledge-based filtering of the DMRs, we performed a methylation quantitative loci (mQTL) analysis (rs708727 and rs960603). Results. On average, the epigenetic age was 73 years in both groups, which represents a difference of over 20 years between epigenetic and chronological age in both affected and unaffected individuals. Methylation analysis revealed 11 DMRs between groups, which contain six genes and two pseudogenes. These genes are involved in cell cycle regulation, embryogenesis, synthesis of ceramides, and migration of interneurons to the cerebral cortex. One of the six genes is PM20D1, for which altered expression has been reported in LOAD. After genotyping previously reported mQTL SNPs for the gene, we found that average methylation in the PM20D1 DMR differs between genotypes for rs708727, but not for rs960603. Conclusions. This work supports the possible role of PM20D1 in protection against AD, by showing differential methylation in blood of affected and unaffected nonagenarians. Our results also support the influence of genetic factors on PM20D1 methylation levels.Ítem El curioso caso de los hongos de Coto Brus y Osa(2024) Mardones Hidalgo, Melissa; Rojas Alvarado, Carlos AlonsoAl iniciar un proceso de análisis de los registros de hongos en Costa Rica, nos sorprendimos de ver el alto porcentaje de recolectas en dos sitios al sur del país. En esta pequeña nota resumimos esos datos y los colocamos en el contexto de la investigación micológica, temporal y espacial, de las zonas aludidas. Este tipo de prácticas son relevantes para comprender que el conocimiento científico tiene un espíritu colectivo, colaborativo y desinteresado.Ítem M48 comparative whole genome dna methylation profiling in costa rican nonagenarians with and without dementia: significant difference between chronological and epigenetic age and further evidence for a role of PM20D1(2019) Coto Vílchez, Carolina; Chavarria Soley, Gabriela; Mora Villalobos, Lara; Genis, Alma; Martínez Magaña, Jaime; Nicolini Sánchez, José Humberto; Raventós Vorst, HenrietteBackground: Alzheimer's disease (AD) is a complex disorder that results from a combination of genetic and non-genetic risk factors. There are genetic variants that may be protective against the development of dementia at advanced ages. Most epigenetic and non-epigenetics studies of successful cognitive aging have focused on individuals between 65 and 85 years old, there isn't much representation of nonagenarians or centenarians. There is abundant evidence about methylation patterns alterations in individuals with dementia compared with non-affected ones, but not much information about epigenetic markers of normal cognitive aging. Methods: In this study, we compared whole blood DNA methylation profiles of nonagenarians of Costa Rica, 21 cognitively healthy (mean age 93, SD=2.8) and 11 with dementia (mean age 95, SD=3.4), using the Infinium MethylationEPIC BeadChip. We calculated the epigenetic age based on Horvath's epigenetic clock. We used two different approaches; DMRcate and Bumphunter, to identify differentially methylated regions (DMRs). Results: On average, the epigenetic age was 73 years in both groups, which represents a difference between the epigenetic age and the chronological age of 23 years in the case of cognitive healthy people and of 22 in the case of people with dementia. The analysis revealed 11 DMRs between both groups, within which five genes, and two pseudogenes are located. Discussion: Epigenetic age results are consistent with other publications on nonagenarians and also on an aged Costa Rican population. However, in these studies the difference between epigenetic and chronological age is not as important as in our sample. The DMRs genes are involved in cell cycle regulation, embryogenesis, synthesis of ceramides, and migration of interneurons to the cerebral cortex. One of the five genes that we found differentially methylated is PM20D1. Consistently with other studies, we found that the gene is hypermethylated in AD. Association studies have found that this gene is associated with AD, also it is a QTL of both expression and methylation. PM20D1 potentially protect against AD and that loss of this expression is a risk factor for AD.Ítem Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients(2020-12-07) Stertz, Laura; Di Re, Jessica; Pei, Guangsheng; Fries, Gabriel R.; Mendez, Emily Frances; Li, Shenglan; Smith Callahan, Laura; Raventós Vorst, Henriette; Tipo, Jerricho; Cherukuru, Rohan; Zhao, Zhongming; Liu, Ying; Jia, Peilin; Laezza, Fernanda; Walss Bass, ConsueloHuman-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 3β, 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 βIII 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.Ítem SU14 Morphological and immunocytochemical characterization of human-derived astrocytes from subjects with the NRG1 p.V266L genetic variant(2019) Daniela Ugalde Araya; Stertz, Laura; Walss Bass, Consuelo; Raventós Vorst, HenrietteBackground: A valine to leucine variant (p.V266L) in the transmembrane domain of neuregulin 1 (NRG1) was associated with schizophrenia in the Central Valley of Costa Rica (CVCR) population. To determine its functional significance, we are studying its biological effects in different cell types. Due to the importance of the glial cells in the Central Nervous System, we have generated astrocytes derived from induced pluripotent stem cells (iPSCs) from unaffected CVCR subjects, with and without the p.V266L variant, to explore the role of this variant in these cells. Methods: Lymphoblastoid cells lines (LCLs) from 4 unaffected subjects were transformed into iPSCs using Episomal iPSC Reprogramming Kit. Neuronal Precursor Cells were generated using AggreWell methodology and cultured in N2B27 medium complemented with 5ng/mL CTNF, 10ng/mL BMP4 and 20ng/mL FGF2 for differentiation into astrocytes. Lipofectamine transfection was used to evaluate the morphology of the astrocytes (area) and the diameter of the nucleus was measure using DAPI. Immunocytochemistry was used to measure total corrected cell fluorescence (TCCF) of GFAP, CD44, S100B, and ALDH1L1 markers. The astrocytes with the NRG1 variant had larger areas than the non-mutated ones, whereas no significant differences between both groups were found when the diameter of the nucleus was compared. The TCCF of GFAP, CD44, and S100B was higher in cells with the variant; only ALDH1L1 did not present significant differences between groups. The TCCF was measured using ImageJ and the results were analyzed using R. Results: Astrocytes with the NRG1 variant have larger areas (p<0.05), while no significant differences were found for the diameter of the nucleus (p=0.0545). The TCCF of S100B, GFAP and CD44 was higher in cells with the variant (p<0.05); only ALDH1L1 did not present significant differences (p=0.26) between groups. Discussion: Studies in animal models have shown that the presence of this variant in III NRG prevents the cleavage of the intracellular domain by the enzyme β secretase, and the extracellular domain by the enzyme γ secretase. This generates the complete reversal of the signaling pathway and an alteration in expression of genes involved in cell survival, growth and maintenance. Our cell model shows changes in the area and the expression of markers with the p.V266L variant, which might reflect both structural and metabolic alterations induced by this mutation also in astrocytes. We found larger astrocytes with larger nucleus in comparisons with studies in animal models. Our results are in agreement with previous research that show that human astrocytes are substantially larger and have more complex processes than rodent cells. Also, we show that the astrocytes in which the variant is present tend to be of a larger size. The explanation of this difference between astrocytes with and without the variant could be mediated by the differences in expression of markers used in this study. GFAP and CD44 participate in the dynamics of the cellular cytoskeleton while S100B and ALDH1L1 are involved with growth and proliferation processes. These results support a possible functional role for the p.V266L NRG1 variant in modulating astrocytic morphology and activity, and may have implications for schizophrenia. In addition, these results prove the feasibility and utility of this cell model to functionally characterize the p.V266L NRG1 variant and other genetic mutations in human astrocytes derived from EBV LCL through the iPSC technique.Ítem Underlying domains of anxiety trait in a Costa Rican sample: Preliminary results(2020) Ugalde Araya, Karen Daniela; Coto Vílchez, Maria Carolina; Ávila Aguirre, Alejandro; Chavarría Soley, Gabriela; Raventós Vorst, Henriette; Contreras Rojas, JavierBackground. 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.