- Email: [email protected]
555. Gene Expression Differences Associated with Major Psychiatric Disorders in the Human Prefrontal Cortex and Hippocampus
Biological Psychiatry
Friday Abstracts
1
National Institute of Mental Health, 2National Institute of Dental and Craniofacial Research
Background: McCune-Albright syndrome (MAS) is a rare genetic condition arising from a somatic activating mutation of GNAS, which leads to overproduction of cAMP. The mutation can involve any or all embryological layers leading to a wide variety of clinical manifestations such as fibrous dysplasia and café-au-lait spots (often lateralized), as well as endocrinopathies. This study describes psychiatric and neuropsychological findings among youth with MAS, which may be associated with neurobiological mechanisms underlying MAS pathophysiology. Methods: This is a cross-sectional study of patients with MAS ages 8 to 25 who are enrolled in a natural history study. Eighteen underwent a structured psychiatric interview; a subset (N511) underwent neuropsychological evaluation. Results: Mean age of the subjects was 15.7 years and 55.6% were female. Eleven of eighteen subjects (61.1%) met criteria for a current psychiatric disorder: anxiety (38.9%), mood (22.2%), and psychotic disorders (16.7%). Thirteen of eighteen (72.2%) met criteria for a lifetime psychiatric disorder: anxiety (55.6%), mood (33.3%), and psychotic disorders (16.7%). While the mean full-scale IQ score (104.9; SD515.1) was within the average range, the magnitude of discrepancy between verbal and nonverbal intelligence was markedly elevated: 38.7% higher than in the general population. Conclusions: The rate of psychopathology in this cohort of youth with MAS is remarkably high compared with the general population. In addition, neuropsychological findings suggest possible lateralization of brain involvement. Our findings lend support to the further study of neurobiological mechanisms in specific brain regions/circuits expressing the GNAS mutation that may underlie the development of psychiatric and cognitive abnormalities. Supported By: NIMH Intramural Research Program, Office of the Clinical Director Keywords: Genetics, Rare Disorders, Neurobiology, Phenotyping, Youth
554. Application of Growth Mixture Modeling in Antidepressant Treatment Response Studies Ming Lin2, Vaibhav Narayan1, Wayne C. Drevets1, Jieping Ye2, and Qingqin Li1 Janssen Research & Development, LLC, 2University of Michigan
1
Background: There is heterogeneity in the therapeutic response to antidepressant among major depressive disorder (MDD) patients. Methods: We investigated studies without and with placebo arm in their response trajectories by applying growth mixture modeling (GMM) to the clinical datasets from the STAR*D study and a Janssen clinical trial. The best growth mixture model was compared to a latent class model based on baseline DSM-IV depression symptom and selected IDS items alone. Both models were characterized by their treatment response outcome and other clinical characteristics. Furthermore, genetic predictors were used to predict the class membership as compared to shared controls.
S224
Results: In each of the active treatment arms the best growth mixture model is a three class mixture model representing a non-response group (class 1), a responder group with moderate baseline severity (class 2), and a responder group with severe baseline symptom severity (class 3). Class 1 group had high suicidality (68% vs. 42%) and more comorbid anxiety disorder especially PTSD compared to class 2. The GMM identified classes of different characteristics than the classes identified in the latent class analysis (LCA). The three response trajectories identified by GMM were also observed in an independent Janssen clinical study although the proportion of three classes differed. Despite the small sample size from STAR*D genetic subsamples, the preliminary genetic association with the GMM and LCA posterior class membership vs. shared healthy controls identified potential loci of interest. Conclusions: The growth mixture model from two independent clinical datasets identified classes of similar response trajectory. Keywords: Major Depression
555. Gene Expression Differences Associated with Major Psychiatric Disorders in the Human Prefrontal Cortex and Hippocampus Derrek Hibar1, Andrew Jaffe2, Joo Heon Shin2, BrainSeq Consortium2, Thomas Hyde2, Joel Kleinman2, Daniel Weinberger2, Wayne Drevets1, Ziad Saad1, Maura Furey1, and Hartmuth Kolb1 Janssen Research & Development, LLC, 2Lieber Institute for Brain Development 1
Background: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are serious psychiatric illnesses with largely uncharacterized pathophysiology. Gene expression characterization in tissue from disease-relevant regions like dorsolateral prefrontal cortex (DLPFC) and hippocampus can improve our understanding of each disease. Methods: We use RNA-seq to perform four experiments looking at differential gene expression in human DLPFC: MDD patients (n5146) and controls (n5224), BD patients (n569) and controls (n5224), and two experiments in SCZ patients (n5181; n5163) and controls (n5224; n5236). In a fifth, we examined SCZ patients (n5133) and controls (n5248) in hippocampus. Experiments were adjusted for age, sex, postmortem interval, ancestry, RIN, mitochondrial mapping rate, and latent variation with surrogate variable analysis. Results: We found significant evidence (false discovery rate of q,0.05) for 133 differentially expressed genes (DEG) MDD patients, 87 DEG in BD patients, 128 DEG in SCZ patients in the hippocampus, 47 DEG in SCZ patients in the first experiment in the DLPFC and 13 DEG in the second. Several genes were significant across disorders: LIF is upregulated in MDD, BD and SCZ and IL1RL1 is upregulated in BD and SCZ. Conclusions: LIF, a member of the IL6 cytokine family, interacts with gp130 as well as stimulates ACTH secretion and is differentially expressed (DE) in MDD, BD, and SCZ, potentially a generalized marker of psychiatric illness. IL1RL1 encodes a receptor for IL33 and is DE in BD and SCZ
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
Biological Psychiatry
Friday Abstracts
suggesting a role in disorders with psychotic features. Our findings provide novel insights into the pathophysiology of MDD, BD, and SCZ. Keywords: RNA-seq, Major Depressive Disorder (MDD), Schizophrenia, Bipolar Disorder, cross-disorder
556. Adiponectin Gene Polymorphism and Seasonality in the Old Order Amish 1
2
3
Uttam Raheja , Naila N. Karim , Kathleen A. Ryan , Gagan V. Nijjar4, Alan R. Shuldiner3, Braxton D. Mitchell3, and Teodor T. Postolache2 1
Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine; Emory University School of Medicine, 2Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, 3Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, 4Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine; Department of Psychiatry, Kaiser Permanente Santa Rosa Medical Center Background: Seasonal changes in mammals are considered adaptive physiological capabilities to use temporal cues (e.g. photoperiod) to anticipate rather than purely react to seasonal harsh thermoregulatory demands combined with scarce food availability. We have recently reported that levels of adiponectin – an adipocytokine with antiinflammatory activity, levels of which are found to be decreased in obesity, diabetes, and hypertension as well as in depression – are lower in Amish individuals with seasonal affective disorder (SAD) than in those without SAD. As a SNP of the adiponectin gene has been previously linked with adiponectin levels, we examined the relationship between the adiponectin SNP rs2241766 and mood seasonality. We also analyzed associations of seasonality with SNPs previously associated with SAD, obesity, BMI, and metabolic syndrome. Methods: We studied 863 participants (418 men and 445 women, age 5 56.0 6 15.3 years) from the Amish Complex Genetic Disease Research Program with both global seasonality scores (GSS), calculated from the Seasonality Pattern Assessment Questionnaires) and 1,000 genome imputation genotype data. TA mixed models were employed to test GSS- "metabolic" SNPs associations. Results: Following adjustment for age, sex, and BMI, rs2241766 was associated with GSS(β50.77, SE50.30, p50.01). The association of neither rs2241766 nor any other candidate SNP with GSS withstood adjustment for multiple comparisons. Conclusions: Our findings did not support the hypothesized associations between "metabolic" SNPs and GSS. Longitudinal and interventional approaches will be further used to investigate the adiponectin-seasonality link. In the long run this may lead to flattening fall/winter increases in food craving, intake, and BMI. Supported By: 1K18MH093940-01. The study was also funded in part by the Mid-Atlantic Nutrition Obesity Research Center Pilot NORC grant P30 DK072488 from NIDDK, NIH Keywords: adiponectin, gene polymorphisms, seasonality, seasonal affective disorder, Amish
557. Pharmacogenetic Association of Lithium Treatment Response with Bcl2 Polymorphism in Bipolar Disorder Ravi Nadella1, Pradip Paul1, Vaisnvy Kapur1, Lakshmi Narayanan Kota1, Gayatri Saraf1, Biju Viswanath1, Meera Purushottam1, Alessio Squassina2, Maria Del Zompo2, and Sanjeev Jain1 1
National Institute of Mental Health and Neurosciences, Bangalore, India, 2University of Cagliari, Sardinia, Italy
Background: Lithium is first line drug for treatment of Bipolar Disorder (BD), however it mechanism is still not known.Bcl2 an anti apoptotic protein whose gene maps to 18q21.3. Linkage studies have suggested that 18q21-22 locus harbours risk genes for BD(McMahon et al., 2001;)Recent studies showed suggestive role of Bcl2 in pathophysiology of BD(Chen et al. 2015; Soeiro-deSouza et al. 2013;). The current study is to see association of Bcl2 rs956572 polymorphism with lithium treatment response in BD Methods: BD subjects (N5226) using DSMIV criteria were recruited from the outpatient service of NIMHANS. Treatment response was assessed using “Retrospective criteria of long term treatment response in research subjects with bipolar disorder” for whom NIMH life charts were available (n5187). DNA was isolated from peripheral blood and genotyping of Bcl2 rs956572 was carried out using RFLP (n5163). Results: Mean age at onset for BD (N 5 226) was 21.1 6 6.2 years. Subjects treated with lithium (n5187) were categorised as excellent responders (53.7%, score $ 7), partial responders (24.6%, score 4-6) and non-responders (17.6%, score #3). No statistical difference was noted among the clinical variables between different lithium response groups. The genotype frequencies in the study group followed the Hardy Weinberg equilibrium. There was no association of this SNP with clinical parameters like age of onset and response to lithium treatment (χ253.81 and p50.14) Conclusions: No association is found with Bcl2 polymorphism and lithium response Keywords: Bipolar Disorder, bcl2, lithium response
558. Association of CRHR1 TAT Haplotype with Cognitive Features of Major Depressive Disorder Elena Davis, Jennifer Keller, Joachim Hallmayer, Heather Ryan, Greer Murphy, Ian Gotlib, and Alan Schatzberg Stanford University Background: Corticotropin-releasing-hormone (CRH) signaling through CRH receptor 1 has been shown to contribute to morphological changes in the hippocampus and alterations in learning and memory function. A haplotype of alleles T-A-T in a set of common polymorphisms in the gene encoding for CRH receptor 1 (CRHR1) has been associated with depression vulnerability, elevated cortisol, and alterations in cognitive functioning. The present study investigated the relationship between the TAT haplotype and specific symptoms of depression, self-reported ruminative behaviors, and neuropsychological performance on a learning and memory task.
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
S225
Friday Abstracts
1
National Institute of Mental Health, 2National Institute of Dental and Craniofacial Research
Background: McCune-Albright syndrome (MAS) is a rare genetic condition arising from a somatic activating mutation of GNAS, which leads to overproduction of cAMP. The mutation can involve any or all embryological layers leading to a wide variety of clinical manifestations such as fibrous dysplasia and café-au-lait spots (often lateralized), as well as endocrinopathies. This study describes psychiatric and neuropsychological findings among youth with MAS, which may be associated with neurobiological mechanisms underlying MAS pathophysiology. Methods: This is a cross-sectional study of patients with MAS ages 8 to 25 who are enrolled in a natural history study. Eighteen underwent a structured psychiatric interview; a subset (N511) underwent neuropsychological evaluation. Results: Mean age of the subjects was 15.7 years and 55.6% were female. Eleven of eighteen subjects (61.1%) met criteria for a current psychiatric disorder: anxiety (38.9%), mood (22.2%), and psychotic disorders (16.7%). Thirteen of eighteen (72.2%) met criteria for a lifetime psychiatric disorder: anxiety (55.6%), mood (33.3%), and psychotic disorders (16.7%). While the mean full-scale IQ score (104.9; SD515.1) was within the average range, the magnitude of discrepancy between verbal and nonverbal intelligence was markedly elevated: 38.7% higher than in the general population. Conclusions: The rate of psychopathology in this cohort of youth with MAS is remarkably high compared with the general population. In addition, neuropsychological findings suggest possible lateralization of brain involvement. Our findings lend support to the further study of neurobiological mechanisms in specific brain regions/circuits expressing the GNAS mutation that may underlie the development of psychiatric and cognitive abnormalities. Supported By: NIMH Intramural Research Program, Office of the Clinical Director Keywords: Genetics, Rare Disorders, Neurobiology, Phenotyping, Youth
554. Application of Growth Mixture Modeling in Antidepressant Treatment Response Studies Ming Lin2, Vaibhav Narayan1, Wayne C. Drevets1, Jieping Ye2, and Qingqin Li1 Janssen Research & Development, LLC, 2University of Michigan
1
Background: There is heterogeneity in the therapeutic response to antidepressant among major depressive disorder (MDD) patients. Methods: We investigated studies without and with placebo arm in their response trajectories by applying growth mixture modeling (GMM) to the clinical datasets from the STAR*D study and a Janssen clinical trial. The best growth mixture model was compared to a latent class model based on baseline DSM-IV depression symptom and selected IDS items alone. Both models were characterized by their treatment response outcome and other clinical characteristics. Furthermore, genetic predictors were used to predict the class membership as compared to shared controls.
S224
Results: In each of the active treatment arms the best growth mixture model is a three class mixture model representing a non-response group (class 1), a responder group with moderate baseline severity (class 2), and a responder group with severe baseline symptom severity (class 3). Class 1 group had high suicidality (68% vs. 42%) and more comorbid anxiety disorder especially PTSD compared to class 2. The GMM identified classes of different characteristics than the classes identified in the latent class analysis (LCA). The three response trajectories identified by GMM were also observed in an independent Janssen clinical study although the proportion of three classes differed. Despite the small sample size from STAR*D genetic subsamples, the preliminary genetic association with the GMM and LCA posterior class membership vs. shared healthy controls identified potential loci of interest. Conclusions: The growth mixture model from two independent clinical datasets identified classes of similar response trajectory. Keywords: Major Depression
555. Gene Expression Differences Associated with Major Psychiatric Disorders in the Human Prefrontal Cortex and Hippocampus Derrek Hibar1, Andrew Jaffe2, Joo Heon Shin2, BrainSeq Consortium2, Thomas Hyde2, Joel Kleinman2, Daniel Weinberger2, Wayne Drevets1, Ziad Saad1, Maura Furey1, and Hartmuth Kolb1 Janssen Research & Development, LLC, 2Lieber Institute for Brain Development 1
Background: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are serious psychiatric illnesses with largely uncharacterized pathophysiology. Gene expression characterization in tissue from disease-relevant regions like dorsolateral prefrontal cortex (DLPFC) and hippocampus can improve our understanding of each disease. Methods: We use RNA-seq to perform four experiments looking at differential gene expression in human DLPFC: MDD patients (n5146) and controls (n5224), BD patients (n569) and controls (n5224), and two experiments in SCZ patients (n5181; n5163) and controls (n5224; n5236). In a fifth, we examined SCZ patients (n5133) and controls (n5248) in hippocampus. Experiments were adjusted for age, sex, postmortem interval, ancestry, RIN, mitochondrial mapping rate, and latent variation with surrogate variable analysis. Results: We found significant evidence (false discovery rate of q,0.05) for 133 differentially expressed genes (DEG) MDD patients, 87 DEG in BD patients, 128 DEG in SCZ patients in the hippocampus, 47 DEG in SCZ patients in the first experiment in the DLPFC and 13 DEG in the second. Several genes were significant across disorders: LIF is upregulated in MDD, BD and SCZ and IL1RL1 is upregulated in BD and SCZ. Conclusions: LIF, a member of the IL6 cytokine family, interacts with gp130 as well as stimulates ACTH secretion and is differentially expressed (DE) in MDD, BD, and SCZ, potentially a generalized marker of psychiatric illness. IL1RL1 encodes a receptor for IL33 and is DE in BD and SCZ
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
Biological Psychiatry
Friday Abstracts
suggesting a role in disorders with psychotic features. Our findings provide novel insights into the pathophysiology of MDD, BD, and SCZ. Keywords: RNA-seq, Major Depressive Disorder (MDD), Schizophrenia, Bipolar Disorder, cross-disorder
556. Adiponectin Gene Polymorphism and Seasonality in the Old Order Amish 1
2
3
Uttam Raheja , Naila N. Karim , Kathleen A. Ryan , Gagan V. Nijjar4, Alan R. Shuldiner3, Braxton D. Mitchell3, and Teodor T. Postolache2 1
Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine; Emory University School of Medicine, 2Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, 3Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, 4Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine; Department of Psychiatry, Kaiser Permanente Santa Rosa Medical Center Background: Seasonal changes in mammals are considered adaptive physiological capabilities to use temporal cues (e.g. photoperiod) to anticipate rather than purely react to seasonal harsh thermoregulatory demands combined with scarce food availability. We have recently reported that levels of adiponectin – an adipocytokine with antiinflammatory activity, levels of which are found to be decreased in obesity, diabetes, and hypertension as well as in depression – are lower in Amish individuals with seasonal affective disorder (SAD) than in those without SAD. As a SNP of the adiponectin gene has been previously linked with adiponectin levels, we examined the relationship between the adiponectin SNP rs2241766 and mood seasonality. We also analyzed associations of seasonality with SNPs previously associated with SAD, obesity, BMI, and metabolic syndrome. Methods: We studied 863 participants (418 men and 445 women, age 5 56.0 6 15.3 years) from the Amish Complex Genetic Disease Research Program with both global seasonality scores (GSS), calculated from the Seasonality Pattern Assessment Questionnaires) and 1,000 genome imputation genotype data. TA mixed models were employed to test GSS- "metabolic" SNPs associations. Results: Following adjustment for age, sex, and BMI, rs2241766 was associated with GSS(β50.77, SE50.30, p50.01). The association of neither rs2241766 nor any other candidate SNP with GSS withstood adjustment for multiple comparisons. Conclusions: Our findings did not support the hypothesized associations between "metabolic" SNPs and GSS. Longitudinal and interventional approaches will be further used to investigate the adiponectin-seasonality link. In the long run this may lead to flattening fall/winter increases in food craving, intake, and BMI. Supported By: 1K18MH093940-01. The study was also funded in part by the Mid-Atlantic Nutrition Obesity Research Center Pilot NORC grant P30 DK072488 from NIDDK, NIH Keywords: adiponectin, gene polymorphisms, seasonality, seasonal affective disorder, Amish
557. Pharmacogenetic Association of Lithium Treatment Response with Bcl2 Polymorphism in Bipolar Disorder Ravi Nadella1, Pradip Paul1, Vaisnvy Kapur1, Lakshmi Narayanan Kota1, Gayatri Saraf1, Biju Viswanath1, Meera Purushottam1, Alessio Squassina2, Maria Del Zompo2, and Sanjeev Jain1 1
National Institute of Mental Health and Neurosciences, Bangalore, India, 2University of Cagliari, Sardinia, Italy
Background: Lithium is first line drug for treatment of Bipolar Disorder (BD), however it mechanism is still not known.Bcl2 an anti apoptotic protein whose gene maps to 18q21.3. Linkage studies have suggested that 18q21-22 locus harbours risk genes for BD(McMahon et al., 2001;)Recent studies showed suggestive role of Bcl2 in pathophysiology of BD(Chen et al. 2015; Soeiro-deSouza et al. 2013;). The current study is to see association of Bcl2 rs956572 polymorphism with lithium treatment response in BD Methods: BD subjects (N5226) using DSMIV criteria were recruited from the outpatient service of NIMHANS. Treatment response was assessed using “Retrospective criteria of long term treatment response in research subjects with bipolar disorder” for whom NIMH life charts were available (n5187). DNA was isolated from peripheral blood and genotyping of Bcl2 rs956572 was carried out using RFLP (n5163). Results: Mean age at onset for BD (N 5 226) was 21.1 6 6.2 years. Subjects treated with lithium (n5187) were categorised as excellent responders (53.7%, score $ 7), partial responders (24.6%, score 4-6) and non-responders (17.6%, score #3). No statistical difference was noted among the clinical variables between different lithium response groups. The genotype frequencies in the study group followed the Hardy Weinberg equilibrium. There was no association of this SNP with clinical parameters like age of onset and response to lithium treatment (χ253.81 and p50.14) Conclusions: No association is found with Bcl2 polymorphism and lithium response Keywords: Bipolar Disorder, bcl2, lithium response
558. Association of CRHR1 TAT Haplotype with Cognitive Features of Major Depressive Disorder Elena Davis, Jennifer Keller, Joachim Hallmayer, Heather Ryan, Greer Murphy, Ian Gotlib, and Alan Schatzberg Stanford University Background: Corticotropin-releasing-hormone (CRH) signaling through CRH receptor 1 has been shown to contribute to morphological changes in the hippocampus and alterations in learning and memory function. A haplotype of alleles T-A-T in a set of common polymorphisms in the gene encoding for CRH receptor 1 (CRHR1) has been associated with depression vulnerability, elevated cortisol, and alterations in cognitive functioning. The present study investigated the relationship between the TAT haplotype and specific symptoms of depression, self-reported ruminative behaviors, and neuropsychological performance on a learning and memory task.
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
S225