- Email: [email protected]
SIMILARITIES IN THE GENE AND PROTEIN EXPRESSION SUBSTRATES OF SCHIZOPHRENIA AND BIPOLAR DISORDER
S8
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
NON-SPECIFICITY OF RISK FACTORS FOR SCHIZOPHRENIA: POPULATION-BASED STUDIES Mark Weiser Tel-Aviv University, Tel-Aviv, Israel The question if mental disorders are separate and different disease entities, or lie on a continuum, has been debated for more than a century. This paper uses population-based epidemiological data to examine this issue using two different approaches, one based on diagnoses, the other on cognition. Diagnostic approach: We analyzed a population-based dataset to examine the relative risk of hospitalization for schizophrenia and affective disorders among siblings of patients with schizophrenia and siblings of patients with affective disorder. The siblings of 6,111 consecutively admitted patients with schizophrenia (ICD F20.0-20.9) or affective disorder (ICD F30.0-39.9) were identified from the Israeli Psychiatric Hospitalization Registry, and age and gender matched controls (n=74,988) were identified from the Israeli Population Registry. Psychiatric hospitalizations of siblings and controls were recorded from the registry. Results: Compared to controls, risk for schizophrenia was higher among persons with one or two siblings with schizophrenia (OR=7.02, 95% CI: 5.84-8.44) and persons with three or more (OR=30.14, 95% CI: 19.02-47.74) siblings with schizophrenia. In addition, risk of affective disorder was higher among participants with one or two siblings with schizophrenia (OR=7.08, 95% CI=5.54-9.06) and participants with three or more siblings with schizophrenia (OR=26.15, 95% CI=13.86-49.31). Persons with siblings with affective disorder also had a higher risk of schizophrenia (OR=3.43, 95% CI: 2.09-5.64), affective disorder (OR=6.22, 95% CI=3.72-10.41). Cognition approach: We examined a sample from a population-based cohort of 523,375, 16- to 17-year-old male adolescents who had been assessed by the Israeli Draft Board. Cognitive test scores were examined in sib-pairs discordant for nonpsychotic (n=19,489) and psychotic (n=888) disorders and compared with 224,082 individuals from sibships with no evidence of mental illness. Results: There was a gradient in cognitive performance (worst to best) from individuals currently affected by psychotic illnesses (Cohen’s d=0.82), followed by individuals currently affected by non-psychotic illness (Cohen’s d=0.58), unaffected siblings of individuals affected by psychotic illness (Cohen’s d=0.37), unaffected siblings of individuals affected by non-psychotic illness (Cohen’s d=0.27), and members of sibships with no evidence of mental illness. Unaffected siblings of both psychotic and non-psychotic individuals from multiple affected sibships (more than one affected sibling) had worse cognitive test scores compared with unaffected siblings from simplex sibships (only one affected sibling). The results from these two large population based studies support the notion that cognitive impairment and risk for schizophrenia and other psychiatric disorders is familial, increasing with the familial load of illness and cutting across diagnostic entities.
BRAIN CHANGES IN SCHIZOPHRENIA AND BIPOLAR DISORDER: IS THERE A GENETIC OVERLAP? René Kahn University Medical Center Utrecht, Utrecht, Netherlands The nosological dichotomy between schizophrenia and bipolar disorder as formulated by Kraepelin is currently questioned stimulated by the finding that schizophrenia and bipolar disorder partly share a common genetic origin. Although both disorders are characterized by changes in brain structure, family studies suggest more segregating than overlapping neuroanatomical abnormalities in both disorders. We investigated whether patients with schizophrenia and bipolar disorder display overlapping abnormalities in brain volumes and cortical thickness, and whether these are caused by shared genetic or environmental influences. Magnetic resonance imaging brain scans were made of monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia, concordant and discordant for bipolar disorder, and healthy comparison twin pairs were compared using structural equation modeling. A total of 310 individuals from 158 (152 complete/6 incomplete) twin pairs were included: 26 pairs discordant for schizophrenia (13 MZ, 13 DZ), 49 pairs with bipolar disorder (9MZ, 4 DZ concordant; 14 MZ, 22 DZ discordant), and 83 (44 MZ, 39 DZ) healthy twin pairs. Estimates of additive genetic and common and unique environmental
contributions for schizophrenia and bipolar disorder to overlapping and non-overlapping volumes and cortical thickness. Higher genetic liabilities for both schizophrenia and bipolar disorder were associated with lower white matter volume, thinner left and right parahippocampi, and right orbitofrontal cortex; and thicker left temporoparietal, and left superior motor cortices. Brain structures reflect both overlapping and segregating genetic liabilities for schizophrenia and bipolar disorder. The overlapping smaller white matter volume and common areas of thinner cortex suggest that both disorders share genetic (neurodevelopmental) roots.
SIMILARITIES IN THE GENE AND PROTEIN EXPRESSION SUBSTRATES OF SCHIZOPHRENIA AND BIPOLAR DISORDER Vahram Haroutunian The Mount Sinai School of Medicine, New York, NY, USA The explosion of gene and protein expression studies of the past decade and half has suggested many commonalities in the neurobiological substrates of schizophrenia. The genes and proteins involved have included, but have not been limited to, those associated with the cell cycle program, myelination, and the nodes of Ranvier. Recent evidence linking ANK3 (ankyrin-G) SNPs to bipolar disorder have been found to affect the expression of node of Ranvier genes and proteins in schizophrenia. Some evidence, for example from studies of suicide, suggests that the potentially epigenetic alterations in the serotonin 2C receptor occur in suicide completers, irrespective of the underlying or associated schizophrenia or bipolar disorder. Even neuroanatomical studies based on cell shape and number, have suggested that abnormalities may cut across diagnostic categories and be associated with psychotic symptoms as opposed to a specific axis one diagnosis. It may be argued that the neurobiological commonalities that will be discussed in gene and protein expression between different serious mental illnesses are mere artifacts of postmortem changes, the exposure of study subjects to common medications and/or social and environmental influences. Several lines of evidence dispute these latter possibilities. In addition to the genetic susceptibility loci that are independent of postmortem or environmental factors, direct studies of the brain show that these same commonalities are not evident in cohorts that share many features of the potentially artifactual influences. For example, comparison of postmortem specimens from elderly schizophrenics and age-matched dementia sufferers reveals common changes in genes associated with autophagy, but not with myelination, neurotransmission, neurotrophism, saltatory conduction or synapse maintenance. Further support for common neurobiological substrates of schizophrenia and bipolar disorder comes from recent weighted gene coexpression network analyses (WGCNA). Schizophrenia-related transcriptome alterations converge with GWAS that show a myelin-associated module is significantly enriched with genes related to schizophrenia AND bipolar disorder in GWAS studies but not with genes associated with other neuropsychiatric disorders. Other modules that are differentially expressed in schizophrenia relative to unaffected controls (e.g., microglia/immune response and mitochondria) show no evidence for pronounced genetic enrichment and may represent either secondary phenomena or be attributable to environmental or other factors. Mounting evidence suggests that conceptualizing the neurobiology of psychiatric disorders along parameters of symptom dimensions, such as psychosis or suicidality may be more closely aligned with neurobiology, than the partitions dictated by traditional nosology. Consideration of symptom-based neurobiological substrates may reveal novel therapeutic targets and treatments that cut across the boundaries that currently define neuropsychiatric disease and constrain clinical, neuropsychological and pharmacological research.
SCHIZOPHRENIA AND BIPOLAR DISORDER GENETICS: OVERLAPPING AND DISTINGUISHING FEATURES Michael O’Donovan Cardiff University, Cardiff, Wales, United Kingdom Recent genome wide studies have identified multiple risk alleles for schizophrenia and/or bipolar disorder. These can be divided into those that are common and are associated with small effects (e.g. the expanded MHC complex, TCF4, ZNF804A, mir137 locus, CACNA1C) and those that are rare
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
NON-SPECIFICITY OF RISK FACTORS FOR SCHIZOPHRENIA: POPULATION-BASED STUDIES Mark Weiser Tel-Aviv University, Tel-Aviv, Israel The question if mental disorders are separate and different disease entities, or lie on a continuum, has been debated for more than a century. This paper uses population-based epidemiological data to examine this issue using two different approaches, one based on diagnoses, the other on cognition. Diagnostic approach: We analyzed a population-based dataset to examine the relative risk of hospitalization for schizophrenia and affective disorders among siblings of patients with schizophrenia and siblings of patients with affective disorder. The siblings of 6,111 consecutively admitted patients with schizophrenia (ICD F20.0-20.9) or affective disorder (ICD F30.0-39.9) were identified from the Israeli Psychiatric Hospitalization Registry, and age and gender matched controls (n=74,988) were identified from the Israeli Population Registry. Psychiatric hospitalizations of siblings and controls were recorded from the registry. Results: Compared to controls, risk for schizophrenia was higher among persons with one or two siblings with schizophrenia (OR=7.02, 95% CI: 5.84-8.44) and persons with three or more (OR=30.14, 95% CI: 19.02-47.74) siblings with schizophrenia. In addition, risk of affective disorder was higher among participants with one or two siblings with schizophrenia (OR=7.08, 95% CI=5.54-9.06) and participants with three or more siblings with schizophrenia (OR=26.15, 95% CI=13.86-49.31). Persons with siblings with affective disorder also had a higher risk of schizophrenia (OR=3.43, 95% CI: 2.09-5.64), affective disorder (OR=6.22, 95% CI=3.72-10.41). Cognition approach: We examined a sample from a population-based cohort of 523,375, 16- to 17-year-old male adolescents who had been assessed by the Israeli Draft Board. Cognitive test scores were examined in sib-pairs discordant for nonpsychotic (n=19,489) and psychotic (n=888) disorders and compared with 224,082 individuals from sibships with no evidence of mental illness. Results: There was a gradient in cognitive performance (worst to best) from individuals currently affected by psychotic illnesses (Cohen’s d=0.82), followed by individuals currently affected by non-psychotic illness (Cohen’s d=0.58), unaffected siblings of individuals affected by psychotic illness (Cohen’s d=0.37), unaffected siblings of individuals affected by non-psychotic illness (Cohen’s d=0.27), and members of sibships with no evidence of mental illness. Unaffected siblings of both psychotic and non-psychotic individuals from multiple affected sibships (more than one affected sibling) had worse cognitive test scores compared with unaffected siblings from simplex sibships (only one affected sibling). The results from these two large population based studies support the notion that cognitive impairment and risk for schizophrenia and other psychiatric disorders is familial, increasing with the familial load of illness and cutting across diagnostic entities.
BRAIN CHANGES IN SCHIZOPHRENIA AND BIPOLAR DISORDER: IS THERE A GENETIC OVERLAP? René Kahn University Medical Center Utrecht, Utrecht, Netherlands The nosological dichotomy between schizophrenia and bipolar disorder as formulated by Kraepelin is currently questioned stimulated by the finding that schizophrenia and bipolar disorder partly share a common genetic origin. Although both disorders are characterized by changes in brain structure, family studies suggest more segregating than overlapping neuroanatomical abnormalities in both disorders. We investigated whether patients with schizophrenia and bipolar disorder display overlapping abnormalities in brain volumes and cortical thickness, and whether these are caused by shared genetic or environmental influences. Magnetic resonance imaging brain scans were made of monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia, concordant and discordant for bipolar disorder, and healthy comparison twin pairs were compared using structural equation modeling. A total of 310 individuals from 158 (152 complete/6 incomplete) twin pairs were included: 26 pairs discordant for schizophrenia (13 MZ, 13 DZ), 49 pairs with bipolar disorder (9MZ, 4 DZ concordant; 14 MZ, 22 DZ discordant), and 83 (44 MZ, 39 DZ) healthy twin pairs. Estimates of additive genetic and common and unique environmental
contributions for schizophrenia and bipolar disorder to overlapping and non-overlapping volumes and cortical thickness. Higher genetic liabilities for both schizophrenia and bipolar disorder were associated with lower white matter volume, thinner left and right parahippocampi, and right orbitofrontal cortex; and thicker left temporoparietal, and left superior motor cortices. Brain structures reflect both overlapping and segregating genetic liabilities for schizophrenia and bipolar disorder. The overlapping smaller white matter volume and common areas of thinner cortex suggest that both disorders share genetic (neurodevelopmental) roots.
SIMILARITIES IN THE GENE AND PROTEIN EXPRESSION SUBSTRATES OF SCHIZOPHRENIA AND BIPOLAR DISORDER Vahram Haroutunian The Mount Sinai School of Medicine, New York, NY, USA The explosion of gene and protein expression studies of the past decade and half has suggested many commonalities in the neurobiological substrates of schizophrenia. The genes and proteins involved have included, but have not been limited to, those associated with the cell cycle program, myelination, and the nodes of Ranvier. Recent evidence linking ANK3 (ankyrin-G) SNPs to bipolar disorder have been found to affect the expression of node of Ranvier genes and proteins in schizophrenia. Some evidence, for example from studies of suicide, suggests that the potentially epigenetic alterations in the serotonin 2C receptor occur in suicide completers, irrespective of the underlying or associated schizophrenia or bipolar disorder. Even neuroanatomical studies based on cell shape and number, have suggested that abnormalities may cut across diagnostic categories and be associated with psychotic symptoms as opposed to a specific axis one diagnosis. It may be argued that the neurobiological commonalities that will be discussed in gene and protein expression between different serious mental illnesses are mere artifacts of postmortem changes, the exposure of study subjects to common medications and/or social and environmental influences. Several lines of evidence dispute these latter possibilities. In addition to the genetic susceptibility loci that are independent of postmortem or environmental factors, direct studies of the brain show that these same commonalities are not evident in cohorts that share many features of the potentially artifactual influences. For example, comparison of postmortem specimens from elderly schizophrenics and age-matched dementia sufferers reveals common changes in genes associated with autophagy, but not with myelination, neurotransmission, neurotrophism, saltatory conduction or synapse maintenance. Further support for common neurobiological substrates of schizophrenia and bipolar disorder comes from recent weighted gene coexpression network analyses (WGCNA). Schizophrenia-related transcriptome alterations converge with GWAS that show a myelin-associated module is significantly enriched with genes related to schizophrenia AND bipolar disorder in GWAS studies but not with genes associated with other neuropsychiatric disorders. Other modules that are differentially expressed in schizophrenia relative to unaffected controls (e.g., microglia/immune response and mitochondria) show no evidence for pronounced genetic enrichment and may represent either secondary phenomena or be attributable to environmental or other factors. Mounting evidence suggests that conceptualizing the neurobiology of psychiatric disorders along parameters of symptom dimensions, such as psychosis or suicidality may be more closely aligned with neurobiology, than the partitions dictated by traditional nosology. Consideration of symptom-based neurobiological substrates may reveal novel therapeutic targets and treatments that cut across the boundaries that currently define neuropsychiatric disease and constrain clinical, neuropsychological and pharmacological research.
SCHIZOPHRENIA AND BIPOLAR DISORDER GENETICS: OVERLAPPING AND DISTINGUISHING FEATURES Michael O’Donovan Cardiff University, Cardiff, Wales, United Kingdom Recent genome wide studies have identified multiple risk alleles for schizophrenia and/or bipolar disorder. These can be divided into those that are common and are associated with small effects (e.g. the expanded MHC complex, TCF4, ZNF804A, mir137 locus, CACNA1C) and those that are rare