Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, ther... more Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–...
Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypoma... more Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.
Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological trait... more Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877,P = 6.76E–10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of ...
... NeuroReport 13:13, 1603-1606. 2. Rico Buchli, Assane Ndoye, John G. Rodriguez, Shaheen Zia, R... more ... NeuroReport 13:13, 1603-1606. 2. Rico Buchli, Assane Ndoye, John G. Rodriguez, Shaheen Zia, Robert J. Webber, Sergei A. Grando. ... 6. J. CHRISTIAN GILLIN, JOHN R. KELSOE, CHARLES A. KAUFMAN, JOEL E. KLEINMAN, S. CRAIG RISCH, DAVID S. JANOWSKY. ...
Background Delusions, false beliefs held in the face of disconfirming evidence, are a prevalent a... more Background Delusions, false beliefs held in the face of disconfirming evidence, are a prevalent and highly distressing feature of psychotic disorders. The neurobiology of delusions remains unknown but recent evidence suggests a role for abnormal prediction error neural signaling. Prediction error is neurocognitive process in which the brain signals the need to update beliefs when presented with information that disconfirms expectations. Task based neuroimaging studies have identified delusional beliefs correlate with altered activation in frontal and subcortical brain regions during prediction error, though such work is limited in scope. In a large sample of transdiagnostic psychotic patients we modeled the resting state effective connectivity of the delusion-associated predication error (D-PE) circuit. Methods Resting state fMRI was obtained from 289 psychotic subjects (schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features) and 219 healthy controls, recr...
Background Psychiatry aspires to disease understanding and precision medicine. Biological researc... more Background Psychiatry aspires to disease understanding and precision medicine. Biological research supporting such missions in psychosis may be compromised by continued reliance on clinical phenomenology in the search for pathophysiological mechanisms. A transdiagnostic deep phenotyping approach, such as that used by the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP), offers a promising strategy for discovery of biological mechanisms underlying psychosis syndromes. The B-SNIP consortium has identified biological subtypes of psychosis, Biotypes, which outperform conventional DSM diagnoses when accounting for variance of multiple external validating measures. While these biological distinctions are scientifically remarkable, their resulting clinical manifestations and potential utility in clinical practice is of paramount importance. Methods Approximately 1500 psychosis cases and 450 healthy persons were administered the B-SNIP biomarker battery (including MRI, EEG...
Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, ther... more Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–...
Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypoma... more Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.
Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological trait... more Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877,P = 6.76E–10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of ...
... NeuroReport 13:13, 1603-1606. 2. Rico Buchli, Assane Ndoye, John G. Rodriguez, Shaheen Zia, R... more ... NeuroReport 13:13, 1603-1606. 2. Rico Buchli, Assane Ndoye, John G. Rodriguez, Shaheen Zia, Robert J. Webber, Sergei A. Grando. ... 6. J. CHRISTIAN GILLIN, JOHN R. KELSOE, CHARLES A. KAUFMAN, JOEL E. KLEINMAN, S. CRAIG RISCH, DAVID S. JANOWSKY. ...
Background Delusions, false beliefs held in the face of disconfirming evidence, are a prevalent a... more Background Delusions, false beliefs held in the face of disconfirming evidence, are a prevalent and highly distressing feature of psychotic disorders. The neurobiology of delusions remains unknown but recent evidence suggests a role for abnormal prediction error neural signaling. Prediction error is neurocognitive process in which the brain signals the need to update beliefs when presented with information that disconfirms expectations. Task based neuroimaging studies have identified delusional beliefs correlate with altered activation in frontal and subcortical brain regions during prediction error, though such work is limited in scope. In a large sample of transdiagnostic psychotic patients we modeled the resting state effective connectivity of the delusion-associated predication error (D-PE) circuit. Methods Resting state fMRI was obtained from 289 psychotic subjects (schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features) and 219 healthy controls, recr...
Background Psychiatry aspires to disease understanding and precision medicine. Biological researc... more Background Psychiatry aspires to disease understanding and precision medicine. Biological research supporting such missions in psychosis may be compromised by continued reliance on clinical phenomenology in the search for pathophysiological mechanisms. A transdiagnostic deep phenotyping approach, such as that used by the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP), offers a promising strategy for discovery of biological mechanisms underlying psychosis syndromes. The B-SNIP consortium has identified biological subtypes of psychosis, Biotypes, which outperform conventional DSM diagnoses when accounting for variance of multiple external validating measures. While these biological distinctions are scientifically remarkable, their resulting clinical manifestations and potential utility in clinical practice is of paramount importance. Methods Approximately 1500 psychosis cases and 450 healthy persons were administered the B-SNIP biomarker battery (including MRI, EEG...
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