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Preclinical studies indicate a link between the kynurenine pathway and monocyte chemoattractant protein-1 (MCP-1), but there is a lack of clinical studies examining this further. We here perform a secondary analysis of kynurenine metabolites and MCP-1 in cerebrospinal fluid of 23 twins affected from schizophrenia, bipolar disorder or unaffected. We show an association between MCP-1 and kynurenic acid (KYNA), driven by unique environmental influences and a less pronounced association between MCP-1 and tryptophan. No association was detected between MCP-1 and quinolinic acid. Further studies on the mechanism behind the putative relationship between KYNA and MCP-1 are needed.

Schizophrenia is a complex neurodevelopmental disorder with high rate of morbidity and mortality. While the heritability rate is high, the precise etiology is still unknown. Although schizophrenia is a central nervous system disorder, studies using peripheral tissues have also been established to search for patient specific biomarkers and to increase understanding of schizophrenia etiology. Among all peripheral tissues, fibroblasts stand out as they are easy to obtain and culture. Furthermore, they keep genetic stability for long period and exhibit molecular similarities to cells from nervous system. Using a unique set of fibroblast samples from a genetically isolated population in northern Sweden, we performed whole transcriptome sequencing to compare differentially expressed genes in seven controls and nine patients. We found differential fibroblast expression between cases and controls for 48 genes, including eight genes previously implicated in schizophrenia or schizophrenia related pathways; HGF, PRRT2, EGR1, EGR3, C11orf87, TLR3, PLEKHH2 and PIK3CD. Weighted gene correlation network analysis identified three differentially co-expressed networks of genes significantly-associated with schizophrenia. All three modules were significantly suppressed in patients compared to control, with one module highly enriched in genes involved in synaptic plasticity, behavior and synaptic transmission. In conclusion, our results support the use of fibroblasts for identification of differentially expressed genes in schizophrenia and highlight dysregulation of synaptic networks as an important mechanism in schizophrenia.

Background: Non-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members., Methods: Family members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton™ System. Validation of identified variants was performed with Sanger sequencing., Results: The linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders., Conclusions: DNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.

Background: Using scanning electron microscopy, microscopic structures have been identified in fresh cerebrospinal fluid (CSF) in patients with schizophrenia and bipolar disorder, but only rarely in control subjects. However, it has not been determined whether these microscopic particles represent state or trait markers, i.e. if their presence is related to clinical manifestations of the disease or if they also can be found in as yet asymptomatic individuals with a genetic liability. This question can be addressed by studying twins discordant or concordant for schizophrenia or bipolar disorder., Methodology/principal Findings: We investigated microscopic structures in CSF in 102 individuals: 21 monozygotic and 16 dizygotic twins affected or not affected with schizophrenia, schizoaffective disorder or bipolar disorder and in 65 healthy singleton controls. A first and a second fraction of CSF was freshly applied on filters and examined by scanning electron microscopy technique. Spherical particles with lipid appearance averaging between 0.1 to 8.0 µm in diameter were detected in the center of the filter as well as located in the margins of larger aggregates binding in a viscous state. Structures were found in 12 of 17 probands, 5 of 12 healthy co-twins and 3 of 73 healthy controls. Thus, a positive microscopic finding significantly increased the likelihood of belonging to the proband group (OR=48, 95% CL: 8.2-550, p<0.0001) and the co-twin-group (OR=16, 95% CL: 2.0-218, p=0.006). Age, sex, history of alcohol abuse or anxiety syndrome, somatic disorder and markers of acute inflammatory activity did not account for group differences; nor did exposure to psychotropic medication., Conclusion: Presence of microscopic particles in CSF may possibly reflect trait dependent genetic or environmental vulnerability in patients with schizophrenia, schizoaffective disorder or bipolar disorder.

The aim was to perform a bibliometric study, and compare the quantity of publications on schizophrenia with the total medical literature in Medline during 57 years, 1950-2006. The annual additions of literature to Medline are continually increasing and form the Medline growth curve. Comparisons of the number of publications on schizophrenia, or any other disease, to this curve, may be used to estimate the research activity. Methods for the identification of relevant references to papers on schizophrenia were evaluated and three different samples were operationally defined, retrieved and counted. During 1950-2006, 16.28 million references were added to Medline. Nearly 68000, 0.42%, references were related to schizophrenia. The percentage of papers on schizophrenia among the psychiatric literature decreased from 5.2 to 2.6%. The present study indicates that the number of references on schizophrenia in Medline has followed the general increase of medical publications. This pattern differs compared to some other research fields such as dementia, HIV, and peptic ulcer. Samples of references on schizophrenia may be retrieved in Medline by operational definitions of search methods. The quantity of schizophrenia research during 57 years has kept pace with the total medical literature. One interpretation of the results is that more resources are needed to enhance research activities on schizophrenia., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Extended pedigrees are not only very useful to identify disease genes for rare Mendelian conditions, but they may also help unravel the genetics of complex diseases such as schizophrenia. In this study we performed genome-wide multipoint non-parametric linkage (NPL) score calculations using 825 microsatellites and 5,366 single nucleotide polymorphisms (SNPs), respectively, and searched for haplotypes shared by affected individuals, in three multiplex families including 29 genotyped affected individuals which in total contains 49 relative pairs useful for linkage studies. The most consistent results for microsatellites and SNPs were observed on 2q12.3-q14.1 (NPL scores 2.0, empirical P-value 0.009). However, the overall highest NPL score was observed on chromosome 2q33.3 using SNPs (NPL score 2.2, empirical P-value 0.007). Other chromosomal regions were detected on 5q15-q22.1, with microsatellites (NPL scores 1.7, empirical P-value 0.021) and with SNPs (NPL scores 2.0, empirical P-value 0.010) and on 5q23.1 (NPL score 1.9, empirical P-value 0.012) and 8q24.1-q24.2 (NPL score 2.1, empirical P-value 0.009) when using SNPs. The analysis of extended pedigrees allowed the search for haplotypes inherited identical by decent (IBD) by affected individuals. In all regions with NPL score >1.9 we found haplotypes inherited IBD by multiple cases. However, no common haplotypes were found for affected individuals in all families. In conclusion our NPL results support earlier findings suggesting that 2q and possibly 5q and 8q contain susceptibility loci for schizophrenia. Haplotype sharing in families helped to delimit the detected regions that potentially are susceptibility loci for schizophrenia.

Plasma concentration of arginine vasopressin (AVP) and melatonin and serum osmolality were measured at noon and at midnight in individuals living in the northern hemisphere on March 22-23, June 13-14, September 26-27, and December 12-13 in 35 healthy volunteers (15 men and 20 women) aged 60-74 years. The nocturnal increase in melatonin was highest in the autumn and lowest in the winter in both sexes. The midnight serum osmolality level was lower in the autumn than in any other time of the year. In both the men and the women the AVP level was higher in winter than in any other season (P < 0.01 and P < 0.0001, respectively). In men, the AVP level was higher at noon than at midnight in 49% of the investigated 24 hr periods, at the same level in 15% and lower in 36% (NS). The corresponding figures for women were 55%, 25%, and 20%, respectively (P < 0.05). This study suggests a possible relationship between melatonin and serum osmolality.

Objective: To validate the use of a recently observed guanine to adenine mutation in exon 10 in the porphobilinogen deaminase (PBGD) gene as a diagnostic marker of acute intermittent porphyria (AIP). To evaluate the efficiency of the traditional biochemical diagnostic methods., Design: Matched and blinded case-control study (1:4)., Setting: A primary health care centre in Arjeplog, the National Porphyria Research Unit and a department of clinical genetics in Stockholm., Subjects: A total of 48/49 (98%) patients over the age of 15 years living in Arjeplog with AIP, diagnosed according to standard clinical and biochemical criteria. For each AIP patient, four controls were matched for age, sex and geographical area and 164/196 (86%) participated. In the validity study, 35 patients were selected as indisputable AIP gene carriers, according to strict biochemical criteria, and 92 matched controls were selected with strict exclusion criteria., Main Outcome Measures: Validity, specificity and sensitivity of DNA diagnosis for this AIP mutation. Specificity and sensitivity of traditional biochemical methods., Results: Validity study: the mutation was found in all 35 individuals classified as carriers of AIP. None of the 92 controls had the mutation. Evaluation study: all 48 AIP gene carriers, diagnosed by traditional methods, had the mutation, as had one of the control persons. In an inconclusive group of five persons with heredity for AIP, two had a positive DNA test., Conclusions: The PBGD mutation analysis was found to have full specificity and sensitivity and can be used as the sole diagnostic method in the family complex studied, representing the major AIP mutation in Sweden. The traditional diagnostic methods, used in optimal combinations, work in most cases, but they do not show high precision. However, they must be used when the specific mutation in the PBGD gene is not known.

This study compares the clinical characteristics of 127 patients with major depression, 99 with a seasonal and 28 with a non-seasonal pattern. Non-seasonal depressives had significantly higher scores in the Comprehensive Psychopathological Rating Scale, and the Hamilton Depression Rating Scale. Increased appetite and carbohydrate craving, were more frequently reported among patients with a seasonal pattern. Compared to previous reports, the Swedish patients with seasonal depression had less atypical vegetative symptomatology. The symptoms sadness, suicidal thoughts, slowness of movement, gastrointestinal symptoms, and weight loss were more frequent in the patients with a non-seasonal pattern. The clinical symptomatology has a low specificity compared to the seasonal pattern in diagnosing seasonal affective disorder according to DSM-III-R for seasonal and non-seasonal patterns.

The circannual secretion of melatonin in 14 Swedish and 15 Italian patients suffering from episodic cluster headache was compared with 14 Swedish and 15 Italian healthy controls matched for sex and age. Overnight samples of urine were collected once a month from 8 to 14 months and kept at -20 degrees C until analysed with RIA. The melatonin concentrations in nocturnal urine were permanently low in cluster headache and there was no consistent change of the melatonin concentration in relation to cluster periods occurring during the study. There was no definitive circannual or infraannual rhythmicity of melatonin in patients or controls. Multiple analysis of variance with repeated measurements showed a significant effect of disease (p < 0.05), but not of time. Sex, geographical location, age, and smoking also had significant effects (p < 0.001) on the melatonin concentrations. Lower melatonin levels in cluster headache patients than in controls may in part be related to a larger number of smokers in the patient group. The relation between tobacco use and melatonin should be further studied.

Genetic linkage studies of a kindred from Sweden segregating for schizophrenia have been performed using a genetic model (autosomal dominant, f = 0.72, q = 0.02, phenocopies = 0.001) as described in Kennedy et al., 1988. Analyses of the restriction fragment length polymorphism (RFLP), allele-specific oligonucleotides (ASO), and short tandem repeat (STR also called microsatellite) data for 180 polymorphisms (individual probe-enzyme, ASO, or STR systems) at 155 loci have been completed using the MLINK and LIPED programs. Linkage to schizophrenia was excluded, under the given model, at 47 loci; indeterminate lod scores occurred at 108 loci. The total exclusion region across 20 chromosomes is estimated at 330 cM; 211 cM excluded by pairwise analyses and 119 cM previously excluded by multipoint analyses (Kennedy et al., 1989: Schizophr Bull 15:383-391; Moises et al. 1991: Genet Epidemiol 2:99-110; Hallmayer et al., 1992: Arch Gen Psychiatry 49:216-219).

The discovery of a functional polymorphism within the dopamine D4 receptor gene (DRD4) has not only strengthened the hypotheses implicating DRD4 in the etiology of neuropyschiatric disorders, but also provided a genetic marker for testing these hypotheses. The possibility of the dopamine D4 receptor as a candidate gene for schizophrenia was investigated in a large Swedish kindred segregating for schizophrenia. Linkage to schizophrenia was tested by linkage analyses of 6 polymorphic markers (at 4 loci) in chromosome 11p15.5 including the dopamine D4 receptor (DRD4) and the tyrosine hydroxylase (TH) loci. Schizophrenia was excluded from close linkage to the DRD4 locus using two of the polymorphisms located within the dopamine D4 receptor gene. The first DRD4 polymorphism consists of variation in the number of a 48 bp imperfect direct repeat in the third exon; the second consists of a variable number of repeated G nucleotides in the first intron. In addition, some of the individuals homozygous for four or seven copies of 48 bp repeat alleles were tested for previously reported sequence variation among repeats. No single haplotype of the DRD4 alleles or haplotype of other markers in chromosome 11p15.5 was found to be common to the schizophrenic individuals in this family. Therefore, we find no evidence for linkage of the D4 receptor, or this region of 11p15.5, with genetic susceptibility to schizophrenia in this kindred.

Psychiatric research in the five Nordic countries has yielded a substantial body of work during recent years-e.g., on Alzheimer's disease, schizophrenia and neurotransmitters. Owing to their geographic position and the reliability of their demographic records, the Nordic countries are uniquely suited to epidemiological studies-e.g., of mental disorders over time. Research spans both the fields of biological and clinical community psychiatry in all five countries, though the emphasis varies somewhat: the focus in Sweden and Denmark being more on biological psychiatry, while in Norway and Finland it is more on community, adolescent, and emergency psychiatry.

Family, twin, and adoption studies suggest that genetic factors play an important role in the etiology of schizophrenia. Detection of single gene(s) involved in a higher susceptibility to a hereditary disease is possible with linkage analysis. The effects of serotonin2-receptor antagonists on symptoms of schizophrenia suggest that a mutation in the gene coding for this receptor subtype might be involved in the pathophysiology of this disease. Recently a copy DNA encoding the serotonin 5-HT2 receptor has been isolated and with a human 5-HT2 receptor copy DNA probe the HTR2 locus has been mapped to chromosome 13. Using multipoint linkage analysis between schizophrenia and genetic markers spanning the region of the HTR2 locus, we were able to exclude linkage between this candidate gene and schizophrenia in a Swedish kindred. Given this result, we conclude that the serotonin 5-HT2 receptor gene itself is not a major susceptibility gene for schizophrenia in this family.

The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score, less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.

A polydiagnostic computerized diagnostic system for psychosis was used in a Swedish family complex, and 51 patients with psychiatric symptomatology were examined with eight main diagnostic systems for schizophrenia and three systems for schizophrenic subgroups. All patients fulfilled the criteria for schizophrenia according to Taylor et al., 50 according to Carpenter, 41 according to RDC, and 31 of the 51 according to DSM-III and DSM-III-R. The hypothesis that the patients in the Swedish family complex differ from other phenotypes of schizophrenia must be refuted based on the data of the present study.

Erythrocyte catechol-O-methyltransferase (COMT) activity has been analyzed in 185 individuals. The activities showed a trimodal frequency distribution. This suggests an autosomal codominant inheritance of the human erythrocyte COMT activity. The mean male COMT activity was 18.9 +/- 7.0 (S.D.) nmol/ml RBC/h. The mean female activity was 16.1 +/- 6.3 nmol/ml RBC/h and the frequency distribution pattern for women was shifted towards lower values.

The association of hereditary ring sideroblastic anaemia with Christmas disease in a Swedish family is described. We have studied the transmission of the sideroblastic trait, in relation to HLA groups and Christmas disease, and also evaluated the erythrocyte morphology, uroporphyrinogen-I-synthetase activity and S-ferritin for the detection of latent cases of ring sideroblastic anaemia. The proband had ring sideroblastic anaemia, Christmas disease and haemochromatosis. 3 cases of ring sideroblastic anaemia were found among the 12 family members studied. Using the factor IX deficiency as a marker of the X chromosome, it appeared that autosomal transmission of the sideroblastic trait was most likely. The sideroblastic trait did not seem to be linked to HLA-A3-alloantigen. Erythrocyte morphology was normal in all non-anaemic subjects. S-ferritin was found to be increased in all 3 cases of sideroblastic anaemia as well as in 1 non-anaemic relative. Erythrocyte uroporphyrinogen-I-synthetase was elevated in 10 of the 12 family members; those with sideroblastic anaemia had the highest values indicating that uroporphyrinogen-I-synthetase is of importance in the disturbed haem-synthesis of ring sideroblastic anaemia. This interpretation is supported by the positive correlation between S-ferritin values and the uroporphyrinogen-I-synthetase activity.

In a retrospective study over a 20-year period we found in the Umeå region in Sweden 11 patients (7 women and 4 men, mean age 67 years) with both hepatocellular carcinoma and acute intermittent porphyria. This coincidence was highly significant. Concomitant existence of portal cirrhosis of the liver was demonstrated in those 5 patients in whom it could be examined.

Monoamine oxidase activity (MAO) was determined in platelets in samples from a North-Swedish pedigree with a high frequency of schizophrenia. The MAO assay was performed with phenethylamine as substrate and with two concentrations of oxygen (0.06 and 0.12 mM). A tendency to lowered Vmax and increased apparent Km values was observed among the schizophrenic subjects, although there were no statistically significant differences in apparent Km and Vmax values between schizophrenics and their non-schizophrenic relatives.

Conflicting reports on the association between platelet MAO activity and schizophrenia prompted a critical review and determinations on identical samples at one laboratory in Sweden and one in the U.S.A. Samples originated from eight schizophrenics and 27 relatives belonging to a large pedigree, thus ensuring biological homogeneity. In the USA laboratory, a significantly lower MAO activity was found in the schizophrenics when benzylamine or beta-phenylethylamine was used as substrate (but not with tryptamine), while a similar result was obtained in the Swedish laboratory when tryptamine was used (but not with benzylamine or beta-phenylethylamine). Comparisons between materials examined in different laboratories do not seem meaningful until differences in methodologies have been clarified. At present there is neither proof nor disproof of MAO being a "genetic marker" for vulnerability to the schizophrenic disorder.

Plasma dopamine beta-hydroxylase (DBH) activity was determined in 115 members of a North Swedish geographical isolate with a high frequency of schizophrenia, of which 30 persons had schizophrenia, and was compared with a Middle Swedish population of 185 apparently healthy persons. There was no significant difference between the schizophrenic group and their healthy relatives or between the North and Middle-Swedish populations. The number of persons with very low plasma DBH activity in the North Swedish population appeared to be less than those in the control population.

A filter paper dry blood spot procedure for the determination of whole blood uroporphyrinogen-I-synthase (UIS) activity is presented. The method is based on the concept of enzyme specific activity, the enzyme activity being related to the haemoglobin concentration of the assay sample. The diagnostic capacity with regard to the acute intermittent porphyria (AIP) gene carrier state is shown to be equivalent to that of a washed red cell reference method. On grounds of easy capillary blood sampling, uncomplicated and safe mail specimen transport and simple laboratory reception routines, the method is stated to be well adapted for use in AIP preadolescent population screening.

Schizophrenia is a severe mental illness with a typically chronic course affecting nearly 1% of the human population. It is generally accepted that genetic factors have an important pathogenic role in a substantial portion of schizophrenia cases; however, despite decades of family studies, there is no agreed-upon mode of inheritance. The discovery of genetic aetiologic factors and resolution of the inheritance pattern(s) will undoubtably emerge from genetic linkage studies. With these objectives in mind, we undertook a linkage project, starting in 1985, in a previously well-documented kindred from north Sweden. Multipoint linkage analyses were used to screen the proximal long arm of chromosome 5 using restriction fragment length polymorphism (RFLP) markers at five loci and the distal long arm using RFLPs at two loci, one of which was the locus for the glucocorticoid receptor. We found strong evidence against linkage between schizophrenia and the seven loci. These results, together with the positive evidence for linkage of schizophrenia with markers in the proximal long arm of chromosome 5 lead us to conclude that the genetic factors underlying schizophrenia are heterogeneous.

Twenty-six mentally retarded patients from a North Swedish geographically isolated population were studied. The mentally retarded patients were short with pycnic body type. Neurological and psychiatric stigmata of variating functions and degrees were recorded. Neurogenic hearing defects, impaired vision, pathological EEG, widened subarachnoidal space found in CT, were among these stigmata. In three patients a urinary substance, probably urocanyl-glycine, was found. The erythrocyte uroporphyrinogen-I-synthetase activity was high in four patients. Chromosome analysis showed some abnormalities which, however, were not systematically present. In the near family 23 persons with schizophrenia were found. The relationship between the mental retardation and the schizophrenic psychosis in the present families has not been explained. Further studies are called for to elucidate the genetic and environmental factors responsible for the two conditions.