Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

Incidence of cancer among persons with schizophrenia and their relatives.

BACKGROUND: It has repeatedly been reported that the risk for cancer in patients with schizophrenia is different from that of the general population, specifically a lower risk for lung cancer despite increased smoking. Confirmation of these associations could lead to hypotheses on shared risk or protective factors, either genetic or environmental. METHODS: From Finland's National Hospital Discharge and Disability Pension registers, Helsinki, we identified a cohort of 26 996 individuals born between 1940 and 1969 and treated for schizophrenia between 1969 and 1991. They were followed up for cancer from 1971 to 1996 by record linkage with the Finnish Cancer Registry, yielding 446 653 person-years at risk, and standardized incidence ratios (SIRs) were calculated. Likewise, 39 131 parents and 52 976 siblings of the patients with schizophrenia were followed up to explore familial genetic hypotheses on deviations in cancer risk. RESULTS: In patients with schizophrenia, an increased overall cancer risk was found (724 cases observed vs 619 expected; SIR, 1.17; 95% confidence interval [CI], 1.09-1.25). Half of the excess cases were attributable to lung cancer (SIR, 2.17; 95% CI, 1.78-2.60), and the strongest relative increase in risk was in pharyngeal cancer (SIR, 2.60; 95% CI, 1.25-4.77). Cancer incidence in siblings (SIR, 0.89; 95% CI, 0.83-0.94) and parents (SIR, 0.91; 95% CI, 0.89-0.93) was consistently lower than that in the general population. CONCLUSION: Although specific lifestyle factors, particularly tobacco smoking and alcohol consumption, probably account for the increased cancer risk in patients with schizophrenia, the decreased risk in relatives would be compatible with a postulated genetic risk factor for schizophrenia offering selective advantage to unaffected relatives.

Continuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family study.

BACKGROUND: It is widely acknowledged that the genetic diatheses for schizophrenia and affective disorders are independent. However, there are increasing doubts about this classic view, and empirical evidence for a dichotomy of these two prototypes of functional psychoses is limited. A controlled family study of consecutive admissions was conducted to determine whether familial risks for schizophrenic (SCZ) and affective disorders were independent or overlapping. METHODS: Index probands met Research Diagnostic Criteria for SCZ (n = 146), schizoaffective (SA [n = 115]), bipolar (BP [n = 80]), or unipolar major depressive (UP [n = 184]) disorder. Comparison probands met Research Diagnostic Criteria for alcoholism (n = 64) or were sampled from the general population (n = 109). A total of 2845 first-degree relatives were blindly diagnosed from interview, informant, and/or record data, with direct interviews completed in 2070 (82% of living first-degree relatives). RESULTS: By Cox's proportional hazards analysis, SCZ, SA, BP, and UP disorders were familial, in that each group of relatives had an increased lifetime morbid risk (vs those with alcoholism and those from the general population) for the proband's diagnosis. The SCZ and BP disorders were transmitted independently: only probands with manic disorders (BP or SA-BP subtype) showed increased familial risks of BP disorder, and only probands with prominent SCZ features (SCZ or SA) showed increased familial risks of SCZ disorder. However, SCZ probands had an increased familial risk for UP disorder (as did SA, BP, and UP probands) and for the SA-UP subtype. Aggregation of depression in families of SCZ probands could not be explained by the subtype of depression, broad or narrow definition of SCZ disorder, presence or absence of history of depression in SCZ probands, whether onset of depression in a relative occurred before or after onset of a proband's SCZ disorder, or assortative mating. CONCLUSIONS: These data suggest that there could be a familial relationship between the predispositions to schizophrenia and to major depression. We discuss a number of alternative hypotheses about the nature of this possible relationship.

Evidence against linkage of schizophrenia to chromosome 5q11-q13 markers in systematically ascertained families.

Ten pedigrees systematically ascertained in Germany were tested for linkage to chromosome 5q11-q13. In order to replicate the previous report by Sherrington et al (1988), families with a bipolar family member were omitted from the lod score calculations, all diagnoses were based upon Research Diagnostic Criteria, and four different models of the affection status were calculated, including the model for which Sherrington et al calculated the highest lod scores. None of the families investigated showed a positive lod score. Using multipoint linkage analyses, we were able to exclude the region for which a positive linkage has been reported.

DAT1 gene polymorphism in alcoholism: a family-based association study.

BACKGROUND: The present study tests the hypothesis that the 9-repeat allele of the dopamine transporter gene (DAT1; SLC6A3) is more frequent in alcohol-dependent probands--and in particular those with severe withdrawal symptoms (seizures and/or delirium)--compared to nonalcoholics. METHODS: To avoid stratification effects, the family-based association approach of Falk and Rubinstein was used in our sample of 87 alcohol-dependent probands and their biological parents. RESULTS: By applying a family-based association approach, we were not able to detect significant association between allele 9 at DAT1 (SLC6A3) and alcoholism as well as between patients with or without severe withdrawal symptoms. CONCLUSIONS: Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.

Association between novelty seeking and the type 4 dopamine receptor gene in a large Finnish cohort sample.

OBJECTIVE: An association between the type 4 dopamine receptor (DRD4) gene and the behavioral trait of novelty seeking has been reported, but several studies have failed to replicate this finding. In the present study, the authors tested for this association in a representative sample from the Finnish population. METHOD: The authors administered the Temperament and Character Inventory to 4,773 individuals from the 1966 birth cohort of northern Finland. They then genotyped 190 subjects with extreme scores for a 48 base-pair repeat polymorphism in the DRD4 gene. RESULTS: There was a significant difference in allele frequencies between the two groups. The 2- and 5-repeat alleles were significantly more common in the group of high scorers than in the group of low scorers. CONCLUSIONS: These results confirm the original findings of an association between the DRD4 gene and novelty seeking, while showing that novelty seeking is probably not influenced by the polymorphism itself but, rather, a different DNA variant in the DRD4 gene or another gene in linkage disequilibrium with it.

Concordance for sex and the pseudoautosomal gene hypothesis revisited: no evidence of increased sex concordance in a nationwide Finnish sample of siblings with paternally derived schizophrenia.

OBJECTIVE: This study set out to determine, in a homogeneous sample with nationwide coverage in Finland, whether siblings treated for schizophrenia are more often of the same sex than expected by chance, and whether this is especially so when the disorder is transmitted by their fathers. METHOD: Finnish social and health insurance files as well as hospital discharge registers were searched for probands with schizophrenia from a birth cohort spanning 30 years. Nuclear families were identified by cross-linkage with the national birth register, and the sex distribution observed in multiply affected sibships was compared with expected distributions by maximum likelihood analysis. RESULTS: In the subset of multiply affected sibships with one parent who had schizophrenia (84 fathers and 120 mothers), the observed sex distribution did not deviate from the expected pattern. However, a small and marginally significant excess of sex concordance emerged from the total sample of 1,942 sibships in which there were at least two affected members, irrespective of the parents' affection status. CONCLUSIONS: The results indicate that no above-chance sex concordance in sibships multiply affected with paternally transmitted schizophrenia is present in the genetically homogeneous population of Finland. In view of a virtually unbiased and complete ascertainment procedure and sample sizes one to two orders of magnitude larger than those in previous studies, the authors attribute prior findings of such a concordance to sampling artifacts or chance fluctuations and finally conclude that except for regional genetic isolates, there is no epidemiologic evidence that a gene accounting for substantial susceptibility to schizophrenia in a greater proportion of cases resides in the pseudoautosomal region of the sex chromosomes.

Schizoaffective disorder and affective disorders with mood-incongruent psychotic features: keep separate or combine? Evidence from a family study.

OBJECTIVE: This study investigated whether the distinction between schizoaffective disorder and affective disorders with mood-incongruent psychotic features as described in DSM-III-R is reflected by aggregation of schizophrenia in the families of probands with the former disorder and aggregation of affective disorders mainly among the relatives of probands with the latter type of disorders. METHOD: The probands were 118 inpatients with definite lifetime diagnoses of DSM-III-R schizoaffective disorder or a major mood disorder with incongruent psychotic features according to structured clinical interviews. Diagnostic information on 475 of the probands' first-degree relatives was gathered through direct interviews (with 80% of the living first-degree relatives) or the family history approach. The rates of affective and psychotic disorders among these relatives were then compared with those among the relatives of a comparison group of 109 interviewed individuals from the general population who were matched on sociodemographic factors to the inpatient probands. RESULTS: With regard to the familial aggregation of schizophrenia, the DSM-III-R distinction emerged as valid. However, the risk of unipolar affective disorders was enhanced in the families of all of the subgroups of patients studied. The unipolar/bipolar distinction in both DSM-III-R diagnostic groups was reflected by distinct patterns of bipolar disorders in the relatives. CONCLUSIONS: The results partly support the DSM-III-R dichotomy of schizoaffective disorder and affective disorders with mood-incongruent psychotic features. Although the differences between these two diagnostic groups were significant, the magnitude of the differences remained relatively modest.

Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence.

OBJECTIVE: An association between the 5-HTTLPR short variant polymorphism in the promoter region of the serotonin transporter gene and risk for alcohol dependence has been reported from case-control studies that are, however, prone to chance findings related to artifacts of population structure. The authors sought additional evidence for this association from a family-based study. METHOD: Ninety-two alcohol-dependent probands and their parents were tested for nonrandom transmission of alleles from heterozygous parents to affected probands. RESULTS: Preferential transmission of the short allele was found (65 of 102 transmissions from heterozygous parents). CONCLUSIONS: The results suggest allelic association between a variant in the promoter region of the serotonin transporter gene and the risk for alcohol dependence. However, it remains to be seen whether the functional properties of this variant are directly responsible for the increased risk to alcohol dependence.

Schizophrenia in the genetic isolate of Finland.

We compared the features of schizophrenia in the homogeneous population of Finland (population about 5,000,000) and in an internal isolate in northeastern Finland inhabited in the 1680s by a small group of founders (current population about 18,000) in a register-based epidemiological study. We identified all cases with a diagnosis of schizophrenia in Finland born between 1940-1969 using three national computerized registers and found a total of 267 schizophrenia patients in the internal isolate and 29,124 in Finland. The lifetime prevalence was 2.21% in the internal isolate and 1.21% in Finland, respectively. The age-corrected lifetime risk was 3.2% in the internal isolate and 1.1% in the whole country. The risk of schizophrenia to siblings in the internal isolate was 6.4% (95% confidence interval 0.052, 0.078), 9.1% (95% CI 0.062, 0.130), and 6.8% (95% CI 0.028, 0.135) given 1, 2, or 3 affected siblings, and for all Finland 4.2% (95% CI 0.036, 0.043), 6.4% (95% CI 0.058, 0.071), and 8.7% (95% CI 0.068, 0.107) given 1, 2, or 3, affected siblings, respectively. The mean number of children in schizophrenia families and thus the number of families having at least two affected individuals were clearly higher in the isolate (24.9% vs 9.2%). We did not find any other epidemiological features differing between these two regions. It seems that the family material collected from the internal isolate is a representative subsample from the entire country and hopefully it enables easier identification of at least some predisposing genes for schizophrenia due to its unique population structure.

Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene.

In the present study we sought to identify genetic variation in the 5-HT1A receptor gene which through alteration of protein function or level of expression might contribute to the genetic predisposition to neuropsychiatric diseases. Genomic DNA samples from 159 unrelated subjects (including 45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette's syndrome, as well as 25 healthy controls) were investigated by single-strand conformation analysis. Overlapping PCR (polymerase chain reaction) fragments covered the whole coding sequence as well as the 5' untranslated region of the 5-HT1A gene. The region upstream to the coding sequence we investigated contains a functional promoter. We found two rare nucleotide sequence variants. Both mutations are located in the coding region of the gene: a coding mutation (A-->G) in nucleotide position 82 which leads to an amino acid exchange (Ile-->Val) in position 28 of the receptor protein and a silent mutation (C-->T) in nucleotide position 549. The occurrence of the Ile-28-Val substitution was studied in an extended sample of patients (n = 352) and controls (n = 210) but was found in similar frequencies in all groups. Thus, this mutation is unlikely to play a significant role in the genetic predisposition to the diseases investigated. In conclusion, our study does not provide evidence that the 5-HT1A gene plays either a major or a minor role in the genetic predisposition to schizophrenia, bipolar affective disorder, or Tourette's syndrome.

Potential linkage for schizophrenia on chromosome 22q12-q13: a replication study.

In an attempt to replicate a potential linkage on chromosome 22q12-q13.1 reported by Pulver et al. [1994: Am J Med Genet 54:36-43], we have analyzed 4 microsatellite markers which span this chromosomal region, including the IL2RB locus, for linkage with schizophrenia in 30 families from Israel and Germany. Linkage analysis by pairwise lod score analysis as well as by multipoint analysis did not provide evidence for a single major gene locus. However, a lod score of Zmax = 0.612 was obtained for a dominant model of inheritance with the marker D22S304 at recombination fraction 0.2 by pairwise analysis. In addition, using a nonparametric method, sib pair analysis, a P value of 0.068 corresponding to a lod score of 0.48 was obtained for this marker. This finding, together with those of Pulver et al. [1994: Am J Med Genet 54:36-43] and Coon et al. [1994: Am J Med Genet 54:72-79], is suggestive of a genetic factor in this region, predisposing for schizophrenia in a subset of families. Further studies using nonparametric methods should be conducted in order to clarify this point.

Human delta-opioid receptor gene and susceptibility to heroin and alcohol dependence.

In the present study, we tested the hypothesis that addictive behavior may be influenced by genetic variation in the human delta-opioid receptor gene. We investigated the contribution of a silent T to C change in the coding region to the development of heroin and alcohol dependence using large case-control and family-based association samples. Presence of the C allele was previously reported to significantly increase the risk for heroin dependence. In the present study, however, we did not find statistically significant differences between patients and controls nor did we find preferential transmission of the C allele from parents to affected offspring. Our results, therefore, do not support an association between genetic variation of the delta-opioid receptor and addictive behavior in man.

Further evidence for a susceptibility locus on chromosome 10p14-p11 in 72 families with schizophrenia by nonparametric linkage analysis.

Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage. We obtained highest allele sharing for the two markers D10S582 (61.5% allele sharing, chi2 = 7.6, P = 0.0058) and D10S1423 (59% allele sharing, chi2 = 4.76, P = 0.029). D10S1423 is one of the markers with the highest lod scores in the study of Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557]. GENEHUNTER analysis revealed a nonparametric lod score (NPL) of 3.2 (P = 0.0007) for the marker D10S1714, which lies in the same region. Multipoint affected sib-pair lod score analysis (identity by descent) calculated by ASPEX revealed a lod score of 1.72 for all possible sib-pair combinations (107) and of 2.13, when only independent sib-pairs (87) were counted. Our study provides further evidence for a potential susceptibility locus for schizophrenia on chromosome 10p.

Depression in the community: a comparison of treated and non-treated cases in two non-referred samples.

Family studies in non-patient samples may help to clarify whether or not treatment-seeking behaviour is substantially determined by clinical features of depression. Life-time risks of depression were investigated by structured clinical interviews (SADS-LA) in both a high-risk sample of depressed patients' first-degree relatives and an unscreened control sample of the general population: 34.6% of the high-risk sample versus 23.1% of controls were cases of depression, with a female preponderance in both groups. The rates of treated depression were 17.0% versus 8.5%. Female sex, greater age, higher severity of episodes, manic or hypomanic episodes recurrent course, and introverted and anancastic personality were factors increasing the rate of treated cases in both samples, as well as familial loading with treated depression. Late onset and chronicity of depression did not significantly affect these proportions, but controlling for the effects of retrospective assessment by focusing only on depression within the past year confirmed the results. However, the major finding of a familial influence in treatment-seeking behaviour might be due to a personality factor running in families, as well as to a sharing of common environmental factors.

Personality variations in healthy relatives of schizophrenics.

A familial relationship between schizophrenia and schizotypal personality disorder is widely acknowledged; the familial relationship between schizophrenia and the broad continuum of schizoid personality variation is less clear. In a comprehensive family study healthy relatives of schizophrenics were compared by self rated personality features with relatives of unipolar depressed patients and with relatives of controls. The dimension of schizoidia was not able to distinguish the groups of relatives. However, relatives of schizophrenics (in particular male relatives) scored higher on 'normalized' personality dimensions such as 'rigidity' and 'neuroticism'. Healthy relatives of probands with unipolar depression revealed a similar deviant pattern.

Concordance for gender in sib pairs affected with schizophrenia and related disorders.

An excess concordance by sex among siblings affected with schizophrenia has been proposed by some previous and recent investigators. However, this hypothesis has not been supported by some recent studies having complete ascertainment of probands and relatives. The present report is based on sibships with multiple affected members derived from a family study of systematically recruited inpatients (146 probands with schizophrenia and 132 probands with other psychotic disorders). Evidence for an excess concordance rate for gender among proband-sibling pairs with both members affected is suggested under a broad definition of illness.

Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association.

This study explores the genetic relationship between schizophrenia and the dopamine transporter gene (DAT) by a variety of methods. In a sample of 48 families--each family containing at least one nuclear family with a pair of affected siblings--we performed linkage analysis using the maximum likelihood (LOD score) method as well as sibpair analysis (identity by descent). In addition, we investigated a sample of 108 nuclear families--index case affected with schizophrenia/chronic schizoaffective disorder--for association using the haplotype relative risk method. Linkage between schizophrenia and DAT using two- and three-point linkage analysis was excluded with all disease models employed. No evidence for association between haplotypes of the VNTR-probe of the DAT and schizophrenia has been detected. Thus, a contribution of the DAT gene to the genetic diathesis of schizophrenia is unlikely in the families studied.

Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene.

We report two novel polymorphisms and a rare deletion variant in the human dopaine D4 receptor gene. The two polymorphisms are characterized by single base pair substitutions, namely a G-->C transversion changing codon 11 from GGG (encoding Gly) to CGG (encoding Arg) and a C-->T transition in position -11 upstream from the start codon. The Arg11 variant occurs at a frequency of about 1% and the C-->T transition at a frequency of about 7% in German control subjects (n = 148). Allele frequencies observed in patients suffering from schizophrenia (n = 256) and bipolar affective disorder (n = 99) were similar. The deletion variant is characterized by a 21 bp deletion affecting codons 36 to 42 coding for amino acids Ala-Ala-Leu-Val-Gly-Gly-Val located in the first transmembrane domain of the dopamine D4 receptor. The mutation was identified in a single individual suffering from obsessive-compulsive disorder and panic disorder. We were unable to detect the deletion in patients with schizophrenia and bipolar affective disorder, nor in healthy controls.

hSKCa3: no association of the polymorphic CAG repeat with bipolar affective disorder and schizophrenia.

hSKCa3 is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. Since an association between longer alleles of this CAG repeat and bipolar disorder or schizophrenia has been reported, we genotyped the polymorphic CAG repeat in 91 German family trios of patients with bipolar disorder I and used the transmission disequilibrium test (TDT) to test for association. Applying a dichotomized model (< or = 19 or > 19 CAG triplets), we found no evidence for an association of longer alleles with bipolar disorder (TDT = 0.75, P = 0.386). Regarding the whole range of alleles, there was no preference in transmitting the larger of the two observed alleles from parents to the affected offspring. In parallel we performed an independent case-control study on German patients with bipolar disorder and schizophrenia. Again we did not detect an overrepresentation of longer CAG repeats in patients. Thus, our data do not support the hypothesis that longer CAG repeats in the hSkCa3 gene contribute to the susceptibility for bipolar disorder and schizophrenia.