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P O Nylander

Publications and source records attributed to P O Nylander.

At least 19 recordsLinked to original sources
PubMed1999

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

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.

Adult↗
PubMed1999

Linkage analysis of a large Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23.

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.

Alleles↗
PubMed1998

Linkage analysis of candidate loci in families with recurrent major depression.

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.

Adult↗
PubMed1998

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

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.

Bipolar Disorder↗
PubMed1998

Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13.

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.

Adolescent↗
PubMed1997

Expanded trinucleotide CAG repeats in families with bipolar affective disorder.

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.

Adult↗
PubMed1997

Relationship between prophylactic effect of lithium therapy and family history of 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.

Age of Onset↗
PubMed1996

Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group.

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.

Alleles↗
PubMed1996

Genetic markers associated with high versus low performance on episodic memory tasks.

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.

Adult↗
PubMed1996

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLO-SL): a genealogical study of Swedish families of probable Finnish background.

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.

Bone Diseases↗
PubMed1995

Anticipation in unipolar affective disorder.

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.

Adolescent↗
PubMed1995

Detection of expanded CAG repeats in bipolar affective disorder using the repeat expansion detection (RED) method.

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.

Aged↗
PubMed1995

Anticipation in Swedish families with schizophrenia.

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.

Adolescent↗
PubMed1995

Synergistic interaction between ORM1 and C3 types in disease associations.

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.

Alleles↗
PubMed1995

Orosomucoid and haptoglobin types in patients with sarcoidosis.

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.

Female↗
PubMed1994

Geographical distribution of TTR met30 carriers in northern Sweden: discrepancy between carrier frequency and prevalence rate.

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%.

Adult↗