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

Abstract

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...

Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study

“…67 Even with large sample sizes, and a gene conferring a sixfold increased risk to sibs, if one confines the search to the region of maximal sharing, the gene will be missed over 60% of the time. 68 Hovatta and colleagues noted 69 considerable error in the position of the maximum lod scores, especially for sample sizes of 100 or 200 sib pairs and for the less significant findings. We have also examined this issue by simulation.…”

Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families

“…The COMT enzyme has two forms, a soluble form (S-form) and a membrane-bound form (M-form), with the latter mainly expressed in brain. 1 The COMT gene is located on chromosome 22q11, a region that showed positive results in some linkage studies [2][3][4] but was negative in others. [5][6][7][8] The region is also associated with the velocardiofacial syndrome (VCFS), 9 a genetic disorder characterized by cleft palate, heart defects and characteristic facial appearance.…”

Recent advances in the genetics of schizophrenia

“…This result was not subsequently replicated in a large multicenter study, the Schizophrenia Linkage Collaborative Group III (SLCG III) which included the Irish cohort [86]. Weakly positive results were seen nearby on 5q 33.1 in a Finnish cohort of 62 multiplex families, with a twopoint LOD score of 1.36 at the CSF1R locus [87]. This was subsequently supported by a LOD score > 3 in an extended group of 237 Finnish families [88], though these results on 5q22-31 were somewhat proximal to the original findings on 5q33.1.…”

“…Twin studies have also been used in biometric studies to determine the most likely disease model. Cardno and colleagues performed such an analysis on pooled twin data and found that a model containing additive genetic and environmental effects gave the best fit, with a heritability of 83% (95% CI [74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90] and specific environmental effects of 17% (95% CI 10-26) [13]. Discordant MZ twin studies have also shown that the children of both affected and unaffected MZ twins have similar risks of schizophrenia-like psychosis [14].…”