Ritva Arajärvi

A Genomewide Screen for Schizophrenia Genes in an Isolated Finnish Subpopulation, Suggesting Multiple Susceptibility Loci

Schizophrenia is a severe mental disorder affecting approximately 1% of the worlds 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.

Linkage analysis of putative schizophrenia gene candidate regions on chromosomes 3p, 5q, 6p, 8p, 20p and 22q in a population-based sampled Finnish family set.

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.

Familial loading associates with impairment in visual span among healthy siblings of schizophrenia patients

BACKGROUND The effect of familial loading on neurocognitive deficits in relatives of schizophrenia patients has been detected in family and twin studies. The present study examined this effect among healthy siblings of schizophrenia patients in a Finnish isolate with high prevalence of schizophrenia. METHODS We assessed performance in verbal and visual span tasks, in tests measuring intelligence, and in declarative verbal memory and learning tasks in 31 and 67 healthy siblings from families with one schizophrenia patient, or with two or more patients, respectively. The differences between the groups were tested using linear mixed effects models. RESULTS An effect of familial loading was detected in the backward visual span task, measuring immediate visual memory with requirements from the visual domain of working memory. In this task, the healthy siblings from multiply affected families performed worse than those from the singleton families. CONCLUSIONS The finding that the multiplex vs. singleton differences were selective to the backward visual span task, strengthens the view that the visual domain of working memory may provide a valuable endophenotypic marker for genetic schizophrenia studies.

Prevalence and diagnosis of schizophrenia based on register, case record and interview data in an isolated Finnish birth cohort born 1940–1969

IntroductionSchizophrenia occurs worldwide but the prevalence varies markedly. In Finland, schizophrenia is most prevalent in the northeastern region. Our aims were to reassess the register-, case record- and interview-based lifetime prevalence in a genetically homogeneous birth cohort from an isolate population with earlier reported high prevalence of schizophrenia and a chromosome linkage to chromosome 1q.MethodsWe identified all patients with a diagnosis of schizophrenia [International Classification of Diseases (ICD)-8, ICD-9 or ICD-10 codes], born 1940–1969 in the isolate (n=282) and alive (n=237) in 1998 using the Hospital Discharge, Disability Pension and Free Medicine Registers. The corresponding birth cohort of 14,817 persons and 12,368 alive in 1998 was identified from the National Population Register. We validated 69% of the register diagnosis by making DSM-IV consensus diagnoses, and interviewed 131 (55%) of the 237 patients with SCID-I and SCID-II.ResultsThe register-based lifetime prevalence was 1.5% for schizophrenia and 1.9% for schizophrenia spectrum psychotic disorders: in birth cohorts born 1945 to 1959, the latter prevalence was especially high (2.4%). Of those with a register diagnosis of schizophrenia spectrum psychotic disorder, 69% or 63% also received a record-based consensus diagnosis or SCID interview diagnosis of schizophrenia, and the prevalence was 0.9–1.3 and 0.7–1.2%, respectively, when we reassessed most of the register-based cases. The cumulative incidence of schizophrenia spectrum psychotic disorders in the total birth cohort was 1.9%.ConclusionIn this isolate, the register, DSM-IV consensus and SCID interview-based lifetime prevalence of schizophrenia was internationally high. For genetic research work, the register diagnosis should be reassessed using either structured interview or the best estimate consensus diagnosis.

Affective flattening and alogia associate with the familial form of schizophrenia

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.

Psychosis among "healthy" siblings of schizophrenia patients

BackgroundSchizophrenia aggregates in families and accurate diagnoses are essential for genetic studies of schizophrenia. In this study, we investigated whether siblings of patients with schizophrenia can be identified as free of any psychotic disorder using only register information. We also analyzed the emergence of psychotic disorders among siblings of patients with schizophrenia during seven to eleven years of follow-up.MethodsA genetically homogenous population isolate in north-eastern Finland having 365 families with 446 patients with a diagnosis of schizophrenia was initially identified in 1991 using four nationwide registers. Between 1998 and 2002, 124 patients and 183 siblings in 110 families were contacted and interviewed using SCID-I, SCID-II and SANS. We also compared the frequency of mental disorders between siblings and a random population comparison group sample.ResultsThirty (16%) siblings received a diagnosis of psychotic disorder in the interview. 14 siblings had had psychotic symptoms already before 1991, while 16 developed psychotic symptoms during the follow-up. Over half of the siblings (n = 99, 54%) had a lifetime diagnosis of any mental disorder in the interview.ConclusionRegister information cannot be used to exclude psychotic disorders among siblings of patients with schizophrenia. The high rate of emergence of new psychotic disorders among initially healthy siblings should be taken into account in genetic analysis.

Linkage analysis of schizophrenia controlling for population substructure

Etiological heterogeneity and complexity has hampered attempts to identify predisposing genes for schizophrenia. We sought to minimize the number of segregating genes involved by focusing on a population isolate with elevated disease prevalence. We exploited the well‐established population history, and searched for disease susceptibility loci in families from two alternative founder lineages. We studied 28 schizophrenia pedigrees (123 nuclear families) from an outlying municipality on the eastern border of Finland. We divided the families based on their genealogy and defined two routes of immigration: southern and northern. We examined the kinship coefficients and allele frequency distributions within each group, and performed a linkage analysis based on 497 microsatellite markers across the genome. A high degree of historical relatedness was demonstrated by higher sharing of alleles than predicted by the relationships we identified within the previous four generations alone, as would be expected. Between the two subpopulations, allele frequencies were significantly different, consistent with their isolated genealogies. The southern families showed some evidence of linkage in a schizophrenia locus at 4q23 (Z = 3.3) near our previous finding with quantitative variation in verbal learning and memory [Paunio et al. (2004); Hum Mol Genet 13: 1693–1702], while the northern pedigrees gave most significant evidence on 10q21 (Z = 2.53). Joint analysis of families from both lineages suggested evidence of linkage only at 3p14 (Z = 3.18). Thus the detailed genealogical information led us to identification of distinct linkage signals for schizophrenia susceptibility loci between the three analyses we performed.