R de Frutos

University of Valencia, Valenza, Valencia, Spain

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Publications (77)317.22 Total impact

  • Source
    Psychological Medicine 07/2012; 42(7):1559-65. · 5.59 Impact Factor
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    ABSTRACT: The aims of this study were to review studies on the molecular genetics of child temperament and prospectively analyze infant temperament as a function of the interaction between infant and mother: 5-HTT, DRD4, and MAO-A functional polymorphisms and the mother's emotional state. A prospective study of 317 newborns and their mothers was performed. Infant temperament and the mother's anxiety and confidence in caregiving were evaluated at 8 and 32 weeks after childbirth using the Mother and Baby Scale. The mother's emotional state was evaluated using the Edinburgh Postpartum Depression Scale and the State-Trait Anxiety Inventory. These variables were correlated with 5-HTTLPR and Stin2 variants in the 5-HTT gene and the DRD4 variable number tandem repeats Exon 3 and MAO-A variable number tandem repeats genotypes of both the infants and their mothers. The irritability scores of infants with the 5-HTTLPR s allele showed a linear relationship with their mothers' anxiety of caregiving at 8 (p = .011) and 32 weeks (p = .001), whereas the irritability of infants carrying the HTTLPR ll genotype was independent of their mothers' anxiety. The review of the literature in this field and the results of this study support that the 5-HTTLPR polymorphism moderates the influence of the mother's anxiety on infant irritability.
    Journal of developmental and behavioral pediatrics: JDBP 09/2010; 31(7):545-54. · 2.27 Impact Factor
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    ABSTRACT: To study the role of the serotonin transporter gene (SLC6A4) in the emotional processing of auditory hallucinations can be particularly important to better understand the pathophysiology of auditory hallucinations. Moreover, a poly-morphism located in this gene (5-HTTLPR) has been previously associated with different disorders related to altered emotional responses. The aim of this study was to evaluate the relationship between different polymorphisms of the SLC6A4 gene and different aspects of auditory hallucinations in schizophrenic patients, with a special consideration toward the emotional response to auditory hallucinations. Two samples of 224 patients with auditory hallucinations and 346 healthy subjects were studied. AH were assessed in patients through the PSYRATS scale for auditory hallucinations. Several polymorphisms located within the SLC6A4 gene were analysed through case-control comparisons as well as association analyses with different parameters of auditory hallucinations. No differences were found between patients and controls for any of the analysed polymorphisms (p > 0.05). However, the evaluation of auditory hallucinations parameters showed that the low expressing alleles of the 5-HTTLPR polymorphism were associated with higher levels of intensity of the distress caused by auditory hallucinations (p = 0.049 corrected for the item 'intensity of distress'). There was also a trend with the parameter disruption (p = 0.06 corrected). These two items of the PSYRATS scale are directly related to the emotional dimension of auditory hallucinations. In contrast, we did not observe any association with items related to other dimensions of auditory hallucinations. Our results support a possible role of the serotonin transporter in the emotional response to auditory hallucinations.
    Revista de neurologia 03/2010; 50(6):325-32. · 1.18 Impact Factor
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    ABSTRACT: Schizophrenia is considered a language related human specific disease. Previous studies have reported evidence of positive selection for schizophrenia-associated genes specific to the human lineage. FOXP2 shows two important features as a convincing candidate gene for schizophrenia vulnerability: FOXP2 is the first gene related to a language disorder, and it has been subject to positive selection in the human lineage. Twenty-seven SNPs of FOXP2 were genotyped in a cohort of 293 patients with schizophrenia and 340 controls. We analyzed in particular the association with the poverty of speech and the intensity of auditory hallucinations. Potential expansion of three trinucleotide repeats of FOXP2 was also screened in a subsample. Methylation analysis of a CpG island, located in the first exon of the gene, was performed in post-mortem brain samples, as well as qRT-PCR analysis. A significant association was found between the SNP rs2253478 and the item Poverty of speech of the Manchester scale (p = 0.038 after Bonferroni correction). In patients, we detected higher degree of methylation in the left parahippocampus gyrus than in the right one. FOXP2 might be involved in the language disorder in patients with schizophrenia. Epigenetic factors might be also implicated in the developing of this disorder.
    BMC Medical Genetics 01/2010; 11:114. · 2.54 Impact Factor
  • Schizophrenia Research - SCHIZOPHR RES. 01/2010; 117:452-452.
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    ABSTRACT: Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
    Nature 08/2009; 460(7256):744-7. · 38.60 Impact Factor
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    ABSTRACT: The main goal of this paper is to obtain a classification model based on feed-forward multilayer perceptrons in order to improve postpartum depression prediction during the 32 weeks after childbirth with a high sensitivity and specificity and to develop a tool to be integrated in a decision support system for clinicians. Multilayer perceptrons were trained on data from 1397 women who had just given birth, from seven Spanish general hospitals, including clinical, environmental and genetic variables. A prospective cohort study was made just after delivery, at 8 weeks and at 32 weeks after delivery. The models were evaluated with the geometric mean of accuracies using a hold-out strategy. Multilayer perceptrons showed good performance (high sensitivity and specificity) as predictive models for postpartum depression. The use of these models in a decision support system can be clinically evaluated in future work. The analysis of the models by pruning leads to a qualitative interpretation of the influence of each variable in the interest of clinical protocols.
    Methods of Information in Medicine 04/2009; 48(3):291-8. · 1.08 Impact Factor
  • European Psychiatry - EUR PSYCHIAT. 01/2009; 24.
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    ABSTRACT: Polymorphic variations in the serotonin transporter gene (5-HTT) moderate the depressogenic effects of tryptophan depletion. After childbirth there is a sharp reduction in brain tryptophan availability, thus polymorphic variations in 5-HTT may play a similar role in the post-partum period. To study the role of 5-HTT polymorphic variations in mood changes after delivery. One thousand, eight hundred and four depression-free Spanish women were studied post-partum. We evaluated depressive symptoms at 2-3 days, 8 weeks and 32 weeks post-partum. We used diagnostic interview to confirm major depression for all probable cases. Based on two polymorphisms of 5-HTT (5-HTTLPR and STin2 VNTR), three genotype combinations were created to reflect different levels of 5-HTT expression. One hundred and seventy-three women (12.7%) experienced major depression during the 32-week post-partum period. Depressive symptoms were associated with the high-expression 5-HTT genotypes in a dose-response fashion at 8 weeks post-partum, but not at 32 weeks. High-expression 5-HTT genotypes may render women more vulnerable to depressive symptoms after childbirth.
    The British journal of psychiatry: the journal of mental science 12/2008; 193(5):383-8. · 6.62 Impact Factor
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    ABSTRACT: a woman to become depressed is after childbirth. 1 Post-partum depression affects approximately 13% of women. 2,3 Post-partum depression has a great impact on the family and economy, and is considered a major public health problem. 4,5 There is general agreement that the dramatic physio-logical changes that occur post-partum increase a woman's vulnerability to depressive symptoms, including post-partum depression. 6,7 Pregnancy and delivery are accompanied by hormonal changes as well as lower plasma tryptophan levels, both of which are thought to be aetiologically relevant to the mood changes that follow childbirth. 6,8,9 Although plasma tryptophan availability is not directly related to mood changes, 8 the brain tryptophan availability index is decreased after delivery and is related to depressive symptoms. 10 The mood-lowering effects of experimental tryptophan depletion are controversial, 11 perhaps because of differences in 5-HTT genotype–tryptophan interaction. In women with previous depressive episodes, 5-HTT genotype may moderate the risk for depressive symptoms after tryptophan depletion. 12,13 If childbirth is considered an environmental factor, there may be a strong pathophysiological link between post-partum mood changes and the genes that moderate 5-hydroxy-tryptamine (5-HT) signalling. Jans et al 14 have proposed the concept of 'serotonergic vulner-ability'. Disruption of the serotonergic system may occur at several levels, including tryptophan availability, 5-HT synthesis, release, reuptake or metabolism, and/or pre-or post-synaptic 5-HT receptors. 5-HTT has received special attention because it plays a crucial role in the regulation of serotonergic function. 15,16 In the light of these findings, we designed a prospective longitudinal multicentre study to evaluate interactions between 5-HTT genotype and post-partum mood changes. We hypothesised that 5-HTT genotype would shape the risk for depressive symptoms in post-partum women. We considered three genotype combinations of 5-HTTLPR and Stin2 VNTR polymorphisms that predict differential 5-HTT expression. 17 Given that the acute decline in tryptophan availability that follows childbirth resembles experimental tryptophan depletion, we hypothesised that high-expression 5-HTT genotypes would be associated with depressive symptoms in the weeks following childbirth. Method Participants Between December 2003 and October 2004 women (2–3 days post-partum) were recruited in seven acute care teaching hospitals in Spain and invited to participate in a 32-week follow-up study. All participants were Spanish, not under psychiatric care during pregnancy, and able to understand and answer the clinical questionnaire. Women whose children died after birth were excluded. This study was approved by the institutional review boards of the participating hospitals. All women gave written informed consent. Measures All participants completed a semi-structured interview that included socio-demographic data: age, education level, marital status, number of children and employment status during pregnancy. Personal and family history of psychiatric illness was also recorded. Depression Depressive symptoms were assessed using the total score of the Edinburgh Postnatal Depression Scale (EPDS) 18 with a Spanish validated version. 19 The EPDS 18 is a 10-item self-report scale with Background Polymorphic variations in the serotonin transporter gene (5-HTT) moderate the depressogenic effects of tryptophan depletion. After childbirth there is a sharp reduction in brain tryptophan availability, thus polymorphic variations in 5-HTT may play a similar role in the post-partum period.
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    ABSTRACT: Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited.
    Journal of Psychiatric Research 04/2008; 42(4):278-88. · 4.09 Impact Factor
  • Schizophrenia Research 03/2008; 99(1-3):370-2. · 4.59 Impact Factor
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    ABSTRACT: Sequences homologous to the gypsy retroelement from Drosophila melanogaster are widely distributed among drosophilids. The structure of gypsy includes an open reading frame resembling the retroviral gene env, which is responsible for the infectious properties of retroviruses. In this study we report molecular and phylogeny analysis of the complete env gene from ten species of the obscura group of the genus Drosophila and one species from the genus Scaptomyza. The results indicate that in most cases env sequences could produce a functional Env protein and therefore maintain the infectious capability of gypsy in these species.
    BMC Evolutionary Biology 02/2008; 8:302. · 3.29 Impact Factor
  • Schizophrenia Research 02/2008; 98:106-106. · 4.59 Impact Factor
  • Schizophrenia Research - SCHIZOPHR RES. 01/2008; 102(1):79-79.
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    ABSTRACT: Previous studies on a possible association between CCK-AR polymorphisms and schizophrenia have been controversial. The aim of the present study was to assess a potential association between schizophrenic patients with auditory hallucinations and polymorphisms of the CCK-AR gene. A set of single nucleotide polymorphisms mainly located in the regulatory region of the CCK-AR gene was analysed in a sample of 163 Diagnostic and statistical manual of mental disorders-IV-diagnosed schizophrenic patients and 162 healthy controls. Significant differences in the genotype (P=0.011) and allele (P=0.0009) frequencies of the +121C/G SNP (located in the 5' regulatory region) were found between patients and controls. The excess of the C allele in the patient group remained significant after Bonferroni correction (P=0.03). However, functional in vitro assays, did not reveal significant differences on gene expression between +121G and +121C alleles of this SNP. Further investigations revealed two risk haplotypes: +121C/+978A/+984T (P=0.01) and +121C/+978T/+984C (P=0.0091) as well as a protective haplotype: +121G/+978T/+984T (P=0.0001). Our data support a possible role of the CCK-AR gene in the vulnerability to schizophrenia in patients with auditory hallucinations, and suggest remarkable allele heterogeneity.
    Psychiatric Genetics 05/2007; 17(2):47-53. · 2.37 Impact Factor
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    ABSTRACT: The greatest extent of genetic variation and outcrossing for Lycopersicon pimpinellifolium occurs in northern Peru. This is also the area most affected by EI Niño Southern Oscillation (ENSO). Using morphological and the molecular markers SSRs and AFLPs, we studied the genetic structure of L. pimpinellifolium populations collected after the ENSO event of 1997–1998. This was the most intense in the last century and caused a vast increase in the size of L. pimpinellifolium populations. Populations in the area surveyed were not regionally differentiated. We did not find any cline or eco-geographic association for genetic diversity, and positive correlations between genetic and geographic distances were found only at very short distances. Flooding and water streams caused by ENSO might have facilitated a periodical seed migration from distant areas. Gene flow between populations could then occur, facilitated by the increase in the population sizes of plants and pollinators and by the high levels of stigmatic exsertion. Results revealed a significant lack of heterozygotes in comparison with those expected in a panmictic population without consanguinity. A high degree of endogamy was found in all populations. In this context, endogamy can be explained by the occurrence of crosses between relatives rather than by autogamy. In an area intensely disturbed by ENSO, we found a population that had not been reported by earlier collectors in this region. This yellow-fruited population remained morphologically and molecularly differentiated from all L. pimpinellifolium and L. esculentum populations analyzed.
    Genetic Resources and Crop Evolution 01/2007; 54(2):359-377. · 1.59 Impact Factor
  • Schizophrenia Research 07/2006; 84(2-3):427-9. · 4.59 Impact Factor
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    ABSTRACT: A mutation in the FOXP2 gene has been the first genetic association with a language disorder. Language disorder is considered as a core symptom of schizophrenia. Therefore, the FOXP2 gene could be considered a good candidate gene for the vulnerability to schizophrenia. A set of single nucleotide polymorphisms mainly located in the 5' regulatory region of the FOXP2 gene was analysed in a sample of 186 DSM-IV schizophrenic patients with auditory hallucinations and in 160 healthy controls. Statistically significant differences in the genotype (P=0.007) and allele frequencies (P=0.0027) between schizophrenic patients with auditory hallucinations and controls were found in the single nucleotide polymorphism rs2396753. These P values changed to 0.07 and 0.0273, respectively, after Bonferroni sequential correction. The haplotype rs7803667T/rs10447760C/rs923875A/rs1358278A/rs2396753A (TCAAA) also showed a significant difference confirmed with a permutation test (P=0.009). These results suggested that the FOXP2 gene may confer vulnerability to schizophrenic patients with auditory hallucinations.
    Psychiatric Genetics 05/2006; 16(2):67-72. · 2.37 Impact Factor

Publication Stats

1k Citations
317.22 Total Impact Points


  • 1982–2012
    • University of Valencia
      • Departamento de Genética
      Valenza, Valencia, Spain
  • 2004–2008
    • Hospital Clínico, Maracaibo
      Maracaibo, Estado Zulia, Venezuela
  • 2007
    • Polytechnical University of Valencia
      • Institute for the Preservation and Improvement of Valencian Agro-diversity (COMAV)
      Valencia, Valencia, Spain
  • 2000
    • Universidad de La Laguna
      San Cristóbal de La Laguna, Canary Islands, Spain
  • 1995
    • Imperial Valley College
      Imperial, California, United States
    • University of Vienna
      Wien, Vienna, Austria
  • 1984
    • University of Barcelona
      • Department of Genetics
      Barcelona, Catalonia, Spain