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EVALUATION OF GENE EXPRESSION IN EARLY SUBSTANCE ABUSE
S884 Previous studies suggest that initial sensitivity to alcohol may impact use of the substance: those with low sensitivity may drink more, potentially establishing unhealthy drinking habits that persist into adulthood. The Self-Rating of the Effects of Alcohol (SRE) scale was developed to quantify initial sensitivity to alcohol, and SRE scores have been positively associated with concurrent and later drinking behaviors. Furthermore, evidence suggests that SRE scores are influenced by familial factors, raising the possibility that genetic liability to low alcohol sensitivity may increase risk of later alcohol misuse. We sought to clarify the role of genetic factors on SRE scores in two samples of young adults. Methods: We derived SRE scores in two population-based cohort studies. ALSPAC participants were born between 1991–1992 in the southwest region of England and have been assessed at least once per year since birth. SRE scores were derived based on assessments at ages 15.5, 16.5, and 17.5. S4S participants were students at a large, public, urban university in the southeastern US, enrolled during the fall or spring of their freshman year (2011–2013), and assessed each subsequent spring. Participants were of diverse ancestry and were 18 + years of age at initial enrollment. The first available SRE score was used for subsequent analyses. Phenotypic and genotypic data meeting all quality control filters were available for a total of N= 7339 participants. We conducted Genome-Wide Association Studies (GWAS) within each sample/ancestry group, using ancestry-informative principal components, sex, and age at first available SRE assessment as covariates. Initial GWAS results were meta-analyzed in METAL. SNP-based heritabilities for each sample/ancestry group were estimated in GCTA. Additional secondary analyses were conducted in VEGAS and JEPEGMIX2. Results: A total of 15,642,250 markers were analyzed in at least one group. No individual marker met genome-wide significance criteria. The top marker, rs146298733 (p = 3.16e-07), mapped to an intron in DLGAP1, variants in which have been previously associated with psychiatric outcomes including major depression and obsessive-compulsive disorder. Meta-analysis of GCTA results indicated that SRE is modestly heritable (h2SNP = 0.19, SE = 0.10), though this was driven primarily by the ALSPAC sample, for which assessments were prospective. Pathway analyses implicated the GABAergic system and genes related to thromboxane signaling, both of which have been associated with alcoholrelated phenotypes. Discussion: We present evidence consistent with prior reports that initial sensitivity to alcohol is influenced by genetic factors. Preliminary analyses implicate systems known to influence other alcohol phenotypes and provide novel targets for future analysis. Implicated loci and aggregate genetic risk should be confirmed in independent samples. Heterogeneity across samples suggests that assessment methods are important to SRE measurement, which may have implications for genetic analyses. Further characterization of genetic influences may elucidate mechanisms underlying the pathway from initial sensitivity to alcohol problems.
Abstracts
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.186
SA115. EVALUATION OF GENE EXPRESSION IN EARLY
SUBSTANCE ABUSE n
Fernanda Talarico ,1, Marcos Santoro1, Leticia Spindola1, Vanessa Ota1, Evelin Aline Zanardo2, Leslie Domenici Kulikowski2, Renata Pellegrino3, Pedro Pan1, Ary Gadelha1, Giovanni Salum Junior4, Hakon Hakonarson5, Rodrigo Bressan1, Sintia Belangero1 1
Federal University of Sao Paulo University of Sao Paulo 3 Center for Applied Genomics, Children's Hospital of Philadelphia 4 Hospital De Clinicas De Posto Alegre 5 Children's Hospital of Philadelphia 2
Background: Psychiatric disorders cause an enormous burden of suffering, high morbidity and mortality rates. They are complex diseases characterized by alterations in multiple genes, combined with environmental factors, such as substance abuse. At the time these disorders are diagnosed, most patients need care and treatment for the rest of their lives and few remit completely. Therefore, it is very important to understand the genetic and environmental factors responsible to the transition to a disorder. Thus, longitudinal studies from childhood to adulthood may be very useful to understand the triggers before the transition to psychiatric disorders. The aim of this study is to compare gene expression profiles in a longitudinal cohort of early adolescents with and without substance abuse (alcohol, tobacco, marijuana and others). Methods: In this study, we used a subsample of a Brazilian High Risk Cohort (HRC) for Psychiatric Disorders, consisting of 110 adolescents selected from 750 individuals. To evaluate whether the participants have any disorder (such as ADHD, anxiety), interviewers applied the DAWBA (Development and Well-Being Assessment) in all participants. Their parents answered a drug abuse questionnaire. For the transcriptome, we used the HumanHT-12 v4 Expression BeadChip, comparing substance abusers (N= 98) and non-substance abusers (N= 12). Using methylumi and limma R packages we used the list of the top 100 differentially expressed genes to create a network based in co-expression genes by Cytoscape software and to identify enriched pathways (Reactome base data) and Biological Process (GO base data). Results: We found an association between substance abuse and emotional disorder (X-squared = 5.01, p= 0.025), where among 110 participants, 17 have the disorder, being 5 of them substance abusers, whereas among the remaining 93 (with no disorder), 7 were substance abusers. On the other hand, participants who have any type of hyperactivity had never used drugs. Using the most differentially expressed genes (top 100), we found a total of 18 pathways and 2 biological process significantly associated with
Abstracts
S885
substance use and psychiatric disorder. Among them, the most associated were related to immune system and rRNA processing (p-values o 0.001). Besides, within the top 15 differentially expressed genes, most of them were previously associated with mental illness, substance abuse and dependence (for example, CCR3, and CHST7). Discussion: Although, we found an association between emotional disorders and substance abuse, we cannot say whether this is a cause or consequence. The understanding of the biological alterations that trigger the psychiatric disorders and their association with substance abuse, might help to develop prevention strategies to psychiatric disorders and avoid substance abuse. Furthermore, we found no substance abusers with ADHD which may be related with their age (very young individuals). Although we have found no significant co-expression network, we identified 18 pathways as well as 2 biological processes related to immune system, rRNA processing, among others. Therefore, our results suggest that these pathways could be associated with substance abuse in adolescents. It is also worth to mention that our cohort is a very well clinically characterized and unique sample of adolescents with psychiatric disorders and healthy controls, and we are running next year the 3rd year follow up which may increase the sample size of substance abuser and individuals with psychiatric disorders.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.187
using 2-SNP models not included in the polygenic set, not in LD and under weak (β=0.09), intermediate (β=0.15) and strong (β=0.24) interaction strength and C) a combination containing both a polygenic and epistatic component. Five hundred replicates were simulated per condition. We applied C5.0 in an effort to detect these epistatic interactions. C5.0 is a non-parametric algorithm to generate decision tree-based rulesets. Because of its decision tree basis C5.0 only allows for the Boolean operator OR but does allow for non-binary predictors. Each possible combination from the top node to bottom node in the tree is a so-called ruleset and can be used as a predictor in a regression model. Results: We found C5.0 is highly capable of detecting both epistatic SNPs in 100% of the 500 simulations of the strong interaction, 99.2% of the intermediate interaction and 19.2% of the weak interaction models. For the intermediate and weak interactions C5.0 detected only one of the two epistatic SNPs in 0.8% and 41.2% of the replicates. C5.0 was immune to detecting polygenic additivity at the single SNP level. In the polygenic setting of 30% variation explained by an additive effect, C5.0 detected in 11.4% simulations at least one ruleset with no SNP being included more than 13 times Discussion: These results show that C5.0 is able to detect epistasis even in the presence of a phenotype containing strong-single loci and polygenic components. Further work includes creating an R package that embeds these different components through a penalised regression framework to combine all three types of genetic variation (single loci, polygenic components, epistatic components) to better reflect the underlying biology, and to apply this method to cognitive performance in Major Depressive Disorder.
SA116. A NOVEL APPROACH TO COMBINE GWAS, PGRS
AND GENE-GENE INTERACTIONS IN PSYCHIATRY
Disclosure: Nothing to disclose.
n,1
Joeri Meijsen , Alexandros Rammos2, Riccardo Marioni1, Kristin Nicodemus1 1 2
University of Edinburgh Trinity College Dublin
http://dx.doi.org/10.1016/j.euroneuro.2017.08.188
SA117. ATTITUDE OF INDIAN RESEARCH PARTICIPANTS
TOWARDS PRIVACY AND CONFIDENTIALITY
Background: Studies in psychiatric genetics have focused almost solely on single-loci and polygenic associations and have not included possible interactions. Nicodemus et al. (2014, JAMA Psychiatry) introduced a novel statistical model that incorporates single marker, polygenic and epistatic components to assess the association between SNPs in the ZNF804A pathway and cognitive performance in psychosis. Two-SNP interaction modelling was conducted to test for epistasis. This resulted in a regression model that contained the polygenic score and two two-SNP interaction terms, where the epistatic component explained more variation in cognition than the polygenic score. This model is still relatively simplistic in modelling the genetic architecture of complex traits; in particular, the epistatic component, as the model only allowed for pairwise interactions between SNPs. We sought to implement a more flexible specification of the epistatic component by the use of non-parametric rule sets via the algorithm C5.0. Methods: As a proof-of-principle we simulated multiple phenotypes using SNPs located on chromosome 19 explaining A) 30% polygenic variation B) 30% epistatic variation
n
Triptish Bhatia ,1, Nagendra N. Mishra2, Vishwajit L. Nimgaonkar3, Smita N. Deshpande4, Lisa S. Parker3 1
Indo-US Projects, PGIMER, Dr. R.M.L. Hospital L.S. College, Muzaffarpur B.R.A. Bihar University 3 University of Pittsburgh 4 PGIMER, Dr. R.M.L. Hospital 2
Background: The right to privacy—and the related professional duty of confidentiality—allows participants to limit others’ access to information about themselves while still benefiting from healthcare or benefiting others in research. Like the right to give informed consent, the right to privacy and the confidentiality of health information promote wellbeing and protect autonomy or self-determination. This paper reports the first empirical study in India of the beliefs and expectations of patients/participants, their relatives, and IEC members regarding privacy/confidentiality.
Abstracts
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.186
SA115. EVALUATION OF GENE EXPRESSION IN EARLY
SUBSTANCE ABUSE n
Fernanda Talarico ,1, Marcos Santoro1, Leticia Spindola1, Vanessa Ota1, Evelin Aline Zanardo2, Leslie Domenici Kulikowski2, Renata Pellegrino3, Pedro Pan1, Ary Gadelha1, Giovanni Salum Junior4, Hakon Hakonarson5, Rodrigo Bressan1, Sintia Belangero1 1
Federal University of Sao Paulo University of Sao Paulo 3 Center for Applied Genomics, Children's Hospital of Philadelphia 4 Hospital De Clinicas De Posto Alegre 5 Children's Hospital of Philadelphia 2
Background: Psychiatric disorders cause an enormous burden of suffering, high morbidity and mortality rates. They are complex diseases characterized by alterations in multiple genes, combined with environmental factors, such as substance abuse. At the time these disorders are diagnosed, most patients need care and treatment for the rest of their lives and few remit completely. Therefore, it is very important to understand the genetic and environmental factors responsible to the transition to a disorder. Thus, longitudinal studies from childhood to adulthood may be very useful to understand the triggers before the transition to psychiatric disorders. The aim of this study is to compare gene expression profiles in a longitudinal cohort of early adolescents with and without substance abuse (alcohol, tobacco, marijuana and others). Methods: In this study, we used a subsample of a Brazilian High Risk Cohort (HRC) for Psychiatric Disorders, consisting of 110 adolescents selected from 750 individuals. To evaluate whether the participants have any disorder (such as ADHD, anxiety), interviewers applied the DAWBA (Development and Well-Being Assessment) in all participants. Their parents answered a drug abuse questionnaire. For the transcriptome, we used the HumanHT-12 v4 Expression BeadChip, comparing substance abusers (N= 98) and non-substance abusers (N= 12). Using methylumi and limma R packages we used the list of the top 100 differentially expressed genes to create a network based in co-expression genes by Cytoscape software and to identify enriched pathways (Reactome base data) and Biological Process (GO base data). Results: We found an association between substance abuse and emotional disorder (X-squared = 5.01, p= 0.025), where among 110 participants, 17 have the disorder, being 5 of them substance abusers, whereas among the remaining 93 (with no disorder), 7 were substance abusers. On the other hand, participants who have any type of hyperactivity had never used drugs. Using the most differentially expressed genes (top 100), we found a total of 18 pathways and 2 biological process significantly associated with
Abstracts
S885
substance use and psychiatric disorder. Among them, the most associated were related to immune system and rRNA processing (p-values o 0.001). Besides, within the top 15 differentially expressed genes, most of them were previously associated with mental illness, substance abuse and dependence (for example, CCR3, and CHST7). Discussion: Although, we found an association between emotional disorders and substance abuse, we cannot say whether this is a cause or consequence. The understanding of the biological alterations that trigger the psychiatric disorders and their association with substance abuse, might help to develop prevention strategies to psychiatric disorders and avoid substance abuse. Furthermore, we found no substance abusers with ADHD which may be related with their age (very young individuals). Although we have found no significant co-expression network, we identified 18 pathways as well as 2 biological processes related to immune system, rRNA processing, among others. Therefore, our results suggest that these pathways could be associated with substance abuse in adolescents. It is also worth to mention that our cohort is a very well clinically characterized and unique sample of adolescents with psychiatric disorders and healthy controls, and we are running next year the 3rd year follow up which may increase the sample size of substance abuser and individuals with psychiatric disorders.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.187
using 2-SNP models not included in the polygenic set, not in LD and under weak (β=0.09), intermediate (β=0.15) and strong (β=0.24) interaction strength and C) a combination containing both a polygenic and epistatic component. Five hundred replicates were simulated per condition. We applied C5.0 in an effort to detect these epistatic interactions. C5.0 is a non-parametric algorithm to generate decision tree-based rulesets. Because of its decision tree basis C5.0 only allows for the Boolean operator OR but does allow for non-binary predictors. Each possible combination from the top node to bottom node in the tree is a so-called ruleset and can be used as a predictor in a regression model. Results: We found C5.0 is highly capable of detecting both epistatic SNPs in 100% of the 500 simulations of the strong interaction, 99.2% of the intermediate interaction and 19.2% of the weak interaction models. For the intermediate and weak interactions C5.0 detected only one of the two epistatic SNPs in 0.8% and 41.2% of the replicates. C5.0 was immune to detecting polygenic additivity at the single SNP level. In the polygenic setting of 30% variation explained by an additive effect, C5.0 detected in 11.4% simulations at least one ruleset with no SNP being included more than 13 times Discussion: These results show that C5.0 is able to detect epistasis even in the presence of a phenotype containing strong-single loci and polygenic components. Further work includes creating an R package that embeds these different components through a penalised regression framework to combine all three types of genetic variation (single loci, polygenic components, epistatic components) to better reflect the underlying biology, and to apply this method to cognitive performance in Major Depressive Disorder.
SA116. A NOVEL APPROACH TO COMBINE GWAS, PGRS
AND GENE-GENE INTERACTIONS IN PSYCHIATRY
Disclosure: Nothing to disclose.
n,1
Joeri Meijsen , Alexandros Rammos2, Riccardo Marioni1, Kristin Nicodemus1 1 2
University of Edinburgh Trinity College Dublin
http://dx.doi.org/10.1016/j.euroneuro.2017.08.188
SA117. ATTITUDE OF INDIAN RESEARCH PARTICIPANTS
TOWARDS PRIVACY AND CONFIDENTIALITY
Background: Studies in psychiatric genetics have focused almost solely on single-loci and polygenic associations and have not included possible interactions. Nicodemus et al. (2014, JAMA Psychiatry) introduced a novel statistical model that incorporates single marker, polygenic and epistatic components to assess the association between SNPs in the ZNF804A pathway and cognitive performance in psychosis. Two-SNP interaction modelling was conducted to test for epistasis. This resulted in a regression model that contained the polygenic score and two two-SNP interaction terms, where the epistatic component explained more variation in cognition than the polygenic score. This model is still relatively simplistic in modelling the genetic architecture of complex traits; in particular, the epistatic component, as the model only allowed for pairwise interactions between SNPs. We sought to implement a more flexible specification of the epistatic component by the use of non-parametric rule sets via the algorithm C5.0. Methods: As a proof-of-principle we simulated multiple phenotypes using SNPs located on chromosome 19 explaining A) 30% polygenic variation B) 30% epistatic variation
n
Triptish Bhatia ,1, Nagendra N. Mishra2, Vishwajit L. Nimgaonkar3, Smita N. Deshpande4, Lisa S. Parker3 1
Indo-US Projects, PGIMER, Dr. R.M.L. Hospital L.S. College, Muzaffarpur B.R.A. Bihar University 3 University of Pittsburgh 4 PGIMER, Dr. R.M.L. Hospital 2
Background: The right to privacy—and the related professional duty of confidentiality—allows participants to limit others’ access to information about themselves while still benefiting from healthcare or benefiting others in research. Like the right to give informed consent, the right to privacy and the confidentiality of health information promote wellbeing and protect autonomy or self-determination. This paper reports the first empirical study in India of the beliefs and expectations of patients/participants, their relatives, and IEC members regarding privacy/confidentiality.