Genetic association studies of symptoms, comorbidity and outcome in bipolar disorder and schizophrenia

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)

Troponin T levels associated with genetic variants in NOTCH2 and MTNR1B in women with psychosis

Psychosis patients have increased prevalence of metabolic disorders, which increase the risk for cardiovascular disease. Elevated troponin T level is an early biomarker of cardiovascular damage. We tested for association between troponin T levels and genetic risk variants of elevated blood glucose level in psychosis. Glucose and troponin T levels correlated positively. MTNR1B rs10830963 and NOTCH2 rs10923931 associated with troponin T levels in women, adjusted for glucose levels. These findings may indicate metabolic genetic influences on troponin T levels among women with psychosis

Cognitive manic symptoms in bipolar disorder associated with polymorphisms in the DAOA and COMT genes.

INTRODUCTION: Bipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function. METHODOLOGY: Focusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes. [Table: see text]. RESULTS: The finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model. [Table: see text] [Table: see text]. CONCLUSION: Identifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population

P2RX7: expression responds to sleep deprivation and associates with rapid cycling in bipolar disorder type 1.

Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling.To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients.Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients.Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044).P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10(-9)). The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45-0.49, p = 0.003-0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls.Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system

Haplotype association of haplotype group 1 in bipolar 1 patients with cognitive manic symptoms (CMS) compared with non-CMS patients or ABD controls in the <i>DAOA</i> gene.

a<p>frequency (F) in sample.</p>b<p>gender and rs1718119 as covariates.</p>c<p>odds ratios (OR) for each haplotype.</p

Allelic association in bipolar 1 patients with cognitive manic symptoms (CMS) patients compared to non-CMS and to ABD controls in the <i>DAOA</i> and <i>COMT</i> genes.

a<p>SNP (minor allele(a)/major allele(b)).</p>b<p>gender and rs1718119 as covariate.</p>c<p>point-wise p-value from 10,000 pemutations with no covarite (EMP1).</p>d<p>corrected empirical p-value by max (T) permutation.</p>e<p>odds ratio (OR), the proportion of minor versus major allele affected (cognitive manic symptoms factor)/proportion of minor versus major allele unaffected (non-cognitive manic symptoms factor or ABD controls).</p>*<p>significant after correction for multiple testing by max (T) permutation.</p

LD structure of a) the <i>DAOA</i> gene and b) the <i>COMT</i> gene, showing the SNPs analyzed.

<p>The numbers in the squares represent the pair-wise Dvalue, empty squares stand for D = 1. Pink-red color indicates a pair-wise LOD >2 with color intensity proportional to D. With squares indicates LOD<2. Haplotype blocks are formed if 95% of comparisions are strong LD that is the 95% CI of Dis within [0.7-0.98]. Haplotype group 1 includes rs3916967, rs2391191, rs1935062.</p

Clinical characteristics of the Bipolar 1 patient sample.

*<p>having all three symptoms: talkativeness, distractibility, and tought disorder.</p

SNPs analyzed in <i>P2RX7</i> gene.

a<p>Data from <a href="http://www.ensembl.org" target="_blank">www.ensembl.org</a> . Minor allele first.</p>b<p>Minor allele first, data from <a href="http://www.hapmap.org" target="_blank">www.hapmap.org</a>.</p>*<p>Ancestral allele in CEU population data (CEPH (Utah residents with ancestry from northern and western Europe)) from <a href="http://www.ncbi.nlm.nih.gov" target="_blank">www.ncbi.nlm.nih.gov</a>.</p><p>MAF, minor allele frequency.</p