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.

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.

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, 1 5q, 2,3 6p, 4 8p, 1 20p, 5 and 22q. 6,7 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.We identified all Finnish patients with schizophrenia born between 1940 and 1969 (n = 29 124). 8 Patients who had received disability pension or free medication because of schizophrenia were identified from two registers of the Social Insurance Institution, and patients who had been hospitalized for schizophrenia were identified from the National Hospital Discharge Register. All three registers were computerized in 1968; ICD-8 diagnostic criteria and codes were used before 1987, since when psychiatric diagnoses have been coded according to ICD-9 applying DSM-III-R diagnostic criteria. We accepted all probands with a 295 diagnosis according to the ICD-8 and ICD-9 numbering scheme; this includes patients with schizophrenia, schizophreniform disorder, and schizoaffective disorder. Parents and siblings were identified from the National Population Register, and information on these relatives was linked to the health care registers to obtain data on their hospital treatments, pensions, and free medications.From these pedigrees, families with at least three affected family members were identified (n = 312), and those with at least one unaffected and three affected children were asked to participate in the study. If both parents were affected, the family was excluded. Diagnoses were confirmed as described in methods. Some families refused to participate and some were excluded because of uncertain diagnoses, and finally 62 families were used for molecular genetic studies out of 102 families who were asked to participate. Three different diagnostic classes were constructed as follows: class 1 contained 137 cases of DSM-IV schizophrenia, class 2 added 23 cases with schizoaffective disorder, and class 3 another 29 individuals with schizophrenia spectrum conditions (schizophreniform disorder, schizotypal personality disorder, schizoid personality disorder, delusional disorder, brief psychotic disorder, and psychotic disorder NOS). Patients with bipolar disorder or major depressive disorder were classifie...

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