Genetic association studies of symptoms, comorbidity and outcome in bipolar disorder and schizophrenia
Author: Hukic, Dzana Sudic
Date: 2016-05-27
Location: Thoraxaulan, N2:U1, N-huset, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Inst för molekylär medicin och kirurgi / Dept of Molecular Medicine and Surgery
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Thesis (4.017Mb)
Abstract
Schizophrenia and bipolar disorder are complex brain disorders. Research has focused on
applying brain research to understand the etiology, as well as clinical research to improve
treatment, prognosis and progression. Schizophrenia and bipolar disorder are not lethal in and
of themselves, but suicide and the presence of associated physical illnesses are of great
concern, since these are the major causes of shortened life in afflicted individuals. In
particular, the prevalence of type 2 diabetes and cardiovascular disease are twice as great in
schizophrenia and bipolar disorder. By shifting the focus to underlying, sometimes comorbid
causes, it is possible to increase knowledge of morbidity and mortality in cardiovascular
disease, and thus improve the prognosis and progression for individuals with schizophrenia
and bipolar disorder. Another interesting strategy for better understanding such complex
disorders is to limit examination to symptoms in order to distinguish the genetics of the
symptoms from the disorder itself. Genetic association studies are often used to investigate
complex disease. The aim of this thesis was to investigate genetic associations between gene
variants and metabolic risk factors in schizophrenia and bipolar disorder patients. An
additional aim was to investigate known psychiatric risk genes in the dopamine system and
their association to cognitive function.
In Study I, D-amino acid oxidase activator gene (DAOA) and catechol-O-methyltransferase gene (COMT) were analyzed for allelic association to cognitive dysfunction in bipolar disorder patients. In Studies II-V, common metabolic risk gene variants were analyzed for allelic association to metabolic risk factors in schizophrenia and bipolar disorder patients, and to disorders per se. In Study VI, metabolic risk variants were analyzed for possible association to high-sensitive troponin T levels, which is a sensitive biomarker of cardiovascular damage in patients with acute coronary syndrome.
In study I, single nucleotide polymorphisms in D-amino acid oxidase activator gene (DAOA) and catechol-O-methyltransferase gene (COMT) were associated to cognitive dysfunction in bipolar disorder patients. Data also suggest interaction between these genes. In studies II-V, single nucleotide polymorphisms in common metabolic risk genes: insulin-like growth factor II mRNA binding protein 2 (IGF2BP2), neurogenic locus notch homolog 2 (NOTCH2), thyroid adenoma associated (THADA), wolfram syndrome 1 (WFS1), purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7), and melatonin receptor 1B (MTNR1B) were associated with increased fasting plasma glucose in schizophrenia. Peroxisome proliferatoractivated receptor delta gene (PPARD) was associated with schizophrenia independent of glucose levels. Single nucleotide polymorphisms in common metabolic risk genes: calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), melanoma inhibitory activity family, member 3 (MIA3), purinergic receptor P2X, ligand-gated ion channel, 7 gene (P2RX7), muscle RAS oncogene homolog gene (MRAS), SMAD family member 3 gene (SMAD3), peroxisome proliferator-activated receptor delta gene (PPARD), melatonin receptor 1B gene (MTNR1B), neurogenic locus notch homolog 2 gene (NOTCH2), HNF1 homeobox B gene (HNF1B) were associated with increased waist circumference in schizophrenia patients. Peroxisome proliferator-activated receptor delta gene (PPARD), melatonin receptor 1B gene (MTNR1B), neurogenic locus notch homolog 2 gene (NOTCH2), and homeobox B gene (HNF1B) were associated with schizophrenia irrespective of waist circumference. A genetic overlap between schizophrenia and bipolar disorder was identified through an association between melatonin receptor 1B gene (MTNR1B) and increased fasting plasma glucose also in bipolar disorder patients. Neurogenic locus notch homolog 2 gene (NOTCH2) was associated to bipolar disorder per se. In study VI, melatonin receptor 1B gene (MTNR1B) and neurogenic locus notch homolog 2 gene (NOTCH2) were associated with high-sensitive troponin T levels in schizophrenia women.
Our genetic findings regarding D-amino acid oxidase activator gene (DAOA) and catecholO-methyltransferase gene (COMT) are in line with the dopamine hypothesis of cognitive function. Single nucleotide polymorphisms that increase metabolic risk in the general population are associated with elevated plasma glucose and increased waist circumference among schizophrenia and bipolar disorder patients, as well as with schizophrenia and bipolar disorder per se. The melatonin receptor 1B gene (MTNR1B) –dependent vulnerability for elevated fasting plasma glucose levels is evident in both schizophrenia and bipolar disorder. Neurogenic locus notch homolog 2 gene (NOTCH2) is associated to both to schizophrenia and bipolar disorder type 1 per se. These findings may reflect increased metabolic genetic vulnerability in schizophrenia and bipolar disorder patients, as well as common genetics between type 2 diabetes mellitus and these psychiatric disorders. In addition, in women with schizophrenia, there is a possible metabolic genetic component affecting high-sensitive troponin T levels, a biomarker for cardiovascular damage in individuals with acute coronary syndrome (chest pain).
In Study I, D-amino acid oxidase activator gene (DAOA) and catechol-O-methyltransferase gene (COMT) were analyzed for allelic association to cognitive dysfunction in bipolar disorder patients. In Studies II-V, common metabolic risk gene variants were analyzed for allelic association to metabolic risk factors in schizophrenia and bipolar disorder patients, and to disorders per se. In Study VI, metabolic risk variants were analyzed for possible association to high-sensitive troponin T levels, which is a sensitive biomarker of cardiovascular damage in patients with acute coronary syndrome.
In study I, single nucleotide polymorphisms in D-amino acid oxidase activator gene (DAOA) and catechol-O-methyltransferase gene (COMT) were associated to cognitive dysfunction in bipolar disorder patients. Data also suggest interaction between these genes. In studies II-V, single nucleotide polymorphisms in common metabolic risk genes: insulin-like growth factor II mRNA binding protein 2 (IGF2BP2), neurogenic locus notch homolog 2 (NOTCH2), thyroid adenoma associated (THADA), wolfram syndrome 1 (WFS1), purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7), and melatonin receptor 1B (MTNR1B) were associated with increased fasting plasma glucose in schizophrenia. Peroxisome proliferatoractivated receptor delta gene (PPARD) was associated with schizophrenia independent of glucose levels. Single nucleotide polymorphisms in common metabolic risk genes: calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), melanoma inhibitory activity family, member 3 (MIA3), purinergic receptor P2X, ligand-gated ion channel, 7 gene (P2RX7), muscle RAS oncogene homolog gene (MRAS), SMAD family member 3 gene (SMAD3), peroxisome proliferator-activated receptor delta gene (PPARD), melatonin receptor 1B gene (MTNR1B), neurogenic locus notch homolog 2 gene (NOTCH2), HNF1 homeobox B gene (HNF1B) were associated with increased waist circumference in schizophrenia patients. Peroxisome proliferator-activated receptor delta gene (PPARD), melatonin receptor 1B gene (MTNR1B), neurogenic locus notch homolog 2 gene (NOTCH2), and homeobox B gene (HNF1B) were associated with schizophrenia irrespective of waist circumference. A genetic overlap between schizophrenia and bipolar disorder was identified through an association between melatonin receptor 1B gene (MTNR1B) and increased fasting plasma glucose also in bipolar disorder patients. Neurogenic locus notch homolog 2 gene (NOTCH2) was associated to bipolar disorder per se. In study VI, melatonin receptor 1B gene (MTNR1B) and neurogenic locus notch homolog 2 gene (NOTCH2) were associated with high-sensitive troponin T levels in schizophrenia women.
Our genetic findings regarding D-amino acid oxidase activator gene (DAOA) and catecholO-methyltransferase gene (COMT) are in line with the dopamine hypothesis of cognitive function. Single nucleotide polymorphisms that increase metabolic risk in the general population are associated with elevated plasma glucose and increased waist circumference among schizophrenia and bipolar disorder patients, as well as with schizophrenia and bipolar disorder per se. The melatonin receptor 1B gene (MTNR1B) –dependent vulnerability for elevated fasting plasma glucose levels is evident in both schizophrenia and bipolar disorder. Neurogenic locus notch homolog 2 gene (NOTCH2) is associated to both to schizophrenia and bipolar disorder type 1 per se. These findings may reflect increased metabolic genetic vulnerability in schizophrenia and bipolar disorder patients, as well as common genetics between type 2 diabetes mellitus and these psychiatric disorders. In addition, in women with schizophrenia, there is a possible metabolic genetic component affecting high-sensitive troponin T levels, a biomarker for cardiovascular damage in individuals with acute coronary syndrome (chest pain).
List of papers:
I. Dzana Sudic Hukic, Louise Frisén, Lena Backlund, Catharina Lavebratt, Mikael Landén, Lil Träskman-Bendz, Gunnar Edman, Martin Schalling, Urban Ösby. Cognitive manic symptoms in bipolar disorder associated with polymorphisms in the DAOA and COMT genes. PLos One 2013 Jul 5;8(7):e67450.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Dzana Sudic Hukic, Eric Olsson, Agneta Hildnig, Claes-Göran Östensson, Harvest F Gu, Ewa Ehrenborg, David Erlinge, Gunnar Edman, Martin Schalling, Catharina Lavebratt, and Urban Ösby. Genes associated with increased fasting glucose in patients with schizophrenia spectrum disorders. J. Diabetes Metabolism 2015, 6(3):1000512.
Fulltext (DOI)
III. Dzana Sudic Hukic, Catharina Lavebratt, Louise Frisén, Lena Backlund, Agneta Hilding, Claes-Göran Östenson, David Erlinge, Ewa Ehrenborg, Martin Schalling, Urban Ösby. Melatonin receptor 1B gene associated with increased fasting glucose in bipolar disorder. Psychiatric Genetics 2016, 00:000–000.
Fulltext (DOI)
Pubmed
IV. Dzana Sudic Hukic, Urban Ösby, Eric Olsson, Agneta Hilding, Claes-Göran Östensson, Harvest F Gu, Ewa Ehrenborg, Gunnar Edman, Martin Schalling, Catharina Lavebratt, Louise Frisén. Genetic variants of increased waist circumference in psychosis. [Manuscript]
V. Dzana Sudic Hukic, Catharina Lavebratt, Louise Frisén, Lena Backlund, Agneta Hilding, Harvest F Gu, Claes-Göran Östensson, David Erlinge, Ewa Ehrenborg, Martin Schalling, Urban Ösby. NOTCH2 associated with bipolar disorder. [Manuscript]
VI. Dzana Sudic Hukic, Catharina Lavebratt, Eric Olsson, Claes-Göran Östensson, Sven V. Eriksson, David Erlinge, Martin Schalling, Urban Ösby.Troponin T levels associated with genetic variants in NOTCH2 and MTNR1B in women with schizophrenia. [Manuscript]
I. Dzana Sudic Hukic, Louise Frisén, Lena Backlund, Catharina Lavebratt, Mikael Landén, Lil Träskman-Bendz, Gunnar Edman, Martin Schalling, Urban Ösby. Cognitive manic symptoms in bipolar disorder associated with polymorphisms in the DAOA and COMT genes. PLos One 2013 Jul 5;8(7):e67450.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Dzana Sudic Hukic, Eric Olsson, Agneta Hildnig, Claes-Göran Östensson, Harvest F Gu, Ewa Ehrenborg, David Erlinge, Gunnar Edman, Martin Schalling, Catharina Lavebratt, and Urban Ösby. Genes associated with increased fasting glucose in patients with schizophrenia spectrum disorders. J. Diabetes Metabolism 2015, 6(3):1000512.
Fulltext (DOI)
III. Dzana Sudic Hukic, Catharina Lavebratt, Louise Frisén, Lena Backlund, Agneta Hilding, Claes-Göran Östenson, David Erlinge, Ewa Ehrenborg, Martin Schalling, Urban Ösby. Melatonin receptor 1B gene associated with increased fasting glucose in bipolar disorder. Psychiatric Genetics 2016, 00:000–000.
Fulltext (DOI)
Pubmed
IV. Dzana Sudic Hukic, Urban Ösby, Eric Olsson, Agneta Hilding, Claes-Göran Östensson, Harvest F Gu, Ewa Ehrenborg, Gunnar Edman, Martin Schalling, Catharina Lavebratt, Louise Frisén. Genetic variants of increased waist circumference in psychosis. [Manuscript]
V. Dzana Sudic Hukic, Catharina Lavebratt, Louise Frisén, Lena Backlund, Agneta Hilding, Harvest F Gu, Claes-Göran Östensson, David Erlinge, Ewa Ehrenborg, Martin Schalling, Urban Ösby. NOTCH2 associated with bipolar disorder. [Manuscript]
VI. Dzana Sudic Hukic, Catharina Lavebratt, Eric Olsson, Claes-Göran Östensson, Sven V. Eriksson, David Erlinge, Martin Schalling, Urban Ösby.Troponin T levels associated with genetic variants in NOTCH2 and MTNR1B in women with schizophrenia. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Ösby, Urban
Issue date: 2016-05-06
Rights:
Publication year: 2016
ISBN: 978-91-7676-246-2
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