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LEUKOCYTE TELOMERE LENGTH ANALYSIS IN CHILDREN AND ADOLESCENTS AT RISK OF DEVELOPING MENTAL DISORDERS
Abstracts
Background: ReMaFaSt study is the first Argentinean study aimed to evaluate the biochemical markers of resilience. Resilience is the capacity and dynamic process of adaptively overcoming stress and adversity while maintaining normal psychological and physical functioning. Stressful life events, trauma, and chronic adversity can have a substantial impact on brain function and structure, and can result in the development of Post-Traumatic Stress Disorder (PTSD), depression and other psychiatric disorders. However, most individuals do not develop such illnesses after experiencing stressful life events, and are thus thought to be resilient. The risk of mental illness is defined by the relationship between genetic predisposition and environmental factors after a life stress. Early stress factors are a key for “turning on” diseases. Several resilience or vulnerability (features and state) markers have been identified in patients. Often the patient´s relatives share the traumatic experience. Our patients develop depression or PTSD but often their families do not, despite enduring the same traumatic experience. So why do not relatives develop illness? The aim of the study is to look at missing markers of resilience (genetic and PINE markers) as well as lower environmental vulnerability. Methods: Adult first degree healthy relatives of patients were invited to participate in the ReMaFaSt study. All participants gave written informed consent before the procedures and the aim of the study were explained completely. A total of 25 first degree patients relatives. First degree relatives were defined as father, mother, brothers, sisters and children. Inclusion criteria: first degree relatives psychiatrically healthy, aged between 21–70 y/o have undergone the same traumatic experience as our patients with depression or PTSD (DSM V). Exclusion criteria: psychopathic features, severe organic diseases or psychiatric disease. Beck, HAM D, CAPS-5, neurocognitive testing, Trail Mb were used to evaluate the psychiatric condition of the participants. Thus, our aim was to determine genetic variants of 5-HTTLPR among other biochemical tests; metabolic testing (BMI, Glycosylated, hemoglobin, lipids profile, Waist-hip ratio), and PNIE testing –periferical- (cortisol rhythm, FUC, DHEA, Thyroid profile, NK cells, CD4/CD8 ratio). Results: The preliminary results show an increase in l/l variant of 5-HTTLPR among (at least one l allele has been found) first degree relatives of depressive and PTSD patients compared to affected patients. Immunological response, rhythm of cortisol secretion and metabolic determination trend were normal in our sample. Discussion: This is an ongoing study with a very small sample. However, the normal clinical test and the l/l genotype suggest a protective factor for PTSD and MDD.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.268
SU80. LEUKOCYTE TELOMERE LENGTH ANALYSIS IN CHILDREN AND ADOLESCENTS AT RISK OF DEVELOPING MENTAL DISORDERS
S931 n
Danilo Micali1, Gabriela Xavier ,1, Leticia Spindola1, Vanessa Ota1, Pawan Murawa1, Priscila Tampaku1, Patricia Moretti2, Pedro Pan1, Luis Rohde3, Ary Gadelha1, Diego Mazzotti4, João Sato5, Giovanni Salum Junior6, Rodrigo Bressan1, Sintia Belangero1 1
Federal University of Sao Paulo University of Brasilia 3 Federal University of Rio Grande do Sul 4 Chidren's Hospital of Philadelphia 5 Universidade Federal do ABC 6 Hospital das Clínicas de Porto Alegre 2
Background: Telomeres are DNA-protein complexes that constitutes the terminal portions of chromosomes, providing them stability and protection and go through physiological shortening along cell cycles. However, this shortening can be intensified by cytokines, stress hormones and oxidation exposition. After reaching a critical length, telomere shortening leads to senescence or apoptosis. Telomere Length (TL) is altered in cancer, diabetes, cardiovascular and autoimmune diseases. Additionally, TL has been described as related to psychiatric disorders like Major Depressive Disorders (MDD), Bipolar Disorder (BD) and Schizophrenia (SCZ). TL was found to have a dose-dependent association with stress in childhood, however it is not clear whether this shortening can be used as a diagnosis and progression biomarker. This study investigated the association between leucocyte TL and psychiatric diagnosis, psychiatric symptoms and child maltreatment and also verified association of TL with age and gender. Methods: The 559 participants of this study were a subsample of the High Risk Cohort (HRC) Study for Psychiatric Disorders in Childhood, a large prospective community school-based study in Brazil. Blood sample were collected 6 to 8 months after parent interview, in which participants were assessed using Development and Well-Being Assessment (DAWBA) to evaluate psychiatric diagnosis according to the DSM-IV. Psychopathology was assessed by the Child Behavior Checklist (CBCL). DSM-oriented scaled were used and grouped in Internalizing and Externalizing groups of symptoms. Child Maltreatment (CM) measure was based on four questions answered by parents and children about the history of physical abuse, neglect, emotional maltreatment and sexual abuse. The 394 children and adolescents with no DSM-IV disorder in DAWBA assessment composed the healthy control group. Leucocyte TL measurement was performed by quantitative qPCR. Study population description as well as CBCL and CM means between case and controls were analyzed by Student's T test. Association of TL with gender and age or psychiatric symptoms was analyzed by generalized linear model (GLzM). Results: In this study population, no association between TL and age or gender was observed. Equally, absence of distress, fear and behavior disorders showed no association with TL. The weak positive correlation (r2 =0,01) between externalizing CBCL and TL obtained was proved not significant after Bonferroni correction. And no associations between TL and CM or between CM and gender were shown. However, after sorting the cohort by gender, a negative
S932
Abstracts
correlation (p= 0,014; OR = 0,938; IC 95%= 0,891 – 0,987; r2 = 0,021) between TL and CM were observed in boys. Discussion: This was a cross sectional study which does a momentary analysis of the TL and the mental state of individuals. The number of participants and the complete psychiatric framework brings to it a strong statistical power and although there is no association between TL and age, gender, CBCL, absence of distress, fear and behavior disorders were observed, a correlation between TL and CM was found only in boys but not in girls. The high levels of estrogen in girls might act as a protective factor indirectly influencing TL in this gender. Thus, this study points out that males who experienced more early life traumas seem to have shorter TL.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.269
SU81. COMPREHENSIVE EVALUATION OF ENRICHMENT FOR CIRCADIAN CLOCK GENE SETS IN PSYCHIATRIC TRAITS: SPECIFIC ENRICHMENT IN CLINICAL RESPONSE TO LITHIUM n
Sergi Papiol ,1, Urs Heilbronner2, Liping Hou3, (ConLiGEn) The International Consortium on Lithium Genetics, Michael McCarthy4, Caroline Nievergelt4, Enda Byrne5, Francis McMahon3, Thomas Schulze1 1
Institute of Psychiatric Phenomics and Genomics, LudwigMaximilian-University of Munich 2 Institute of Psychiatric Phenomics and Genomics, Medical Center of the University of Munich 3 Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services 4 VA San Diego Healthcare System, University of California San Diego 5 Queensland Brain Institute, The University of Queensland
Background: A disrupted circadian clock has been linked to the risk of several neuropsychiatric disorders. Likewise, circadian rhythms have been suggested as mediators of the mechanism of action of lithium in bipolar disorder. Nonetheless the relationship between the ‘clock genes’ that regulate circadian rhythms and lithium treatment response is not completely understood. To our knowledge there has not been a systematic pathway / enrichment analysis of clock genes in the context of psychiatric traits, in general, and of clinical response to lithium, in particular. The objective of this study was to perform formal gene set enrichment analyses for circadian clock genes, using publicly available GWAS summary statistics from several psychiatric disorders, as well as the results from The International Consortium on Lithium Genetics (ConLiGen) GWAS (Hou et al., 2016). Methods: Based on previous literature (Pizarro et al., 2013; Chen et al., 2016) and available resources (e.g. http://circadb.hogeneschlab.org/) curated gene sets related to circadian control were generated. These sets can be
divided in three categories: clock modulator (upstream) genes, core clock genes and clock controlled (downstream) genes. GWAS summary statistics from schizophrenia, bipolar disorder, major depressive disorder, ADHD, autism, Alzheimer's disease and continuous/dichotomous lithium response were used as reference. Gene set enrichment analyses were carried out using both INRICH and MAGMA. Results: Gene set enrichment analyses using INRICH and MAGMA reported a significant enrichment of a set of 19 genes that constitute the ‘core clock’ in the dichotomous lithium response phenotype (INRICH: empirical P = 0.001; corrected P= 0.008; MAGMA: competitive P= 0.005; corrected P= 0.0336). None of the circadian gene sets showed a significant enrichment in any of the other psychiatric traits included in this study (all corrected P40.05). Discussion: Our results suggest the involvement of those genes that constitute the core clock machinery in the determination of the clinical response to lithium in bipolar disorder patients. The specificity of these results suggests that the participation of circadian rhythms is especially relevant in the modulation of lithium response rather than in the overall risk of mental illness. A better understanding of potential links between circadian mechanisms, genetic risk factors, and the lithium treatment response may open new avenues into the clinical management of bipolar disorder.
Funding: DFG Grants SCHU 1603/5-1 and SCHU 1603/7-1; Lisa-OehlerFoundation. SP was supported by a 2016 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.270
SU82. RNA SIGNATURE OF TREATMENT RESPONSE IN FIRST-EPISODE PSYCHOSIS n
Réjane Troudet ,1, Wafa Bel Haj Ali2, Caroline Barau3, Anne Boland-Auge4, Jean-François Deleuze4, Marion Leboyer5, Stéphane Jamain2, OPTiMiSE Consortium6 1
Inserm U955, Psychiatrie Translationnelle, Université Paris Est, Faculté de Médecine 2 Inserm U955, Psychiatrie Translationnelle, Université Paris Est, Faculté de Médecine, Fondation FondaMental, Créteil France 3 AP-HP, Hôpital H. Mondor – A. Chenevier, Plateforme de Ressources Biologiques, Créteil, France 4 Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France 5 Inserm U955, Psychiatrie Translationnelle, Université Paris Est, Faculté de Médecine, Fondation FondaMental, AP-HP, Hôpital H. Mondor – A. Chenevier, Pôle de Psychiatrie, Créteil, France
Background: ReMaFaSt study is the first Argentinean study aimed to evaluate the biochemical markers of resilience. Resilience is the capacity and dynamic process of adaptively overcoming stress and adversity while maintaining normal psychological and physical functioning. Stressful life events, trauma, and chronic adversity can have a substantial impact on brain function and structure, and can result in the development of Post-Traumatic Stress Disorder (PTSD), depression and other psychiatric disorders. However, most individuals do not develop such illnesses after experiencing stressful life events, and are thus thought to be resilient. The risk of mental illness is defined by the relationship between genetic predisposition and environmental factors after a life stress. Early stress factors are a key for “turning on” diseases. Several resilience or vulnerability (features and state) markers have been identified in patients. Often the patient´s relatives share the traumatic experience. Our patients develop depression or PTSD but often their families do not, despite enduring the same traumatic experience. So why do not relatives develop illness? The aim of the study is to look at missing markers of resilience (genetic and PINE markers) as well as lower environmental vulnerability. Methods: Adult first degree healthy relatives of patients were invited to participate in the ReMaFaSt study. All participants gave written informed consent before the procedures and the aim of the study were explained completely. A total of 25 first degree patients relatives. First degree relatives were defined as father, mother, brothers, sisters and children. Inclusion criteria: first degree relatives psychiatrically healthy, aged between 21–70 y/o have undergone the same traumatic experience as our patients with depression or PTSD (DSM V). Exclusion criteria: psychopathic features, severe organic diseases or psychiatric disease. Beck, HAM D, CAPS-5, neurocognitive testing, Trail Mb were used to evaluate the psychiatric condition of the participants. Thus, our aim was to determine genetic variants of 5-HTTLPR among other biochemical tests; metabolic testing (BMI, Glycosylated, hemoglobin, lipids profile, Waist-hip ratio), and PNIE testing –periferical- (cortisol rhythm, FUC, DHEA, Thyroid profile, NK cells, CD4/CD8 ratio). Results: The preliminary results show an increase in l/l variant of 5-HTTLPR among (at least one l allele has been found) first degree relatives of depressive and PTSD patients compared to affected patients. Immunological response, rhythm of cortisol secretion and metabolic determination trend were normal in our sample. Discussion: This is an ongoing study with a very small sample. However, the normal clinical test and the l/l genotype suggest a protective factor for PTSD and MDD.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.268
SU80. LEUKOCYTE TELOMERE LENGTH ANALYSIS IN CHILDREN AND ADOLESCENTS AT RISK OF DEVELOPING MENTAL DISORDERS
S931 n
Danilo Micali1, Gabriela Xavier ,1, Leticia Spindola1, Vanessa Ota1, Pawan Murawa1, Priscila Tampaku1, Patricia Moretti2, Pedro Pan1, Luis Rohde3, Ary Gadelha1, Diego Mazzotti4, João Sato5, Giovanni Salum Junior6, Rodrigo Bressan1, Sintia Belangero1 1
Federal University of Sao Paulo University of Brasilia 3 Federal University of Rio Grande do Sul 4 Chidren's Hospital of Philadelphia 5 Universidade Federal do ABC 6 Hospital das Clínicas de Porto Alegre 2
Background: Telomeres are DNA-protein complexes that constitutes the terminal portions of chromosomes, providing them stability and protection and go through physiological shortening along cell cycles. However, this shortening can be intensified by cytokines, stress hormones and oxidation exposition. After reaching a critical length, telomere shortening leads to senescence or apoptosis. Telomere Length (TL) is altered in cancer, diabetes, cardiovascular and autoimmune diseases. Additionally, TL has been described as related to psychiatric disorders like Major Depressive Disorders (MDD), Bipolar Disorder (BD) and Schizophrenia (SCZ). TL was found to have a dose-dependent association with stress in childhood, however it is not clear whether this shortening can be used as a diagnosis and progression biomarker. This study investigated the association between leucocyte TL and psychiatric diagnosis, psychiatric symptoms and child maltreatment and also verified association of TL with age and gender. Methods: The 559 participants of this study were a subsample of the High Risk Cohort (HRC) Study for Psychiatric Disorders in Childhood, a large prospective community school-based study in Brazil. Blood sample were collected 6 to 8 months after parent interview, in which participants were assessed using Development and Well-Being Assessment (DAWBA) to evaluate psychiatric diagnosis according to the DSM-IV. Psychopathology was assessed by the Child Behavior Checklist (CBCL). DSM-oriented scaled were used and grouped in Internalizing and Externalizing groups of symptoms. Child Maltreatment (CM) measure was based on four questions answered by parents and children about the history of physical abuse, neglect, emotional maltreatment and sexual abuse. The 394 children and adolescents with no DSM-IV disorder in DAWBA assessment composed the healthy control group. Leucocyte TL measurement was performed by quantitative qPCR. Study population description as well as CBCL and CM means between case and controls were analyzed by Student's T test. Association of TL with gender and age or psychiatric symptoms was analyzed by generalized linear model (GLzM). Results: In this study population, no association between TL and age or gender was observed. Equally, absence of distress, fear and behavior disorders showed no association with TL. The weak positive correlation (r2 =0,01) between externalizing CBCL and TL obtained was proved not significant after Bonferroni correction. And no associations between TL and CM or between CM and gender were shown. However, after sorting the cohort by gender, a negative
S932
Abstracts
correlation (p= 0,014; OR = 0,938; IC 95%= 0,891 – 0,987; r2 = 0,021) between TL and CM were observed in boys. Discussion: This was a cross sectional study which does a momentary analysis of the TL and the mental state of individuals. The number of participants and the complete psychiatric framework brings to it a strong statistical power and although there is no association between TL and age, gender, CBCL, absence of distress, fear and behavior disorders were observed, a correlation between TL and CM was found only in boys but not in girls. The high levels of estrogen in girls might act as a protective factor indirectly influencing TL in this gender. Thus, this study points out that males who experienced more early life traumas seem to have shorter TL.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.269
SU81. COMPREHENSIVE EVALUATION OF ENRICHMENT FOR CIRCADIAN CLOCK GENE SETS IN PSYCHIATRIC TRAITS: SPECIFIC ENRICHMENT IN CLINICAL RESPONSE TO LITHIUM n
Sergi Papiol ,1, Urs Heilbronner2, Liping Hou3, (ConLiGEn) The International Consortium on Lithium Genetics, Michael McCarthy4, Caroline Nievergelt4, Enda Byrne5, Francis McMahon3, Thomas Schulze1 1
Institute of Psychiatric Phenomics and Genomics, LudwigMaximilian-University of Munich 2 Institute of Psychiatric Phenomics and Genomics, Medical Center of the University of Munich 3 Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services 4 VA San Diego Healthcare System, University of California San Diego 5 Queensland Brain Institute, The University of Queensland
Background: A disrupted circadian clock has been linked to the risk of several neuropsychiatric disorders. Likewise, circadian rhythms have been suggested as mediators of the mechanism of action of lithium in bipolar disorder. Nonetheless the relationship between the ‘clock genes’ that regulate circadian rhythms and lithium treatment response is not completely understood. To our knowledge there has not been a systematic pathway / enrichment analysis of clock genes in the context of psychiatric traits, in general, and of clinical response to lithium, in particular. The objective of this study was to perform formal gene set enrichment analyses for circadian clock genes, using publicly available GWAS summary statistics from several psychiatric disorders, as well as the results from The International Consortium on Lithium Genetics (ConLiGen) GWAS (Hou et al., 2016). Methods: Based on previous literature (Pizarro et al., 2013; Chen et al., 2016) and available resources (e.g. http://circadb.hogeneschlab.org/) curated gene sets related to circadian control were generated. These sets can be
divided in three categories: clock modulator (upstream) genes, core clock genes and clock controlled (downstream) genes. GWAS summary statistics from schizophrenia, bipolar disorder, major depressive disorder, ADHD, autism, Alzheimer's disease and continuous/dichotomous lithium response were used as reference. Gene set enrichment analyses were carried out using both INRICH and MAGMA. Results: Gene set enrichment analyses using INRICH and MAGMA reported a significant enrichment of a set of 19 genes that constitute the ‘core clock’ in the dichotomous lithium response phenotype (INRICH: empirical P = 0.001; corrected P= 0.008; MAGMA: competitive P= 0.005; corrected P= 0.0336). None of the circadian gene sets showed a significant enrichment in any of the other psychiatric traits included in this study (all corrected P40.05). Discussion: Our results suggest the involvement of those genes that constitute the core clock machinery in the determination of the clinical response to lithium in bipolar disorder patients. The specificity of these results suggests that the participation of circadian rhythms is especially relevant in the modulation of lithium response rather than in the overall risk of mental illness. A better understanding of potential links between circadian mechanisms, genetic risk factors, and the lithium treatment response may open new avenues into the clinical management of bipolar disorder.
Funding: DFG Grants SCHU 1603/5-1 and SCHU 1603/7-1; Lisa-OehlerFoundation. SP was supported by a 2016 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.270
SU82. RNA SIGNATURE OF TREATMENT RESPONSE IN FIRST-EPISODE PSYCHOSIS n
Réjane Troudet ,1, Wafa Bel Haj Ali2, Caroline Barau3, Anne Boland-Auge4, Jean-François Deleuze4, Marion Leboyer5, Stéphane Jamain2, OPTiMiSE Consortium6 1
Inserm U955, Psychiatrie Translationnelle, Université Paris Est, Faculté de Médecine 2 Inserm U955, Psychiatrie Translationnelle, Université Paris Est, Faculté de Médecine, Fondation FondaMental, Créteil France 3 AP-HP, Hôpital H. Mondor – A. Chenevier, Plateforme de Ressources Biologiques, Créteil, France 4 Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France 5 Inserm U955, Psychiatrie Translationnelle, Université Paris Est, Faculté de Médecine, Fondation FondaMental, AP-HP, Hôpital H. Mondor – A. Chenevier, Pôle de Psychiatrie, Créteil, France