A large population cohort provides normative data for investigation of temperament.

OBJECTIVE: We evaluated the psychometric properties of widely used scales for assessing temperament in a large birth cohort. We simultaneously compared the properties of the temperament dimensions of the Tridimensional Personality Questionnaire (TPQ) and of the Temperament and Character Inventory (TCI). METHOD: As part of the 31-year follow-up survey of the prospective Northern Finland 1966 Birth Cohort, the TPQ and TCI temperament questions were filled in by 4349 subjects (1974 males, 2375 males). Factor analysis and Cronbach's alpha were used to explore the psychometric properties of the scales. RESULTS: Of the three higher-order dimensions the reward dependence (RD) was the only one performing poorly in our study sample. Cronbach's alpha was higher in the TCI than in the TPQ. CONCLUSION: The results indicate good performance of the TCI and TPQ. Factor analysis support adoption of four temperament dimensions and suggest that developmental work is still needed in the RD dimension.

A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q.

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.

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.

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26.

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.

Seasonal affective disorder and serotonin-related polymorphisms.

Disturbances in central serotonergic systems have been hypothesized to be involved in seasonal affective disorder (SAD). Association between SAD and the shorter allele of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR) has been reported in an American sample. We have genotyped 82 SAD patients and 82 healthy controls from Sweden, Finland, and Germany for this and five other polymorphisms in the genes coding for serotonin receptors 5-HT2A and 5-HT2C, tryptophan hydroxylase and white. No associations with SAD or seasonality (seasonal variations in mood and behavior) were detected. Although minor effects cannot be excluded, our results suggest that these polymorphisms do not play a major role in the pathogenesis of SAD in the northern European population.

Association study of the low-activity allele of catechol-O-methyltransferase and alcoholism using a family-based approach.

Catechol-O-methyltransferase (COMT) is a major component of the metabolic pathways of neurotransmitters such as dopamine, adrenaline, and noradrenaline. The activity of COMT is known to vary within the population; it exists in common high- and low-activity forms that are determined by a Val --> Met polymorphism at amino acid position 108/158 (in soluble or membrane-bound COMT). Recently, the low-activity allele was reported to contribute to the development of late-onset alcoholism in men. The present study extends this study by utilizing a family-based association approach, and by including individuals with early-onset alcoholism. Although no significant transmission disequilibrium was found in the overall sample of 70 parent/offspring trios (TDT = 1.43, P = 0.23), we observed a preferential transmission of the low-activity allele to patients with an early onset of disease (n = 32, TDT = 4.83, P = 0.028). Our results provide further evidence for an involvement of the COMT low-activity allele in the development of alcoholism and demonstrate the need for further studies in large samples of alcoholic patients.

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.

Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22.

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.

Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings.

The serotonergic (5-HT) system has been implicated in the etiopathogenesis of psychoses. Since the 5-HT transporter plays an important role in regulation of 5-HT transmission, its gene can be considered as a candidate for vulnerability to psychiatric disorders. Two polymorphic sites of the 5-HT transporter gene-5-HTTLPR, a VNTR in the 5' regulatory region, and a VNTR in the second intron-were studied in a sample of 61 families with schizophrenia for transmission disequilibrium. Each family contained at least two siblings affected with schizophrenia or schizoaffective disorder (mainly schizophrenic). One hundred and thirty-nine affected offspring with parental information for genotyping, were available for analysis. No preferential transmission of either short or long alleles of the promoter polymorphism was observed. However, a transmission distortion was detected for alleles of the intronic VNTR polymorphism (chi2TDT max =14.33; P = 0.0002; corrected P value = 0.0003) resulting in more frequent than expected transmission of the 12 repeat allele. This finding adds additional evidence to the idea that the serotonergic system may be involved in development of psychoses. Molecular Psychiatry (2000) 5, 91-95.

DRD4 exon III VNTR polymorphism-susceptibility factor for heroin dependence? Results of a case-control and a family-based association approach.

Dopaminergic abnormalities are implicated in the pathogenesis of substance abuse.1 Recently, two reports have been published suggesting an association between opioid dependence and presence of long alleles of the dopamine D4 receptor (DRD4) gene exon III VNTR.2, 3 We have attempted to replicate this finding using a two-tiered strategy employing independent case-control and family-based association samples. Our study was possibly the largest candidate gene association study to date on opioid dependence in a sample of 815 subjects, 396 of whom were patients. We found long alleles of the DRD4 exon III VNTR in similar frequency among 285 heroin addicts and 197 controls. Furthermore, no preferential transmission of long alleles to affected offspring was observed in a sample of 111 patients and their parents. Our results, therefore, do not support the hypothesis that alleles of the DRD4 exon III VNTR are susceptibility factors for opioid dependence in man. Molecular Psychiatry(2000) 5, 101-104.

The genetic epidemiology of schizophrenia and of schizophrenia spectrum disorders.

It has been known for a long time that schizophrenia and several related psychopathological traits aggregate in families on a common genetic basis. Improved methodology of recent family, twin and adoption studies has led to a better unterstanding of which psychopathologically defined syndromes and personality traits are part of a schizophrenia spectrum, and to which degree individual spectrum conditions share the same genetic background with schizophrenia. The spectrum concept has been extended to include neuropsychologically, neurophysiologically and neuroradiologically measurable familial traits as subclinical endophenotypes of schizophrenia that may be more fundamental to the development of the disease than overt psychopathology. This knowledge has been useful in designing molecular genetic linkage and association studies that aim at directly identifying individual risk genes. Replicable linkage findings have emerged from genome scans that imply at least seven chromosomal regions to harbour schizophrenia susceptibility genes. They strengthen the conviction that schizophrenia is indeed a genetically complex disorder, based on a larger number of susceptibility genes with risk-increasing alleles that are common in the population and exert a limited effect on the individual level. Although demanding increased investments into sample collection, genotyping and computational technology, identification of these genetic variants will be possible and worthwhile since they may have a large effect in terms of population attributable risk.

Pharmacogenomics and addiction to opiates.

The risk of initiating and maintaining the use of opiates up to the point of abuse and dependence is to a large degree genetically transmitted and is separate from genetic risk factors for addiction to other drugs of abuse. Pharmacogenetic studies have so far focused on obvious candidate genes that are expected to be involved either in the pharmacokinetics or in the pharmacodynamics of opioids in the mesolimbic reward system of the brain. The few findings of a positive allelic association rarely withstand replication in independent case-control or less stratification-prone family-based association samples. A pharmacogenomic approach in the best sense of the word, however, involves an unbiased, genome-wide, parallel search for risk genes and gene expression patterns. So far, only quantitative trait loci mapping studies of inbred rodent strains and differential expression studies using high-density DNA microarrays fulfill these requirements. The present state of pharmacogenomic and pharmacogenetic studies in animals and humans with respect to opiate addiction is reviewed in this paper.

Susceptibility for alcoholism: DRD4 exon III polymorphism: a case-control and a family-based association approach.

Abstract The present investigation explored whether the 7-repeat allele of the exon III polymorphism in the dopamine D4 receptor gene confers to susceptibility of alcoholism. Using a classical case-control approach we first compared DRD4 exon III VNTR frequencies between alcoholics and ethnically matched controls (sample I). Secondly, we applied a family-based association approach in an independent parent-offspring sample of alcoholics (sample II). All patients underwent an inpatient treatment for alcohol detoxification: sample I comprised 218 alcoholics and 197 ethnically matched controls, sample II included 76 alcoholics plus their biological parents. A higher proportion of addicted individuals in sample I revealed the 7-repeat allele compared to the control sample yielding an odds ratio (OR) of 1.43 (individuals homozygous for 7-repeat allele) and an OR of 1.69 (homozygous and heterozygous 7-repeat allele individuals together). However, we failed to detect preferential transmission from parents to offspring of either the 7-repeat allele or the long alleles (5-7 repeats) of the DRD4 exon III VNTR in the family-based association approach (sample II). The impact of the DRD4 exon III polymorphism on susceptibility to addictive behaviour putatively plays only a minor role in our sample of alcohol-dependent patients, since we were not able to replicate our findings by the family-based association approach. However, a larger sample size by the family-based approach would be needed (approximately > 300 parent-offspring trios) to definitely corroborate or reject the findings from our case-control sample.

[Genetics of schizophrenic disorders. New concepts and findings]. / Genetik schizophrener Störungen. Neuere Konzepte und Befunde.

Schizophrenia is a genetic complex disease as it does not follow monogenic transmission while non-familial environmental factors have a strong additional impact. A heterogeneous, continuous phenotype is transmitted in families which can now be more precisely characterized. Genes coding for proteins with presumed pathophysiological relevance are apparently not playing a major causal role. However, in the last three years several (currently seven) candidate regions have been identified in a replicable manner by linkage studies. These regions are likely to host susceptibility genes for schizophrenia, but none of them has been identified up to now. Given these findings, polygenic transmission has now become very likely. The candidate regions are currently being narrowed down by various promising techniques.

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.

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.

Association between hSKCa3 and schizophrenia not confirmed by transmission disequilibrium test in 193 offspring/parents trios.

A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.

Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families.

Previously reported linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families. Twenty-three short tandem repeat markers were investigated in 57 families containing 103 individuals with bipolar I disorder (BPI), 26 with bipolar II disorder (BPII), nine with schizoaffective disorder of the bipolar type (SA/BP), and 38 individuals with recurrent unipolar depression (UPR). Evidence for linkage was tested with parametric and non-parametric methods under two definitions of the affected phenotype. Analysis of all 57 families revealed no robust evidence for linkage. Following previous reports we performed separate analyses after subdividing the families with respect to the sex of the transmitting parent. Fourteen families were classified as paternal and 12 families as maternal. In 31 families the parental lineage of transmission of the disease could not be determined ('either' families). Evidence for linkage was obtained for chromosomal region 18p11.2 in the paternal families and for 18q22-23 in the 'either' families. The findings on 18p11.2 and 18q22-23 support prior evidence for susceptibility loci in these regions. The parent-of-origin effect on 18p11.2 is confirmed in our sample. The delineation of characteristics of 'either' families requires further study.