Publications by authors named "Judit García-González"

8 Publications

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Behavioral Effects of Developmental Exposure to JWH-018 in Wild-Type and Disrupted in Schizophrenia 1 () Mutant Zebrafish.

Biomolecules 2021 Feb 19;11(2). Epub 2021 Feb 19.

School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK.

Synthetic cannabinoids can cause acute adverse psychological effects, but the potential impact when exposure happens before birth is unknown. Use of synthetic cannabinoids during pregnancy may affect fetal brain development, and such effects could be moderated by the genetic makeup of an individual. Disrupted in schizophrenia 1 () is a gene with important roles in neurodevelopment that has been associated with psychiatric disorders in pedigree analyses. Using zebrafish as a model, we investigated (1) the behavioral impact of developmental exposure to 3 μM 1-pentyl-3-(1-naphthoyl)-indole (JWH-018; a common psychoactive synthetic cannabinoid) and (2) whether moderates the effects of JWH-018. As altered anxiety responses are seen in several psychiatric disorders, we focused on zebrafish anxiety-like behavior. Zebrafish embryos were exposed to JWH-018 from one to six days post-fertilization. Anxiety-like behavior was assessed using forced light/dark and acoustic startle assays in larvae and novel tank diving in adults. Compared to controls, both acutely and developmentally exposed zebrafish larvae had impaired locomotion during the forced light/dark test, but anxiety levels and response to startle stimuli were unaltered. Adult zebrafish developmentally exposed to JWH-018 spent less time on the bottom of the tank, suggesting decreased anxiety. Loss-of-function in increased anxiety-like behavior in the tank diving assay but did not alter sensitivity to JWH-018. Results suggest developmental exposure to JWH-018 has a long-term behavioral impact in zebrafish, which is not moderated by .
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http://dx.doi.org/10.3390/biom11020319DOI Listing
February 2021

The effects of polygenic risk for psychiatric disorders and smoking behaviour on psychotic experiences in UK Biobank.

Transl Psychiatry 2020 09 28;10(1):330. Epub 2020 Sep 28.

School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK.

While psychotic experiences are core symptoms of mental health disorders like schizophrenia, they are also reported by 5-10% of the population. Both smoking behaviour and genetic risk for psychiatric disorders have been associated with psychotic experiences, but the interplay between these factors remains poorly understood. We tested whether smoking status, maternal smoking around birth, and number of packs smoked/year were associated with lifetime occurrence of three psychotic experiences phenotypes: delusions (n = 2067), hallucinations (n = 6689), and any psychotic experience (delusions or hallucinations; n = 7803) in 157,366 UK Biobank participants. We next calculated polygenic risk scores for schizophrenia (PRS), bipolar disorder (PRS), major depression (PRS) and attention deficit hyperactivity disorder (PRS) in 144,818 UK Biobank participants of European ancestry to assess whether association between smoking and psychotic experiences was attenuated after adjustment of diagnosis of psychiatric disorders and the PRSs. Finally, we investigated whether smoking exacerbates the effects of genetic predisposition on the psychotic phenotypes in gene-environment interaction models. Smoking status, maternal smoking, and number of packs smoked/year were associated with psychotic experiences (p < 1.77 × 10). Except for packs smoked/year, effects were attenuated but remained significant after adjustment for diagnosis of psychiatric disorders and PRSs (p < 1.99 × 10). Gene-environment interaction models showed the effects of PRS and PRS (but not PRS or PRS) on delusions (but not hallucinations) were significantly greater in current smokers compared to never smokers (p < 0.002). There were no significant gene-environment interactions for maternal smoking nor for number of packs smoked/year. Our results suggest that both genetic risk of psychiatric disorders and smoking status may have independent and synergistic effects on specific types of psychotic experiences.
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http://dx.doi.org/10.1038/s41398-020-01009-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523004PMC
September 2020

Identification of as a locus affecting nicotine preference in zebrafish and human smoking behaviour.

Elife 2020 03 25;9. Epub 2020 Mar 25.

School of Biological and Chemical Sciences, Queen Mary, University of London, London, United Kingdom.

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F fish, one in the gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.
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http://dx.doi.org/10.7554/eLife.51295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096180PMC
March 2020

Men and women differ in their perception of gender bias in research institutions.

PLoS One 2019 5;14(12):e0225763. Epub 2019 Dec 5.

Wom = n Equity & Research Committee, Society of Spanish Researchers in the United Kingdom (SRUK/CERU), International House, 12 Constance Street, London, United Kingdom.

There is extensive evidence of gender inequality in research leading to insufficient representation of women in leadership positions. Numbers revealing a gender gap in research are periodically reported by national and international institutions but data on perceptions of gender equality within the research community are scarce. In the present study, a questionnaire based on the British Athena Survey of Science, Engineering and Technology (ASSET 2016) was distributed among researchers working in Spain. Consistent with the original UK-based study, women in research perceived a greater degree of gender inequality than men. This difference was consistent from junior to senior positions, within public and private universities as well as research centres, and across all research disciplines. When responses were compared with the existing UK-based questionnaire, researchers in Spain felt that women and men are treated more equally in the workplace, yet they perceived their home departments to be less supportive regarding matters of gender equality. The results of this study provide clear evidence that men and women do not share the same perceptions of gender equality in science and that their differing perceptions are relatively consistent across two major European countries. The fact that men occupy the majority of senior positions while not perceiving the same inequality as women do, may be critical when it comes to ensuring the fair ascent of women to senior positions in an academic system. These data encourage the implementation of measures to ensure that both men and women are aware of gender biases in research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225763PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894819PMC
March 2020

Body composition in anorexia nervosa: Meta-analysis and meta-regression of cross-sectional and longitudinal studies.

Int J Eat Disord 2019 11 12;52(11):1205-1223. Epub 2019 Sep 12.

Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Objective: Clinically, anorexia nervosa (AN) presents with altered body composition. We quantified these alterations and evaluated their relationships with metabolites and hormones in patients with AN longitudinally.

Method: In accordance with PRISMA guidelines, we conducted 94 meta-analyses on 62 samples published during 1996-2019, comparing up to 2,319 pretreatment, posttreatment, and weight-recovered female patients with AN with up to 1,879 controls. Primary outcomes were fat mass, fat-free mass, body fat percentage, and their regional distribution. Secondary outcomes were bone mineral density, metabolites, and hormones. Meta-regressions examined relationships among those measures and moderators.

Results: Pretreatment female patients with AN evidenced 50% lower fat mass (mean difference [MD]: -8.80 kg, 95% CI: -9.81, -7.79, Q = 1.01 × 10 ) and 4.98 kg (95% CI: -5.85, -4.12, Q = 1.99 × 10 ) lower fat-free mass, with fat mass preferentially stored in the trunk region during early weight restoration (4.2%, 95% CI: -2.1, -6.2, Q = 2.30 × 10 ). While the majority of traits returned to levels seen in healthy controls after weight restoration, fat-free mass (MD: -1.27 kg, 95% CI: -1.79, -0.75, Q = 5.49 × 10 ) and bone mineral density (MD: -0.10 kg, 95% CI: -0.18, -0.03, Q = 0.01) remained significantly altered.

Discussion: Body composition is markedly altered in AN, warranting research into these phenotypes as clinical risk or relapse predictors. Notably, the long-term altered levels of fat-free mass and bone mineral density suggest that these parameters should be investigated as potential AN trait markers.

Resumenobjetivo: Clínicamente, la anorexia nervosa (AN) se presenta con alteraciones en la composición corporal. Cuantificamos estas alteraciones y evaluamos longitudinalmente su relación con metabolitos y hormonas en pacientes con AN. MÉTODO: De acuerdo con las pautas PRISMA, realizamos 94 meta-análisis en 62 muestras publicadas entre 1996-2019, comparando hasta 2,319 pacientes mujeres en pre-tratamiento, post-tratamiento, y recuperadas en base al peso con hasta 1,879 controles. Las principales medidas fueron masa grasa, masa libre de grasa, porcentaje de grasa corporal y su distribución regional. Las medidas secundarias fueron densidad mineral ósea, metabolitos y hormonas. Las meta-regresiones examinaron las relaciones entre esas medidas y moderadores.

Resultados: Las pacientes femeninas con AN pre-tratamiento mostraron un 50% menos de masa grasa (MD: -8.80 kg, CI 95%: -9.81, -7.79, Q = 1.01 × 10 ) y 4.98 kg (CI 95%: -5.85, -4.12, Q = 1.99 × 10 ) menos de masa libre de grasa, con masa grasa preferentemente almacenada en la región del tronco durante la recuperación temprana del peso (4.2%, CI 95%: -2.1, -6.2, Q = 2.30 × 10 ). Aunque la mayoría de los rasgos regresaron a los niveles vistos en los controles sanos después de la restauración del peso, la masa libre de grasa (MD: -1.27 kg, CI 95%: -1.79, -0.75, Q = 5.49 × 10 ) y la densidad mineral ósea (MD: -0.10 kg, CI 95%: -0.18, -0.03, Q = 0.01) permanecieron significativamente alteradas. DISCUSIÓN: La composición corporal es marcadamente alterada en la AN, lo que garantiza la investigación en estos fenotipos como predictores de riesgo clínico o de recaída. Notablemente, la alteración a largo plazo de los niveles de masa libre de grasa y densidad mineral ósea sugieren que estos parámetros debe ser investigados como potenciales rasgos indicadores de AN.
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http://dx.doi.org/10.1002/eat.23158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899925PMC
November 2019

Immunomodulatory effects of antipsychotic treatment on gene expression in first-episode psychosis.

J Psychiatr Res 2019 02 10;109:18-26. Epub 2018 Nov 10.

Mental Health Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271, Helsinki, Finland.

Previous studies suggest immunological alterations in patients with first-episode psychosis (FEP). Some studies show that antipsychotic compounds may cause immunomodulatory effects. To evaluate the immunological changes and the possible immunomodulatory effects in FEP, we recruited patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, from the catchment area of the Helsinki University Hospital and the City of Helsinki, Finland. Fasting peripheral blood samples were collected between 8 and 10 a.m. in 10 ml PAXgene tubes. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 147 candidate genes reflecting activation of the immune system. Cases had higher gene expression levels of BDKRB1 and SPP1/osteopontin compared with controls. Of the individual medications used as monotherapy, risperidone was associated with a statistically significant upregulation of 11 immune system genes, including cytokines and cytokine receptors (SPP1, IL1R1, IL1R2), pattern recognition molecules (TLR1, TLR2 and TLR6, dectin-1/CLEC7A), molecules involved in apoptosis (FAS), and some other molecules with functions in immune activation (BDKRB1, IGF1R, CR1). In conclusion, risperidone possessed strong immunomodulatory properties affecting mainly innate immune response in FEP patients, whereas the observed effects of quetiapine and olanzapine were only marginal. Our results further emphasize the importance of understanding the immunomodulatory mechanisms of antipsychotic treatment, especially in terms of specific compounds, doses and duration of medication in patients with severe mental illness. Future studies should evaluate the response pre- and post-treatment, and the possible role of this inflammatory activation for the progression of psychiatric and metabolic symptoms.
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http://dx.doi.org/10.1016/j.jpsychires.2018.11.008DOI Listing
February 2019

Pharmacogenetics of antidepressant response: A polygenic approach.

Prog Neuropsychopharmacol Biol Psychiatry 2017 04 31;75:128-134. Epub 2017 Jan 31.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Background: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.

Methods: Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).

Results: No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.

Discussion: We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.
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http://dx.doi.org/10.1016/j.pnpbp.2017.01.011DOI Listing
April 2017

Validation and genotyping of multiple human polymorphic inversions mediated by inverted repeats reveals a high degree of recurrence.

PLoS Genet 2014 Mar 20;10(3):e1004208. Epub 2014 Mar 20.

Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

In recent years different types of structural variants (SVs) have been discovered in the human genome and their functional impact has become increasingly clear. Inversions, however, are poorly characterized and more difficult to study, especially those mediated by inverted repeats or segmental duplications. Here, we describe the results of a simple and fast inverse PCR (iPCR) protocol for high-throughput genotyping of a wide variety of inversions using a small amount of DNA. In particular, we analyzed 22 inversions predicted in humans ranging from 5.1 kb to 226 kb and mediated by inverted repeat sequences of 1.6-24 kb. First, we validated 17 of the 22 inversions in a panel of nine HapMap individuals from different populations, and we genotyped them in 68 additional individuals of European origin, with correct genetic transmission in ∼ 12 mother-father-child trios. Global inversion minor allele frequency varied between 1% and 49% and inversion genotypes were consistent with Hardy-Weinberg equilibrium. By analyzing the nucleotide variation and the haplotypes in these regions, we found that only four inversions have linked tag-SNPs and that in many cases there are multiple shared SNPs between standard and inverted chromosomes, suggesting an unexpected high degree of inversion recurrence during human evolution. iPCR was also used to check 16 of these inversions in four chimpanzees and two gorillas, and 10 showed both orientations either within or between species, providing additional support for their multiple origin. Finally, we have identified several inversions that include genes in the inverted or breakpoint regions, and at least one disrupts a potential coding gene. Thus, these results represent a significant advance in our understanding of inversion polymorphism in human populations and challenge the common view of a single origin of inversions, with important implications for inversion analysis in SNP-based studies.
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http://dx.doi.org/10.1371/journal.pgen.1004208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961182PMC
March 2014