adrenomedullin and Schizophrenia

Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.. The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders.. The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder.. This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

Topics: Adrenomedullin; Adult; Basic Helix-Loop-Helix Transcription Factors; Bipolar Disorder; Carrier Proteins; Chromosome Mapping; Chromosomes, Human, Pair 11; Cytokines; Depressive Disorder, Major; Female; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Nerve Tissue Proteins; Phenotype; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Schizophrenia; Transcription Factors

The contribution of genetic factors to schizophrenia is well established and recent studies have indicated several strong candidate genes. However, the pathophysiology of schizophrenia has not been totally elucidated yet. To date, studies of monozygotic twins discordant for schizophrenia have provided insight into the pathophysiology of this illness; this type of study can exclude inter-individual variability and confounding factors such as effects of drugs. In this study we used DNA microarray analysis to examine the mRNA expression patterns in the lymphoblastoid (LB) cells derived from two pairs of monozygotic twins discordant for schizophrenia. From five independent replicates for each pair of twins, we selected five genes, which included adrenomedullin (ADM) and selenoprotein X1 (SEPX1), as significantly changed in both twins with schizophrenia. Interestingly, ADM was previously reported to be up-regulated in both the LB cells and plasma of schizophrenic patients, and SEPX1 was included in the list of genes up-regulated in the peripheral blood cells of schizophrenia patients by microarray analysis. Then, we performed a genetic association study of schizophrenia in the Japanese population and examined the copy number variations, but observed no association. These findings suggest the possible role of ADM and SEPX1 as biomarkers of schizophrenia. The results also support the usefulness of gene expression analysis in LB cells of monozygotic twins discordant for an illness.

Topics: Adrenomedullin; Adult; Case-Control Studies; Cells, Cultured; Female; Gene Dosage; Gene Expression Profiling; Humans; Lymphocyte Subsets; Male; Methionine Sulfoxide Reductases; Middle Aged; Oligonucleotide Array Sequence Analysis; Pregnancy; Schizophrenia; Selenoproteins; Twins, Monozygotic; Up-Regulation

To investigate the levels of serum cortisol, dehydroepiandrosterone sulfate (DHEA-S), nitric oxide (NO) and adrenomedullin (AM) in schizophrenic patients.. Sixty-six male patients with chronic schizophrenia and 28 normal male subjects participated in this study. The duration of disease was 145 +/- 120 (mean +/- SD) months. Serum levels of cortisol and DHEA-S were measured by electrochemiluminescence; plasma nitrite levels as an index of NO were measured with the Griess reaction, while plasma AM concentration was measured by using high-performance liquid chromatography.. Patients (12.48 +/- 3.2 microg/dl), as compared to controls (10.31 +/- 3.1 microg/dl), had higher levels of baseline cortisol (p < 0.05). DHEA-S levels were lower in patients though this did not reach statistical significance (302 +/- 156 microg/dl compared to control, 322 +/- 96 microg/dl, p > 0.05). The mean levels of plasma AM and NO in the schizophrenic group (44.33 +/- 5.07 pmol/l and 36.27 +/- 17.6 micromol/l) were significantly higher than the levels in the control group (14.56 +/- 4.03 pmol/l and 32.54 +/- 7.14 micromol/l; p < 0.001, p < 0.03, respectively). There was a positive association between duration of disease and cortisol/DHEA-S ratio and cortisol level.. The data show that schizophrenia is associated with abnormal levels of cortisol, DHEA-S, NO and AM.

Topics: Adrenomedullin; Adult; Case-Control Studies; Chromatography, High Pressure Liquid; Chronic Disease; Dehydroepiandrosterone; Humans; Hydrocortisone; Male; Nitric Oxide; Schizophrenia; Statistics, Nonparametric

Adrenomedullin (ADM) is a 52 amino acid peptide with multiple physiological functions and wide tissue distributions including brain. Recently, elevated plasma levels of ADM were found in patients with schizophrenia, bipolar affective disorder and autism, suggesting the involvement of ADM in the pathophysiology of mental diseases. Using real-time quantitative PCR, we compared the ADM mRNA levels in lymphoblastoid cell lines between schizophrenic patients and controls. Male but not female schizophrenia patients had 2- to 3-fold higher ADM mRNA levels than controls (p<0.01). Our data support that ADM may be associated with the pathophysiology of schizophrenia, although the cause of the association needs further study.

Topics: Adrenomedullin; Adult; Cell Line, Transformed; Cohort Studies; Female; Humans; Lymphocytes; Male; Peptides; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Schizophrenia; Sex Characteristics