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Tiina Paunio

Publications and source records attributed to Tiina Paunio.

16 recordsLinked to original sources
PubMed2006

Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1.

We have previously reported a robust association between an allelic haplotype of 'Disrupted in Schizophrenia 1' (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.

Alleles↗
PubMed2006

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Journal Article↗
PubMed2004

Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q.

Research to identify predisposing genes for complex diseases relying solely on clinical diagnosis is probably not ideal. Here, we analyzed genome-wide data for 168 schizophrenia families using neuropsychological variables associated with disease susceptibility, with the aid of SOLAR, a program for variance-component analysis. The linkage signal was greatly accentuated by application of the quantitative traits compared with diagnosis. We found evidence for a locus for verbal learning and memory on 4q21 (Z=3.01, Z(mp)=3.84 and empiric P=0.031 for delayed memory; Z=2.96, Z(mp)=3.4 and P=0.026 for verbal learning) and suggestive evidence for visual working memory on 2q36 (Z=2.80, Z(mp)=2.08 and P=0.093). In addition, some evidence emerged for a locus for recognition memory on 10p13, visual attention on 15q22 and executive function on 9p22 in the complete sample, as well as for delayed memory on 8q12, semantic clustering and intrusions on 1q42 and visual attention on 3p25 in the genealogically distinctive sample subsets. Of the loci linked to schizophrenia in diverse populations, in addition to the earlier mentioned regions, some evidence of linkage was observed for 2q, 6q, 7q, 11q, 13q, 14q, 18q and 22q. Our results reveal initial information on the effect of the loci associated with schizophrenia in multiple studies, and emphasize the value of trait components in the search for susceptibility loci for complex diseases.

Analysis of Variance↗
PubMed2004

Seasonal affective disorder and the G-protein beta-3-subunit C825T polymorphism.

BACKGROUND: Guanine nucleotide-binding proteins (G-proteins) have been implicated in affective disorders, with reports of altered signal transduction and G-protein levels. Association with seasonal affective disorder (SAD) has been found for the higher activity T-allele of the G-protein beta-3-subunit C825T polymorphism. METHODS: European SAD patients (n = 159) and matched controls (n = 159) were genotyped for the C825T. Seasonality and diurnal preference were investigated in subsets of the material (n = 177 and 92, respectively). RESULTS: We found no association between C825T and SAD (chi(2) =.09, p =.96) or seasonality (F = 1.76, p =.18). There was some evidence for an effect on diurnal preference but only in the control group (n = 46, t = -2.8, Bonferroni corrected p =.045). CONCLUSIONS: These results suggest that the G-protein beta-3-subunit 825 T-allele does not play a major role in susceptibility to seasonal affective disorder in the population studied.

Alleles↗
PubMed2004

RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order.

Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal-fetal genotype incompatibility (MFG) test used in an earlier case-parent trio study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case-parent trios to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the second- and later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects.

Birth Order↗
PubMed2004

Haplotype analysis and identification of genes for a complex trait: examples from schizophrenia.

For more than a decade there has been intensive research into the genetic etiology of schizophrenia, yet it is only recently that the first findings of promising genes associating with the disorder have been reported. Linkage analyses in families collected from different populations have provided relatively well defined genomic loci. These have been typically followed by fine mapping studies using single nucleotide polymorphisms (SNPs). A number of analysis programs have been produced to test SNPs and their haplotypes for association. Typically association has been established to specific haplotypes representing an allelic variant of the corresponding gene. The inherent problem of multiple testing in the analysis of haplotypes needs to be addressed fully, to determine if any of these recent findings can be considered as confirmed susceptibility genes for schizophrenia. However, informative haplotypes have provided a way to define allelic variants of genes associated with schizophrenia in numerous study samples, and are a useful tool in characterizing the extent of allelic diversity of putative schizophrenia susceptibility genes within different populations.

Chromosome Mapping↗
PubMed2003

Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects.

We have previously reported a linkage peak on 1q42 in a Finnish schizophrenia sample. In this study we genotyped 28 single nucleotide polymorphisms (SNPs) from 1q42 covering the three candidate genes TRAX, DISC1 and DISC2, using a study sample of 458 Finnish families ascertained for schizophrenia. Two-point and haplotype association analysis revealed a significant region of interest within the DISC1 gene. A common haplotype (HEP3) was observed to be significantly under-transmitted to affected individuals (P=0.0031). HEP3 represents a two SNP haplotype spanning from intron 1 to exon 2 of DISC1. This haplotype also displayed sex differences in transmission distortion, the under-transmission being significant only to affected females (P=0.00024). Three other regions of interest were observed in the TRAX and DISC genes. However, analysis of only those families with complete genotype information specifically highlights the HEP3 haplotype as a true observation. The finding of a common under-transmitted SNP haplotype might imply that this particular allele offers some protection from the development of schizophrenia. Analysis of component-traits of schizophrenia, derived from the Operational Criteria Checklist of Psychotic Illness (OCCPI), displayed association of HEP3 to features of the general phenotype of schizophrenia, including traits representing delusions, hallucinations and negative symptoms. This study provides further evidence for the hypothesis that the DISC1 gene is involved in the aetiology of schizophrenia, and implies a putative sex difference for the effect of the gene. Our findings would also encourage more detailed analyses of the effect of DISC1 on the component-traits of schizophrenia.

Female↗
PubMed2003

Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder.

We performed a genome-wide scan for susceptibility loci in bipolar disorder in a study sample colleted from the isolated Finnish population, consisting of 41 families with at least two affected siblings. We identified one distinct locus on 16p12 providing significant evidence for linkage in two-point analysis (Z(max)=3.4). Furthermore, three loci with a two-point LOD score >2.0 were observed with markers on 4q32, 12q23 and Xq25, the latter locus having been earlier identified in one extended Finnish pedigree. In the second stage we fine mapped these chromosomal regions and also genotyped additional family members. In the fine mapping stage, 4q32 provided significant evidence of linkage for the three-point analyses (Z(max)=3.6) and 16p12 produced a three-point LOD score of 2.7. Since the identified chromosomal regions replicate earlier linkage findings in either bipolar disorder or other mental disorders, they should be considered good targets for further genetic analyses.

Alleles↗
PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Bipolar Disorder↗
PubMed2003

The interval of linkage disequilibrium (LD) detected with microsatellite and SNP markers in chromosomes of Finnish populations with different histories.

Linkage disequilibrium (LD) has been an efficient tool for fine mapping of monogenic disease genes in population isolates. Its usefulness for identification of predisposing loci for common, polygenic diseases has been challenged on the basis of anticipated allelic and locus heterogeneity. We compared the extent of LD among marker loci in Finnish subpopulations with divergent but well-characterized histories. One study sample represents the early settlement Finnish population, descended from two immigration events 4,000 and 2,000 years ago. The second sample represents the geographically large late settlement region, populated 15 generations ago by several small immigrant groups from the early settlement region. The third is a restricted regional subpopulation in northeastern Finland which was founded 12 generations ago by 39 immigrant families from the late settlement region. We genotyped 243 microsatellite markers and 68 single nucleotide polymorphisms (SNPs) on chromosomes 1q and 5q. The genealogy of the families from the early (n=16) and late settlements (n=54) and the isolated settlement (n=54) was studied in detail back to the 1800s. Microsatellite data revealed greater LD in the young, founder subpopulation than was seen in either of the older populations. Observed linkage disequilibrium correlated not only with physical distance between markers but also with the information content of the markers. Using biallelic SNP markers, significant LD could only be detected up to 0.1 cM. Our results demonstrate the complexity of the concept of 'detectable LD' and emphasize the importance of understanding population history when designing a strategy for disease gene mapping.

Chromosomes, Human, Pair 1↗
PubMed2003

Gelsolin-related familial amyloidosis, Finnish type, in a Portuguese family: clinical and neurophysiological studies.

We report a Portuguese family with familial amyloid polyneuropathy related to gelsolin. There were no known Finnish ancestors, but the same mutation as described in Finnish patients (G654A) was carried. Clinical and neurophysiological investigations were performed in four patients. Corneal lattice dystrophy affected all four patients; an axonal lesion of the facial nerve occurred in three patients; visual tract involvement was documented in one case; and corticospinal and posterior column dysfunction was present in one patient. Polarizing microscopy of skin and muscle samples demonstrated amyloid deposits in two patients; anti-gelsolin immunohistochemistry was positive for amyloidogenic gelsolin. The Finnish mutation of gelsolin protein (G654A) was detected in five family members. The utility of neurophysiological testing in the evaluation and follow-up of this type of amyloidosis is discussed.

Adult↗
PubMed2002

Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference.

Disturbed circadian rhythms have been observed in seasonal affective disorder (SAD). The aim of this study was to further investigate this connection, and to test for potential association between polymorphisms in circadian clock-related genes and SAD, seasonality (seasonal variations in mood and behavior), or diurnal preference (morningness-eveningness tendencies). A total of 159 European SAD patients and 159 matched controls were included in the genetic analysis, and subsets were screened for seasonality (n=177) and diurnal preference (n=92). We found that diurnal preference was associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. The complete case-control material was genotyped for polymorphisms in the CLOCK, Period2, Period3, and NPAS2 genes. A significant difference between patients and controls was found for NPAS2 471 Leu/Ser (chi(2)=9.90, Bonferroni corrected P=0.035), indicating a recessive effect of the leucine allele on disease susceptibility (chi(2)=6.61, Bonferroni corrected P=0.050). Period3 647 Val/Gly was associated with self-reported morningness-eveningness scores (n=92, one-way ANOVA: F=4.99, Bonferroni corrected P=0.044), with higher scores found in individuals with at least one glycine allele (t=3.1, Bonferroni corrected P=0.013). A second, population-based sample of individuals selected for high (n=127) or low (n=98) degrees of seasonality, was also genotyped for NPAS2 471 Leu/Ser. There was no significant difference between these seasonality extreme groups, and none of the polymorphisms studied were associated with seasonality in the SAD case-control material (n=177). In conclusion, our results suggest involvement of circadian clock-related polymorphisms both in susceptibility to SAD and diurnal preference.

Analysis of Variance↗
PubMed2002

RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility.

Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-trio log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia.

Adult↗
PubMed2002

Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia.

Despite evidence for several chromosomal loci linked to schizophrenia, no susceptibility genes have been identified for the disorder. Using quantitative measures of phenotypic affection in place of clinical diagnostic categories or dichotomous classification of the affection status may be more effective in searching for susceptibility genes. Neurocognitive traits have been suggested as putative quantitative endophenotypes of the disorder, but their heritability estimates are not well known. We investigated the heritability of working memory, verbal declarative memory and its different components, and both verbal and visual ability functions in schizophrenia families with a well-ascertained pedigree structure. We also estimated the number of quantitative trait loci (QTLs) contributing to these neurocognitive functions. Additive genetic heritability of the neurocognitive functions was estimated in a sample of schizophrenia patients and their first-degree relatives (N = 264) from an isolated geographical subregion in Finland. The number of QTLs was analyzed using Markov chain Monte Carlo segregation analysis. Significant heritabilities were found in working memory and ability functions. Furthermore, the working memory functions revealed the most restricted number of QTLs. The mean numbers of loci for verbal and visual working memory were 1.2 and 1.0, respectively, with corresponding posterior probabilities of 73% and 70% for at least one locus. In declarative memory variables, the number of loci was more dispersed. Our results suggest that neurocognitive measures, particularly working memory, may provide valid quantitative phenotypic traits for linkage analyses searching predisposing genes for schizophrenia.

Adult↗
PubMed2002

Role of proprotein convertases in the pathogenic processing of the amyloidosis-associated form of secretory gelsolin.

Familial amyloidosis of the Finnish type (FAF) is caused by two proteolytic cleavages of mutant gelsolin leading to the accumulation of FAF amyloid in the patients' tissues. Here, we demonstrate that, in mouse pituitary corticotropic AtT20 cells, the enzyme responsible for the first cleavage of mutant secretory FAF gelsolin to FAF amyloid precursor is present in reasonable amounts. Furthermore, in At T20 cells stably expressing alpha1-PDX a potent inhibitor of most proprotein convertases, this cleavage was inhibited The present data provide strong evidence that proprotein convertases, possibly furin or PC5, are involved in the initialpathological cleavage of mutant secretory FAF gelsolin leading ultimately to the amyloid disease.

Amyloid↗