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Background: Abdominal pain is a common cause of visits to emergency facilities. It is related to psychiatric disorders in primary care, but it is unclear if this also holds in emergency departments. Objective: Is to explore potential differences between diagnostic groups in patients with acute abdominal pain in an emergency ward regarding concurrent somatic-and psychiatric symptoms, 'Length of stay' (LOS) and perceived health. Method: The patients ( N  = 137) were divided into three groups; organic dyspepsia, specific abdominal diagnoses, and non-specific abdominal pain. The Prime-MD results for extra gastrointestinal symptoms (outside the gastrointestinal tract), psychiatric symptoms, frequency of symptoms, self-reported health, and LOS within the month before admittance were compared between the diagnostic groups. Results : There was a significant positive correlation between the number of physical extra gastrointestinal and psychiatric symptoms ( p  < .001), especially regarding anxiety ( p  < .001) and depression ( p  = .002). Patients with organic dyspepsia reported significantly more total ( p  = .016), extragastrointestinal ( p  = .026) (chest pain; p  = .017, dizziness; p  = .004, palpitations; p  = .005, insomnia; p  = .005 and worries; p  = .001), and summarized anxiety and depression symptoms ( p  = .001-0.002) besides poorer general health ( p  < .001) compared to other abdominal conditions. Also, organic dyspepsia patients needed longer hospital stay than the non-specific abdominal group ( p  = .002) but similar to the specific abdominal disorders group. Conclusion: Organic dyspepsia is accompanied by more co-occurring physical, anxiety and depression symptoms as well as poorer perceived health than other abdominal pain conditions and comparably increased LOS. This suggests that psychiatric consultations might be beneficial for diagnosing and treating psychiatric comorbidity in emergency care.

Background: Several conditions presenting with abdominal pain are associated with specific personality factors although it is unclear if this is true also in emergency clinic settings., Objective: To study personality factors among patients with acute abdominal pain in an emergency ward., Methods: Consecutive patients (N = 165) with abdominal symptoms at an emergency clinic were administrated the Temperament and Character Inventory (TCI). Three main groups were identified; specific abdominal diagnoses, (N = 77), non-specific abdominal pain, (N = 67) and organic dyspepsia (N = 21). TCI results were compared between clinical groups and a control group (N = 122)., Results: As compared to individuals with specific abdominal diagnoses and controls, those with organic dyspepsia were significantly more anxious (harm avoidance), (p = 0.003), and had lower ability to cooperate (cooperativeness) (p = 0.048 and p = 0.004 respectively). They were also significantly more unpretentious (self-transcendence) compared to individuals with specific abdominal diagnoses (p = 0.048), non-specific abdominal pain (p = 0.012) and controls (p = 0.004) and evidenced less mature character (sum of self-directedness and cooperativeness) compared to those with specific abdominal diagnoses and controls (p = 0.003)., Conclusion: Individuals seeking care at an emergency clinic with organic dyspepsia showed a distinguishable pattern of personality features that distinguished them from the other comparison groups. Therefore an evaluation of personality factors may add a new dimension to the diagnostic investigation in the emergency care of abdominal pain and contribute to the optimization of the treatment of organic dyspepsia., (Copyright © 2018. Published by Elsevier Inc.)

Objective: We have studied temperament and character in pathological gambling (PG)., Methods: Thirty-eight DSM-IV verified pathological gamblers (31 males and 7 females; mean age 35.4 +/- 10.4 years) were tested with Cloninger's Temperament and Character Inventory (TCI). Matched controls were chosen from the normal population., Results: Pathological gamblers scored higher on the temperament factors novelty seeking (NS) and harm avoidance (HA). The most pronounced difference was found in the character factor self-directedness (SD). The pathological gamblers differed from controls in cooperativeness and self-transcendence. A personality disorder was found in 29% of the pathological gamblers 84% of whom scored either low on SD and high on impulsivity or had a more dishonest behaviour. Two-thirds of pathological gamblers showed immature character with or without high HA in temperament. The other third showed normal-character extravagant behaviour (86%), high impulsivity (36%) and less responsibility (50%) being the most common personality traits., Conclusion: HA and NS might be trait-like characteristics in PG.

Objective: To investigate whether women with postpartum depression differ in personality traits from healthy postpartum women, healthy controls from the normal Swedish population and non-postpartum women with major depression., Methods: Forty-five women with postpartum depression were compared with 62 healthy postpartum women, 62 age-matched, healthy, non-postpartum women from a normal sample and 74 non-postpartum women with major depression from a clinical sample. The edinburgh postnatal depression scale was used in order to screen for postpartum depression. A clinical diagnostic interview was done including a rating with the Montgomery-Asberg depression rating scale. Personality i.e. temperament and character was measured by the temperament and character inventory., Results: Harm avoidance (HA) was higher (p < 0.001) and self-directedness (SD) scored lower (p < 0.001) in women with postpartum depression compared to healthy postpartum women. These differences were the most important differences between these two groups. Women with postpartum depression scored lower (p = 0.001) in cooperativeness (CO) and higher (p = 0.019) in self-transcendence (ST) compared to healthy postpartum women. Women with postpartum depression scored overall similar to women with major depression., Conclusion: High HA and low SD can be seen as vulnerability factors for developing a depression and especially in a stressful situation as childbirth.

Background: The nature of the relationship between personality and bipolar affective disorders is an important but unanswered question., Methods: We have studied personality in bipolar patients by using the Temperament and Character Inventory (TCI). TCI were administered to 100 euthymic bipolar patients and 100 controls from the normal population., Results: Bipolar patients were significantly higher in harm avoidance (HA) and lower in reward dependence (RD), self-directedness (SD), and cooperativeness (CO) than controls. Bipolar patients are more fatigable, less sentimental, more independent, less purposeful, less resourceful, less empathic, less helpful, less pure-hearted, and have less impulse control than controls. Bipolar II patients are more impulsive, more fatigable, less resourceful, and have less impulse control than bipolar I patients., Limitations: Our results are limited to euthymic bipolar patients and cannot be generalized to affective disorders., Conclusions: Even when clinically euthymic on lithium maintenance, bipolar patients continue to have a characteristic cognitive deficit. This is in agreement with cognitive theories about cognitive deficits in depression that are regarded as important vulnerability factors in mood disorders.

We studied the relationship between whiplash injury and personality in 40 whiplash patients who admitted the hospital within 8 h from the car accident and 80 age- and gender-matched controls. For this purpose we used the Temperament and Character Inventory (TCI). We found that personality dimensions in whiplash patients both in the acute phase and at follow-up 2 years later showed the same results, i.e., significantly less Harm Avoidant (less anxious; low HA) than controls, but when dividing patients into groups depending on severity of outcome from whiplash injury 2 years after, no differences were found. According to our results personality symptoms related to whiplash injury is probably not a secondary phenomenon. Whiplash patients were normally developed in character, i.e., self-directedness (SD), and CO (cooperativeness) and therefore in general are capable of coping with their somatic problems.

Objectives: The aim of the study was to examine whether personality, i.e. temperament and character influence suicide attempts in bipolar patients., Methods: Bipolar patients were recruited from lithium dispensaries. Temperament and character inventory (TCI) was administered to 100 euthymic bipolar patients and 100 controls., Results: Age of onset was significantly lower in patients with suicide attempts in the total bipolar group (I and II) and bipolar I patients compared with patients without suicide attempts. Bipolar (I and II) and bipolar I patients with suicide attempts were significantly higher in harm avoidance (HA) and reward dependence compared with patients without suicide attempts. Patients (I and II) with suicide attempts had significantly more anticipatory worry, fatigability and asthenia than patients without suicide attempts. Bipolar I patients with suicide attempts had significantly more fatigability and asthenia and were more dependent than patients without suicide attempts. HA was lowest in patients with no suicide attempts and no family history of suicide, higher in patients with family history of suicide or patients with suicide attempts, and significantly highest in patients with suicide attempts and family history of suicide. Patients with suicide attempts and family history of suicide had more anticipatory worry, fatigability and asthenia. Bipolar disorder was significantly correlated to HA and suicide attempts to HA and PS. Family history of suicide and gender were significantly correlated to suicide attempts., Conclusions: Age of onset, HA, PS, gender and family history of suicide had a moderate to very strong effect on suicide attempts in bipolar patients.

The Temperament and Character Inventory is an internationally used personality questionnaire based on Cloninger's psychobiological theory of personality. Given some limitations of Version 9 a revised version was developed. The structural equivalence of the two versions was demonstrated from a cross-cultural perspective with 309 and 173 healthy volunteers from Sweden and Germany, respectively, who completed both versions in one session. In testing for the replicability of the factors across both samples as well as across both versions, an orthogonal Procrustes rotation method was used. The reliability coefficients for the revision were higher than the former version for both samples. The factor structures of the inventory remain highly equivalent across cultures and across versions. The results indicate a cross-cultural transferability of the Temperament and Character dimensions of the inventory. The stability and the validity of the 7-factor model of personality, as suggested by Cloninger, are supported. The Temperament and Character Inventory-Revised represents an important and useful method for the assessment of personality.

Objectives: The aim of this study was to examine whether personality i.e. temperament and character interacts with age of onset in bipolar disorder., Methods: Bipolar patients were recruited among in- and outpatients from lithium dispensaries of northern Sweden. Patients were diagnosed according to DSM-IV criteria for bipolar disorder type I and II. Temperament and Character Inventory (TCI) was used for measuring personality. TCI was administered to 100 lithium treated bipolar patients and 100 controls., Results: Treatment response was significantly lower (p = 0.005) in patients with early onset compared with late onset. Family history (p = 0.013) and suicide attempts (p = 0.001) were also significantly more common in patients with early onset. Further, patients with early onset were significantly higher (p = 0.045) in the temperament factor harm avoidance (HA) than patients with late onset, but the difference was weak. Patients with early onset had more fear of uncertainty (HA2; p = 0.022) and were more shy (HA3; p = 0.030). Bipolar I patients showed similar results as those in the total bipolar group (I and II), with significantly higher HA (p = 0.019, moderate difference), HA2 (p = 0.015) and HA3 (p = 0.043) in patients with early onset compared with late onset. Bipolar II patients showed no differences between early and late age of onset but the groups are small and the results are therefore uncertain., Conclusions: Early age of onset in bipolar disorder was correlated to an increase in severity, family history, poorer treatment response and poorer prognosis. Early onset was also correlated to personality.

Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.

Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations., (Copyright 2002 Wiley-Liss, Inc.)

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.

Several reports have indicated genetic linkage between markers on the short arm of chromosome 6 and schizophrenia. However, significant threshold levels were not always achieved, and the chromosomal regions identified are large and different in different families. One way to decrease the problem of heterogeneity is to study a single extended pedigree. Here we report the analysis of a very large, previously undescribed pedigree from northern Sweden that includes 31 affected individuals. We typed 16 markers spanning 40 cM on the short arm of chromosome 6. Linkage analysis was performed only with the affected individuals. Suggestive lod scores (maximum 2.6) were obtained with markers on chromosome 6p23 in a single branch of the large pedigree indicating possible heterogeneity inside the family. A haplotype comprising markers from D6S309 to D6S1578 was found to segregate with the disease. This chromosomal region is included within a segment proposed to contain a susceptibility gene for schizophrenia by many other investigators. Our results thus give further support for a possible localization of a susceptibility locus for schizophrenia in 6p23 and help to narrow the candidate chromosomal region to the segment included between markers D6S309 and D6S1578., (Copyright 1999 Wiley-Liss, Inc.)

An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) > 120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.1 on 18q21.1. In a set of patients and controls in which we had previously found a significant difference in RED size distribution, the frequency of expansions at the CTG18.1 locus was 13% in bipolar patients (n = 60) and 5% in controls (n = 114) (P < 0.07) with a significantly different size distribution (P < 0.03). A second set of patients were ascertained from 14 affective disorder families showing anticipation. Twelve of the families had members with RED products > 120 nt. The RED product distribution was significantly different (P < 0.0007) between affected (n = 53) and unaffected (n = 123) offspring. Using PCR, a higher frequency (P < 0.04) of CTG18.1 expansions as well as a different (P < 0.02) repeat size distribution was seen between affected and unaffected offspring. In addition, a negative correlation between RED product size and the age-of-onset could be seen in affected offspring (rs = -0.3, P = 0.05, n = 43). This effect was due to an earlier onset in individuals with long CTG18.1 expansions. No difference in ERDA1 expansion frequency was seen either between bipolar patients (35%, n = 60) and matched controls (29%, n = 114), or between affected and unaffected offspring in the families. We conclude that expanded alleles at the CTG18.1 locus confers an odds ratio of 2.6-2.8 and may thus act as a vulnerability factor for affective disorder, while the ERDA1 locus seems unrelated to disease.

The Temperament and Character Inventory (TCI) is a self-report personality questionnaire based on Cloninger's psychobiological model of personality, which accounts for both normal and abnormal variation in the two major components of personality, temperament and character. Normative data for the Swedish TCI based on a representative Swedish sample of 1,300 adults are presented, and the psychometric properties of the questionnaire are discussed. The structure of the Swedish version replicates the American version well for the means, distribution of scores, and relationships within the between scales and subscales. Further, the Swedish inventory had a reliable factor structure and test-retest performance. The results of this study confirm the theory of temperament and character as a seven-factor model of personality.

Recurrent major depression, RMD, is characterized by the occurrence of depressive episodes in the absence of mania and/or hypomania. In linkage studies, RMD (or, in general, unipolar depression) are frequently grouped together with bipolar illnesses into a broad definition of affective disorders. However, twin studies suggest that RMD and bipolar disorders might have different genetic determinants. The objective of this study was to test a set of families with RMD for linkage to chromosomes that have been recently proposed to contain susceptibility loci for bipolar disorders: chromosomes 16, 18, 21 and the short arm of chromosome 4. We analysed five large families from the northern part of Sweden ascertained through a proband with RMD and containing several patients with RMD. For the genetic analysis, we included only severely affected individuals (those who had at least three episodes that required medical treatment) to increase the chances of finding a larger degree of genetic determination. The genetic model led to a total disease prevalence of 5% in females and 3% in males. We did not find significant evidence for linkage to any of the candidate chromosomes in the combined family set. Only one of the families showed a slight indication for linkage with markers from the pericentromeric region of chromosome 18. A genome scan analysis on an extended collaborative family material with severely affected individuals with RMD should be performed to evaluate whether RMD and bipolar disorders have a different genetic etiology.

PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile frontal-lobe dementia, resulting in death at <50 years of age. Since the 1960s, approximately 160 cases have been reported, mainly in Japan and Finland. The pathogenesis of the disease is unknown. In this article, we report the assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population. By screening five patient samples from 2 Finnish families, followed by linkage analysis of 12 Finnish families, 3 Swedish families, and 1 Norwegian family, we were able to assign the PLO-SL locus to a 9-cM interval between markers D19S191 and D19S420 on chromosome 19q13. The critical region was further restricted, to approximately 1.8 Mb, by linkage-disequilibrium analysis of the Finnish families. According to the haplotype analysis, one Swedish and one Norwegian PLO-SL family are not linked to the chromosome 19 locus, suggesting that PLO-SL is a heterogeneous disease. In this chromosomal region, one potential candidate gene for PLO-SL, the gene encoding amyloid precursor-like protein 1, was analyzed, but no mutations were detected in the coding region.

Clinical anticipation has been reported in bipolar affective disorder (BPAD). The hypothesis that expanded trinucleotide repeats are related to anticipation and transmission pattern in families with bipolar affective disorder is tested in this study. Eighty-seven two-generation pairs of patients recruited from 29 bipolar families were analyzed. The repeat expansion detection method was used to detect CAG repeat expansions between successive generations. Significant changes in age at onset and episode frequency in successive generations were observed. Mean trinucleotide CAG repeat length between parental and offspring generation significantly increased when the phenotype increased in severity, i.e., changed from major depression, single episode or unipolar recurrent depression to BPAD. A parent-of-origin effect was also observed with a significant increase in median length CAG between G1 and G2 with maternal inheritance. This increase was observed notably in female offspring. Our findings indicate for the first time that expansion of CAG repeat length could explain the clinical observation of anticipation in families with BPAD. These results provide further support for expanded trinucleotide repeat sequences as risk factors in major affective disorders.

Lithium therapy response and age of onset (AOO) were studied in 98 patients with bipolar affective disorder (BPAD) who were divided into subgroups depending on type of family history of affective disorders. The highest (33.0 years) and lowest (25.5 years) age of onset were found in nonfamilial patients and in familial patients with a first-degree relative of BPAD, respectively. Nonfamilial patients showed the best response to lithium. There were 0.9 episodes/year off lithium compared to 0.3 episodes/year on lithium (an 88% decrease). A poorer response (a 71% decrease; a reduction from 1.39 episodes per year off lithium to 0.65 on lithium) was found in familial patients with a first-degree relative of BPAD. Differences in serum lithium values between the groups could not explain the observed differences. Thus, familial patients showed a more severe manifestation of the disease with an earlier AOO and a lower prophylactic effect of lithium.

Four Swedish families in northern Sweden with polycystic lipomembranous osteodysplasia (PLO-SL) were studied genealogically. Historical and genealogical date provided evidence for a Finnish origin. Both parents of two of the families could be traced back to Finnish ancestors, and the other two families had a common origin in a region with a known Finnish influence, but without evidence for Finnish ancestry. PLO-SL is the first rare monogenic disease with an autosomal recessive inheritance in Sweden with a probable Finnish origin.

Associations were studied between six serum protein polymorphisms (C3, BF, HP, ORM, TF, and GC) and high versus low scoring on episodic memory tasks in an attempt to identify QTL (quantitative trait loci) contributing to the heritability of this quantitative trait. Since a highly significant sex difference (p = .00002) was found with respect to the distribution of high and low scoring, with men showing a poorer performance, associations were studied separately for males and females. In females significant differences (p < .05) between the high and the low groups were found in four of six marker systems (C3, HP, TF, and CG), whereas in males a significant difference was found only in the HP system. Significant differences from population frequencies were also found more frequently in females than in males. The strongest marker associations were found with complement C3 and the acute-phase reactant HP, which suggests that immune response factors may be of importance in preserving episodic memory function. The overall results appear to indicate that episodic memory is a multifactorial and heritable quantitative trait where sex is an important determinant.

The personality profile of 26 adult migraine patients from a large Swedish family with migraine and 87 controls were studied by means of Cloninger's seven-factor model of Temperament and Character (TCI; Temperament and Character Inventory). For the diagnosis of migraine, a questionnaire, slightly modified to fit the criteria according to the AD HOC committee on the classification of headaches of the International Headache Society, was used. The TCI assesses four dimensions of temperament, including novelty-seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (P), and three dimensions of character, including self-directedness (SD), co-operativeness (C) and self-transcendence (ST). Psychiatric morbidity did not differ between this family and the general population. One migraine patient had double depression (dysthymia and recurrent depression) and one had a personality disorder. No significant difference could be found in the higher order dimensions of temperament (NS, HA, RD and P) and character (SD, C and ST) between migraine patients and controls. However, on the subscale level, NS showed a slightly higher average in NS1 (exploratory excitability) and a significantly higher (p = 0.0448) average in NS2 (impulsivity) in migraine patients compared to controls. Somatic anxiety has been shown to be positively correlated with NS, and especially impulsivity. Our results showed a tendency of this personality profile, and may suggest an association between migraine and somatic anxiety.

Background: An association between schizophrenia and the T102C polymorphism of the gene for 5-hydroxytryptamine type 2a (5-HT2a) receptor has been reported; the proportion of allele 2 of this polymorphism is higher than expected among schizophrenic patients. We looked for an association between schizophrenia and this variant of the 5-HT2a-receptor gene in a large multicentre study., Methods: Seven countries recruited 1210 participants: 571 white schizophrenic patients and 639 ethnically matched controls. All patients had a diagnosis of schizophrenia or schizoaffective disorder. High-molecular-weight DNA was isolated from lymphocytes. PCR amplification and restriction enzyme digestion was used to examine sequence variation of the 5-HT2a-receptor gene. Genotypes 1/1, 1/2, and 2/2 were assigned. Woolf's method was used to look for an association between schizophrenia and allele 2 and the 2/2 genotype., Findings: We found a significant overall association between schizophrenia and allele 2 with an odds ratio of 1.3 (95% Cl 1.1-1.53, p = 0.003). No evidence for heterogeneity was observed between samples. We found a highly significant excess of the 1-2/2-2 genotypes in schizophrenia (p = 0.008) with a relative risk of 1.7 (1.22-2.36) and an attributable fraction of 0.35., Interpretation: Our findings suggest that the gene for 5-HT2a-receptor, or a locus in linkage disequilibrium with it, confers susceptibility to schizophrenia. Allele 2 is common in the population and it is, therefore, likely that this variant, or a nearby polymorphism, may affect a significant proportion of schizophrenic patients.

Nineteen parent-offspring pairs obtained from 14 two-generation families with available medical records and diagnosis of schizophrenia were studied to compare the ages of onset of the parent generation with those of the offspring generation. The mean age of onset for the parent generation was 37.3 +/- 6.0 years and for the offspring generation was 20.8 +/- 4.4. The mean difference was thus 16.5 +/- 6.2, suggesting the occurrence of anticipation in schizophrenia (p < 0.001). Although some ascertainment biases (like reduced fertility in early-onset parents or early detection of symptoms in offsprings of affected parents) may partially contribute to the occurrence of anticipation, this study replicates recent reports of anticipation in several neuropsychiatric disorders, some of which have been shown to be associated with unstable expansions of trinucleotide repeats in the genomic DNA.

Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity and/or decrease in age at onset in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in a neuromuscular disease, various neurodegenerative disorders and mental retardation. We have studied parent-offspring differences in age at onset and disease severity in 31 pairs with unilineal inheritance of unipolar affective disorder (UPAD). Life-table analyses showed a significant decrease in survival to 1st episode of major depression in the offspring generation compared with the parental generation (P = 0.0007). There was also a significant difference in age at onset (P < 0.001) between parents and offsprings. The offspring generation experienced onset 15.6 years earlier and illness 1.5 x more severe than did the parent generation. Furthermore, there was a significant correlation (P < 0.05) in age at onset between parent and offspring generations. When we excluded pairs where the affected parent has an age of onset greater than the age of the child at the time of ascertainment (i.e., 23 pairs left), there was still a significant (P = 0.02) decrease in age at onset (8.4 years) and 1.5 x more severe disease in the offspring generation. No evidence for specific maternal or paternal inheritance was found. We found evidence of anticipation in 75-80% of this sample of unilineal family pairs of UPAD. Anticipation is, thus, an inheritance pattern in a large group of UPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in this group of UPAD. The findings of anticipation in this study of families with UPAD and previous findings in families with BPAD suggest that the variable expression of unstable expansions of trinucleotide repeats may turn out to be the basis of the continuum of liability in affective disorders.

Genetic factors are of major aetiological importance in Bipolar Affective Disorder (BPAD type I and II). The exact mode of inheritance of BPAD is unknown, but the recent demonstration of anticipation suggests that dynamic mutations could be involved in the clinical expression of the disease. We have used the repeat expansion detection (RED) method to test whether the anticipation in BPAD could be explained by the presence of expanded trinucleotide repeat sequences. Using a (CTG)10 oligonucleotide a significantly higher number of expanded CAG repeats were found in the genomic DNA of two independent samples of unrelated BPAD patients of Swedish and Belgian ancestry as compared with normal controls. The difference in repeat number was more consistent if data of the two samples of patients was pooled. In this study a CAG trinucleotide repeat expansion was associated for the first time with a major psychiatric disorder. It is possible that the CAG trinucleotide repeat expansion is involved in the clinical expression of BPAD and that it is the molecular basis explaining the phenomenon of anticipation observed in this disorder., (Copyright 1995 Academic Press, Inc.)

In previous studies of orosomucoid (ORM) types and disease the ORM1 1 type has been found to be associated with sarcoidosis and other immunogenetic diseases, and the ORM 1 2 type with different types of carcinomas. We report significant associations between ORM1 and C3 types in sarcoidosis and breast cancer, but not in healthy individuals. The ORM1 1 and C3S variants in combination increased the risk of sarcoidosis, and the ORM1 2 and C3F variants together gave an increased risk of breast cancer. A probable mechanism may be that the ORM1 and C3 molecules modify the immune response by interacting with the lymphoid cell surface.

Association with HLA and complement factors has been reported in sarcoidosis, and the results of previous studies suggest a multifactorial and immunogenetic etiology of the disease. We have studied two genetic acute-phase reactant systems, orosomucoid (ORM) and haptoglobin (HP), in 226 patients with sarcoidosis and population controls from northern Sweden. Significant allele and phenotype differences between patients and controls were found in both systems. The ORM1 phenotype showed a significant increase in sarcoidosis (RR = 1.34, p = 0.036), which was more pronounced among patients with low (< 1,500 nkat/l) angiotensin-converting enzyme levels (RR = 1.83, p = 0.00065) and hypercalcemia (RR = 3.69, p = 0.0023). The HP1 type was significantly increased among the sarcoidosis patients (RR = 1.57, p = 0.013). The results suggest that the ORM1 1 and HP1 types may be contributory determinants in the multifactorial etiology of sarcoidosis.

Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity or decrease in age at onset or both in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in different disorders. We have studied differences of age at onset and disease severity between two generations in 14 families with unilinear inheritance of bipolar affective disorder (BPAD). There was a significant difference in age at onset (p < 0.008), in episodes per year with (p < 0.006) and without (p < 0.03) lithium treatment, and in total episodes per year (p < 0.002) between generations I and II. Furthermore, there was a highly significant correlation (p < 0.001) in age at onset between generations I and II. No evidence for specific paternal or maternal inheritance was found. We found evidence of anticipation and could rule out ascertainment bias or some other artefact. Anticipation is thus an inheritance pattern in BPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in BPAD.

The first Swedish case of familial amyloidotic polyneuropathy (FAP) was published in 1965. The same transthyretin (TTR met30) mutation as that seen in Japanese, Portuguese, and other populations was also found in Swedish FAP patients. More than 350 patients with clinical manifestations of FAP have been diagnosed in northern Sweden, most of them originating from the areas around Skellefteå and Piteå. The mean age of onset is 56 years, much later than in patients from Japan and Portugal. To estimate the frequency of the TTR met30 mutation in the counties of Västerbotten and Norrbotten, sera from 1276 persons aged 24 to 65 years, randomly sampled from a health programme (MONICA), were screened with the monoclonal antibody FD6. In 19 persons, 13 females and six males, a positive reaction was seen in an Elisa test using this antibody. DNA analysis confirmed the TTR met30 mutation and showed that 18 were heterozygous and one homozygous for this mutation. Other mutations were not looked for in this study. The mean TTR met30 carrier frequency in the area was 1.5% ranging from 0.0 to 8.3% in 23 subpopulations. There was a notable discrepancy between the regional distribution of the TTR met30 allele and the morbidity rate for FAP. The estimated number of TTR met30 gene carriers in a total population of 500,000 in the area is approximately 7500. The penetrance of the TTR met30 mutation shows considerable variation between families, and the overall diagnostic (predictive) value in this population is as low as around 2%.

The population of northern Sweden shows a marked ethnic heterogeneity and a unique distribution of disorders with a monogenic or polygenic background, among them cardiovascular diseases. We have studied variations between 23 North Swedish subpopulations (regions) with respect to hypercholesterolemia and its possible determinants including dietary factors, obesity and the degree of Finnish genetic influence. A significant regional heterogeneity was found concerning hypercholesterolemia, obesity and high consumption of 'boiled' coffee. Hypercholesterolemia showed significant geographical covariations with Finnish genetic influence and consumption of 'boiled' coffee. The results are consistent with the hypothesis that in addition to environmental factors Finnish genetic influence contributes to the development of hypercholesterolemia and thereby to the increased rate of cardiovascular disease found in northern Sweden.

The North-Swedish population is a mixture of Finnish, Saamish and Central-Swedish ethnic groups. We have studied the Finnish and Saamish admixture by means of genetic markers in 23 North-Swedish subpopulations. The Finnish influence was estimated using the transferrin genes B0-1, DCHI and C3 and the enzyme gene SOD1*2, and markers for Saamish influence were the blood group gene ABO*A2, the serum group gene GC*1F and the enzyme gene 6PGD*C. In the subpopulations the Finnish influence (admixture) varied between 0 and 84% and the Saamish influence between 0 and 34%. The Saamish influence was strongest in the western and northern parts of the area. In the northern part of the area, between 1/4 and 1/3 of the gene pool of the present-day population may be Saamish in origin. The Finnish influence was strongest in the northern and northeastern parts of the area. In the subpopulations along the Finnish border, between 60 and 80% of the gene pool may be Finnish in origin. Significant correlations were found between the Saamish marker genes and between the Finnish marker genes. Due to geographical overlapping of Finnish and Saamish influence, significant correlations were also found between Finnish and Saamish marker genes. The geographical pictures of Saamish and Finnish influence in northern Sweden showed a fair agreement with the expectations derived from historical knowledge. Although a substantial part of the genetic heterogeneity of the North-Swedish population is ethnic in origin, it is obvious that founder effect and genetic drift also have played an important role.

Transferrin (TF) C subtypes were studied in Swedish Lapps (Saami) and in Swedes from northern, central and southern Sweden, and the allele frequencies were compared with those in other European populations. The Swedish Lapps were found to have the lowest frequency of the TF*C3 allele (1-2%) so far observed in Europe. Most European populations have TF*C3 allele frequencies between 5 and 7%. Finns differ by having high TF*C3 frequencies (13-14%). The relatively high TF*C3 frequencies found in northeastern Sweden (13%) and in central Sweden (9%) are most likely due to eastern influence. Unlike other genetic markers of eastern influence (e.g. TF*DCHI), which are of Asiatic Mongoloid origin, TF*C3 appears to originate from Finno-Ugric populations.

A mutant variant of the serum protein transthyretin (TTR-met30) appears to be a necessary but not sufficient condition for the development of familial amyloidotic polyneuropathy (FAP). We have studied a number of serum protein markers (alpha 1-antitrypsin, properdin factor B, C3, C4A, C4B, haptoglobin, transferrin and group-specific component) in FAP patients and healthy controls in an attempt to identify additional pathogenic factors which may influence the risk for developing FAP in male and female patients as well as the age of onset of the disease. Statistically significant associations were found in the complement systems C3 and C4A. The C3F variant was significantly increased in all FAP patients with a relative risk (RR) of 2.0, more pronounced in female patients (RR = 2.6) and patients with an early onset of the disease (RR = 4.5). In the FAP patients only the variants A3 and A4 were found in the C4A system. C4A3 was found in all patients, which was significantly higher than in the controls. The remaining serum protein systems showed no statistically significant associations with FAP. The results suggest that genetic variants of complement factors C3 and C4A may interact with the mutant TTR-met30 by modifying the expression and onset of FAP.

The group-specific component (Gc) subtypes were determined by isoelectric focusing and immunoblotting. The gene frequencies in the Swedish Lapps were Gc1F = 0.412, Gc1S = 0.367 and Gc2 = 0.221, which was significantly different from the frequencies found in Finns and in the populations of northern and central Sweden (p less than 0.001). The gene frequencies in the Swedish Lapps, although similar to those in Asiatic populations, are probably not reflecting an Asiatic influence, since the accumulated genetic information on the Swedish Lapps suggests that founder effect and genetic drift are to a large extent responsible for the peculiar gene pool of the original Lapp population.

The frequencies of group-specific component (GC) subtypes were studied in a population of 4,053 conscripts and blood donors from the counties of Västerbotten and Norrbotten in northern Sweden. The individuals were distributed according to place of birth into 23 subpopulations. A significant heterogeneity between the 23 regions was observed for the GC*1F, GC*1S and GC*2 genes, and clines were found for all genes. The frequency of the GC*1F gene was increasing in the northern direction, and the frequencies of the GS*1S and GC*2 genes were increasing in the southern direction. The geographical pattern of the GC*1F gene frequency could be explained in terms of Lappish influence.

The frequencies of transferrin C (TF C) subtypes were studied in 315 Finns, 222 Swedish Lapps and in 4,157 conscripts and blood donors from the counties of Norrbotten and Västerbotten in northern Sweden. The Swedish individuals were distributed according to place of birth into 23 subpopulations or regions. A significant heterogeneity between the 23 regions was observed for the TF C1, C2 and C3 genes and for rare genes. Clines were found for the TF C1 and C3 genes and for rare transferrin genes in northern Sweden. The frequencies of the C1 and C3 genes were increasing in the southwestern and northeastern direction, respectively, and the frequency of the rare transferrin genes was increasing in the northern direction. The geographical picture of the C3 gene and of rare transferrin genes could be interpreted in terms of Finnish influence. The frequency of the TF C3 gene in Finland and northern Sweden (14 and 15%) is the highest so far reported in the world. The overall picture of geographical variations of the C1 and C2 genes were not explainable in terms of ethnic influence and may be caused by random differentiation and/or selective forces.

Frequencies of the A1A2B0 blood group genes were studied in a material of 5,632 conscripts and blood donors from the counties of Norrbotten and Västerbotten in northern Sweden. The individuals were distributed according to place of birth into 23 subpopulations. In northern Sweden different clines were found for the A1, A2 and 0 genes. The frequencies of the A1 and A2 genes were increasing in the northeastern respectively northern direction, and the frequency of the 0 gene was increasing in the southwestern direction. These geographical patterns could be explained in terms of Finnish and Lappish influence.

Frequencies of the 6-phosphogluconate dehydrogenase (6-PGD) genes were studied in a series of 314 Finns from northern Finland and in a material of 4,348 conscripts and blood donors from the counties of Norrbotten and Västerbotten in northern Sweden. The Swedish individuals were distributed into 23 subpopulations according to place of birth. The frequency of the PGDC gene was comparatively high in Finns (5.3%) and showed significant variations between subpopulations (from 5.3 to 0.0%). The frequency of the PGDC gene showed a cline, with a decreasing gene frequency in the north-south direction. This geographical pattern could be explained in terms of Lappish and Finnish influence.

Commercial petrol and two of its components, benzene and 1,2-dichloroethane, were tested for mutagenicity in Drosophila melanogaster. The chemicals were given to larvae through their food supply. A genetically unstable sexlinked test system caused by a transposable genetic element was used. Mutagenicity was measured by the frequency of somatic mutations for eye pigmentation. Commercial petrol and 1,2-dichloroethane showed mutagenic activity. With the system used, benzene did not show any mutagenic activity. The high frequency of mutations induced by 1,2-dichloroethane indicate the existence in Drosophila of a metabolic activating system.