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Context: Patients with schizophrenia have an increased risk of type 2 diabetes mellitus. However, very few studies have dealt with the association of type 1 diabetes and schizophrenia. Preliminary evidence points to a possible inverse association., Objective: To investigate the incidence of schizophrenia in a nationwide cohort of patients with type 1 diabetes born in 1950 through 1959 in Finland., Design: A cohort study of individuals born in 1950 through 1959 with a follow-up of 1969 through 1991., Setting: Finland., Patients: All individuals born in 1950 through 1959 with type 1 diabetes were identified through nationwide registers. The incidence of schizophrenia until 1992 among the total 1950-1959 cohort and in individuals with type 1 diabetes was calculated using information from 3 health care registers., Main Outcome Measure: Incidence of schizophrenia., Results: The incidence of schizophrenia was 0.21 per 10 000 person-years in the group with type 1 diabetes and 0.56 per 10 000 person-years in the group without type 1 diabetes (P < .001)., Conclusion: The incidence of schizophrenia is decreased in patients with type 1 diabetes.

Family history of schizophrenia has been associated with negative symptoms in the clinical picture. Our aim was to examine the signs and symptoms of schizophrenia in a genetically homogeneous isolate and a nationwide multiplex family sample, and to investigate the symptom dimensions and their association with the degree of familial loading for psychotic disorders and with consanguinity. For factor analysis of the Scales for the Assessment of Negative and Positive Symptoms, we included 290 patients with a DSM-IV diagnosis of schizophrenia: 63 multiplex family and 133 singleton patients from the isolate, and 94 nationwide multiplex family patients. The factor analysis yielded four factors. There was a significant difference between the multiplex and singleton patients, the former having more severe affective flattening and alogia. Further, the patients in isolate groups had fewer delusions and hallucinations compared with the whole country multiplex patients regardless of their familial loading for schizophrenia. This may be related to genetic homogeneity in the isolate. We conclude that patients with first-degree relatives with psychotic disorder have more severe negative symptoms.

We identified all cases in Finland (population of 5 million) with a diagnosis of schizophrenia born between 1940 and 1969, using four national computerised registers with high reliability. A sample of 397 families was identified in a genetically homogeneous internal isolate (population of 18,000) in northeastern Finland with high prevalence for schizophrenia and an LOD score of 3.8 in chromosome 1. Our aim was to examine with Operational Criteria Checklist for Psychotic Illness (OCCPI) factor analysis the psychotic and affective signs and symptoms of schizophrenia in this genetically homogeneous population, and compare them with findings from individuals with schizophrenia from multiplex families from the whole country. After collecting all original case notes, we made DSM-IV consensus diagnoses and completed OCCPI ratings on a lifetime basis. For the factor analysis, we accepted 190 patients with a diagnosis of schizophrenia. In addition, 466 schizophrenia patients from 147 multiplex families from the whole country were included in the analysis. The OCCPI factor analysis resulted in four factors: "delusions and hallucinations" and "negative" factors, plus two affective ("manic" and "depressive") factors. We compared the pattern of symptoms among three patient groups: isolate patients who were the only affected individuals in their family, isolate patients who had affected family members, and patients from the whole country with affected family members. We found no clear differences among these groups. However, there were significant differences in the frequency of individual OCCPI items between the study groups. Findings in this schizophrenia OCCPI phenotype study suggest that the clinical picture of schizophrenia in a genetically isolated and homogeneous population closely resembles our nationwide findings in Finland.

We have previously carried out two genome-wide scans in samples of Finns ascertained for schizophrenia from national epidemiological registers. Here, we report data from a third genome scan in a nationwide Finnish schizophrenia study sample of 238 pedigrees with 591 affected individuals. Of the 238 pedigrees, 53 originated from a small internal isolate (IS) on the eastern border of Finland with a well established genealogical history and a small number of founders, who settled in the community 300 years ago. The total study sample of over 1200 individuals were genotyped, using 315 markers. In addition to the previously identified chromosome 1 locus, two new loci were identified on chromosomes 2q and 5q. The highest LOD scores were found in the IS families with marker D2S427 (Z(max) = 4.43) and in the families originating from the late settlement region with marker D5S414 (Z(max) = 3.56). In addition to 1q, 2q and 5q, some evidence for linkage emerged at 4q, 9q and Xp, the regions also suggested by our previous genome scans, whereas, in the nationwide study sample, the region at 7q failed to show further evidence of linkage. The chromosome 5q finding is of particular interest, since several other studies have also shown evidence for linkage in the vicinity of this locus.

We have earlier reported evidence for linkage to two regions on chromosome 1q32--q42 in schizophrenia families collected for two separate studies in Finland. Here we report the results of a fine mapping effort aimed at further definition of the chromosomal region of interest using a large, population-based study sample (221 families, 557 affected individuals). Most affecteds (78%) had a DSM-IV schizophrenia diagnosis and the remaining had schizophrenia spectrum disorders. We genotyped a total of 147 microsatellite markers on a wide 45 cM region of chromosome 1q. The results were analyzed separately for families originating from an internal isolate of Finland and for families from the rest of Finland, as well as for all families jointly. We used traditional two-point linkage analysis, SimWalk2 multipoint analysis and a novel gamete-competition association/linkage method. Evidence for linkage was obtained for one locus in the combined sample (Z(max) = 2.71, D1S2709) and in the nuclear families from outside the internal isolate (Z(max) = 3.21, D1S2709). In the families from the internal isolate the strongest evidence for linkage was obtained with markers located 22 cM centromeric from this marker (Z(max) = 2.30, D1S245). Multipoint analysis also indicated these loci. Some evidence for association with several markers was observed using the gamete-competition method. Interestingly, the strongest evidence for linkage in the combined study sample was obtained for marker D1S2709, which is an intragenic marker of the DISC1 gene, previously suggested as a susceptibility gene for schizophrenia. These results are consistent with the presence of susceptibility gene(s) in this chromosomal region, a result also implied in other recent family studies of schizophrenia.

We report the results of a four-stage genome-wide scan in a schizophrenia study sample consisting of 134 affected sib-pairs collected in Finland. In stage I we genotyped 370 markers from the Weber 6 screening set ( N = 52 affected sib-pairs); in stage II we followed up 40 markers by typing first-degree relatives of the sib-pairs; in stage III we genotyped 15 markers in 134 families; and in stage IV we genotyped a denser marker map in the two most promising regions, one on chromosome 1 and another on chromosome 7, in all families. Diagnoses were based on three nationwide health care registers and consensus diagnosis based on review of all medical records. The most significant finding was a two-point lod score of 3.18 with marker D7S486 using a dominant model and treating all individuals with either schizophrenia, schizoaffective disorder or other schizophrenia spectrum disorder as affected. Multipoint analysis with MAPMAKER/SIBS resulted in a MLS of 3.53 between markers D7S501 and D7S523 using the broadest diagnostic model, including major depressive disorder and bipolar type I as affecteds in addition to the aforementioned phenotypes. These results were obtained by including in the analyses only individuals from the late settlement region of Finland settled in the 16th century. Additionally, some support was obtained for linkage to chromosome 1, in a region previously identified in a genome-wide scan of a study sample from a sub-isolate of Finland. Our data demonstrate the importance of genealogical information for studies aiming at identification of predisposing loci in complex diseases.

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Here, we report the results from a three-stage genomewide screen performed in a study sample from an internal isolate of Finland. An effort was made to identify genes predisposing for schizophrenia that are potentially enriched in this isolate, which has an exceptionally high lifetime risk for this trait. Ancestors of the local families with schizophrenia were traced back to the foundation of the population in the 17th century. This genealogical information was used as the basis for the study strategy, which involved screening for alleles shared among affected individuals originating from common ancestors. We found four chromosomal regions with markers revealing pairwise LOD scores>1.0: 1q32.2-q41 (Z(max)=3.82, dominant affecteds-only model), 4q31 (Z(max)=2. 74, dominant 90%-penetrance model), 9q21 (Z(max)=1.95, dominant 90%-penetrance model), and Xp11.4-p11.3 (Z(max)=2.01, recessive 90%-penetrance model). This finding suggests that there are several putative loci predisposing to schizophrenia, even in this isolate.

During the past decade numerous studies have been published describing chromosomal regions potentially linked with schizophrenia. Unfortunately, none of these studies has been able to conclusively identify any specific gene that predisposes to schizophrenia. Typically evidence for linkage is seen on large chromosomal regions, as expected, containing tens or even hundreds of genes. Furthermore, attempts to replicate the findings have rarely been successful leaving a confusion about the existence of predisposing genes for schizophrenia in a particular region of the genome. We have carried out linkage analysis in a set of 62 pedigrees rising from a genetically isolated population of Finland with markers on six chromosomal regions earlier suggested to harbor predisposing genes for schizophrenia, namely 3p, 5q, 6p, 8p, 20p, and 22q. We were not able to find significant evidence for linkage on any of these chromosomal regions. However, some support for linkage was found on all studied chromosomal regions, except 3p.