-
G Fraser,
R Breuer,
E Vassos,
N Durmishi,
T Silagadze,
M C O'Donovan,
U Thorsteinsdottir,
B Etain,
I Melle,
J B Vincent, [......],
M Arrojo,
M Raleva,
V Kaleda,
J Powell,
B Riley,
K Paketchieva,
N Craddock,
J Sanjuán,
M J Owen,
I Giegling
-
S Steinberg,
S de Jong,
M Mattheisen,
J Costas,
D Demontis,
S Jamain,
O P H Pietiläinen,
K Lin,
S Papiol,
J Huttenlocher, [......],
M Rietschel,
S Cichon,
M Ruggeri,
S Tosato,
A Palotie,
D St Clair,
D Rujescu,
D A Collier,
H Stefansson,
K Stefansson
[show abstract]
[hide abstract]
ABSTRACT: Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.157.
Molecular psychiatry 11/2012; · 15.05 Impact Factor
-
H M Ollila,
S Utge,
E Kronholm,
V Aho,
W Van Leeuwen,
K Silander,
T Partonen,
M Perola,
J Kaprio,
V Salomaa,
M Sallinen,
M Härmä,
T Porkka-Heiskanen, T Paunio
[show abstract]
[hide abstract]
ABSTRACT: Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, β = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, β = 0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P = 0.022, β = 0.063; meta-analysis of both samples P = 8.1(*)10(-6), β = 0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6-fold and decreased in recovery phase (P = 0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep.
Translational Psychiatry. 02/2012; 2:e97.
-
S Steinberg,
O Mors,
A D Børglum,
O Gustafsson,
T Werge,
P B Mortensen,
O A Andreassen,
E Sigurdsson,
T E Thorgeirsson,
Y Böttcher, [......],
I Agartz,
H Petursson,
M M Nöthen,
M Rietschel,
L Peltonen,
D Rujescu,
D A Collier,
H Stefansson,
D St Clair,
K Stefansson
[show abstract]
[hide abstract]
ABSTRACT: A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).
Molecular psychiatry 01/2011; 16(1):59-66. · 15.05 Impact Factor
-
P Soronen,
H M Ollila,
M Antila,
K Silander,
O M Palo,
T Kieseppä,
J Lönnqvist,
L Peltonen,
A Tuulio-Henriksson,
T Partonen, T Paunio
Molecular psychiatry 01/2010; 15(1):4-6. · 15.05 Impact Factor
-
Molecular psychiatry 05/2009; 14(4):351-3. · 15.05 Impact Factor
-
Mym Ng,
Df Levinson,
Sv Faraone,
Bk Suarez,
Le Delisi,
T Arinami,
B Riley, T Paunio,
Ae Pulver,
Irmansyah, [......],
D Curtis,
J Brynjolfson,
T Sigmundsson,
H Petursson,
Ar Sanders,
J Duan,
E Jazin,
M Myles-Worsley,
M Karayiorgou,
Cm Lewis
[show abstract]
[hide abstract]
ABSTRACT: A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142–168 Mb) and 2q (103–134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119– 152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16–33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.
Molecular Psychiatry 01/2009; 14135:774-785. · 13.67 Impact Factor
-
M. Y. Ng,
D. F. Levinson,
S. V. Faraone,
B. K. Suarez,
L. E. DeLisi,
T. Arinami,
B. Riley, T. Paunio,
A. E. Pulver,
Irmansyah, [......],
D. Curtis,
J. Brynjolfson,
T. Sigmundsson,
H. Petursson,
A. R. Sanders,
J. Duan,
E. Jazin,
M. Myles-Worsley,
M. Karayiorgou,
C. M. Lewis
[show abstract]
[hide abstract]
ABSTRACT: A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.
Mol Psychiatry. 01/2009; 14(8):774-85.
-
J Wedenoja,
A Loukola,
A Tuulio-Henriksson, T Paunio,
J Ekelund,
K Silander,
T Varilo,
K Heikkilä,
J Suvisaari,
T Partonen,
J Lönnqvist,
L Peltonen
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2-q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n=1626) allowed replication of linkage on 7q21-32. In a sample of 245 nuclear families (n=1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n=861) of the sample showed significant association to RELN variants for traits related to verbal (P=0.000003) and visual working memory (P=0.002), memory (P=0.002) and executive functioning (P=0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P=0.0004-0.0000000004), memory (P=0.02-0.0001) and executive functioning (P=0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.
Molecular psychiatry 08/2008; 13(7):673-84. · 15.05 Impact Factor
-
W Hennah,
P Thomson,
A McQuillin,
N Bass,
A Loukola,
A Anjorin,
D Blackwood,
D Curtis,
I J Deary,
S E Harris, [......],
E Pylkkö,
M Robinson,
P Soronen,
K Suominen,
J Suvisaari,
S Thirumalai,
D St Clair,
H Gurling,
L Peltonen,
D Porteous
[show abstract]
[hide abstract]
ABSTRACT: Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.
Molecular psychiatry 04/2008; 14(9):865-73. · 15.05 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders. Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, n(affected)=138) and Asperger syndrome (29 families, n(affected)=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1. These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.
Molecular Psychiatry 03/2008; 13(2):187-96. · 13.67 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Family based association tests are widely used to detect genetic effects. The focus of this paper is the maternal-fetal genotype (MFG) incompatibility test, a family based association test which can be used to detect genetic effects that contribute to disease, including alleles in the child that increase disease risk, maternal alleles that increase disease risk in the child, and maternal-fetal genotype incompatibilities. Consideration of incomplete data resulting from using serotypes could expand the power of the MFG test for detecting genetic effects. Serotypes may be all that are available in certain families, or preferred because of convenience or low cost, and thus a modification of the MFG test will allow optimal use of such data. The modified MFG likelihood can accommodate the incomplete data that result from using serotypes rather than the corresponding codominant genotypes. The modified MFG test was evaluated with serotypes and genotypes from families with members affected with schizophrenia. In addition, simulation studies were performed. Results of the data analyses and simulation studies showed that serotypes can be used to augment genotypes within a sample, to increase power to detect effects when the candidate gene produces serotypes.
Annals of Human Genetics 08/2006; 70(Pt 4):541-53. · 2.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously reported evidence of linkage and association between markers on 1q42 and schizophrenia in a study sample of 498 multiply affected Finnish nuclear families, leading to the recent identification of four significantly associated haplotypes that specifically implicate the Translin-Associated Factor X (TRAX) and Disrupted in Schizophrenia 1 and 2 (DISC1 and DISC2) genes in the genetic etiology of schizophrenia. Previously, the DISC genes were found to be disrupted by a balanced translocation (1;11)(q42.1;q14.3) that cosegregated with schizophrenia and related disorders in a large Scottish pedigree. Interestingly, we also reported earlier suggestive linkage between endophenotypic quantitative traits of visual and verbal memory and microsatellite markers in close proximity to TRAX/DISC, on 1q41. Here, we tested if the identified allelic haplotypes of TRAX/DISC would be associated with visual and/or verbal memory function impairments that are known to aggregate with schizophrenia in families. One haplotype of DISC1, HEP3, displayed association with poorer performance on tests assessing short-term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contribute to the observed association to visual working memory. These results provide genetic support to the view that the DISC1 gene contributes to sensitivity to schizophrenia and associated disturbances and affects short-term visual memory functions. This finding should stimulate studies aiming at the molecular characterization of how the specific alleles of DISC1 affect the visual memory functions and eventually participates in the development of schizophrenia.
Molecular Psychiatry 01/2006; 10(12):1097-103. · 13.67 Impact Factor
-
C Johansson,
M Willeit,
R Levitan,
T Partonen,
C Smedh,
J Del Favero,
S Bel Kacem,
N Praschak-Rieder,
A Neumeister,
M Masellis,
V Basile,
P Zill,
B Bondy, T Paunio,
S Kasper,
C Van Broeckhoven,
L G Nilsson,
R Lam,
M Schalling,
R Adolfsson
[show abstract]
[hide abstract]
ABSTRACT: Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD.
One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets.
No association between 5-HTTLPR and SAD was found in the new case-control material, in the combined analysis of all samples, or when only including 316 patients with controls (N = 298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2.24 (1.03-4.91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set.
These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.
Psychological Medicine 08/2003; 33(5):785-92. · 6.16 Impact Factor
-
M. WILLEIT ,
R. LEVITAN ,
T. PARTONEN ,
C. SMEDH ,
J. DEL FAVERO ,
S. BEL KACEM ,
N. PRASCHAK-RIEDER ,
A. NEUMEISTER ,
M. MASELLIS ,
V. BASILE ,
P. ZILL ,
B. BONDY , T. PAUNIO ,
S. KASPER ,
C. VAN BROECKHOVEN ,
L.-G. NILSSON ,
R. LAM ,
M. SCHALLING ,
R. ADOLFSSON
[show abstract]
[hide abstract]
ABSTRACT: Background. Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case–control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD.
Psychological Medicine 06/2003; 33(05):785 - 792. · 6.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Bipolar disorder (BPD) is a common disorder characterized by episodes of mania, hypomania and depression. The genetic background of BPD remains undefined, although several putative loci predisposing to BPD have been identified. We have earlier reported significant evidence of linkage for BPD to chromosome Xq24-q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24-q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family.
Molecular Psychiatry 02/2002; 7(5):453-9. · 13.67 Impact Factor
-
T Paunio,
J Ekelund,
T Varilo,
A Parker,
I Hovatta,
J A Turunen,
K Rinard,
A Foti,
J D Terwilliger,
H Juvonen,
J Suvisaari,
R Arajärvi,
J Suokas,
T Partonen,
J Lönnqvist,
J Meyer,
L Peltonen
[show abstract]
[hide abstract]
ABSTRACT: We have previously carried out two genome-wide scans in samples of Finns ascertained for schizophrenia from national epidemiological registers. Here, we report data from a third genome scan in a nationwide Finnish schizophrenia study sample of 238 pedigrees with 591 affected individuals. Of the 238 pedigrees, 53 originated from a small internal isolate (IS) on the eastern border of Finland with a well established genealogical history and a small number of founders, who settled in the community 300 years ago. The total study sample of over 1200 individuals were genotyped, using 315 markers. In addition to the previously identified chromosome 1 locus, two new loci were identified on chromosomes 2q and 5q. The highest LOD scores were found in the IS families with marker D2S427 (Z(max) = 4.43) and in the families originating from the late settlement region with marker D5S414 (Z(max) = 3.56). In addition to 1q, 2q and 5q, some evidence for linkage emerged at 4q, 9q and Xp, the regions also suggested by our previous genome scans, whereas, in the nationwide study sample, the region at 7q failed to show further evidence of linkage. The chromosome 5q finding is of particular interest, since several other studies have also shown evidence for linkage in the vicinity of this locus.
Human Molecular Genetics 01/2002; 10(26):3037-48. · 7.64 Impact Factor
-
J Ekelund,
I Hovatta,
A Parker, T Paunio,
T Varilo,
R Martin,
J Suhonen,
P Ellonen,
G Chan,
J S Sinsheimer,
E Sobel,
H Juvonen,
R Arajärvi,
T Partonen,
J Suvisaari,
J Lönnqvist,
J Meyer,
L Peltonen
[show abstract]
[hide abstract]
ABSTRACT: We have earlier reported evidence for linkage to two regions on chromosome 1q32--q42 in schizophrenia families collected for two separate studies in Finland. Here we report the results of a fine mapping effort aimed at further definition of the chromosomal region of interest using a large, population-based study sample (221 families, 557 affected individuals). Most affecteds (78%) had a DSM-IV schizophrenia diagnosis and the remaining had schizophrenia spectrum disorders. We genotyped a total of 147 microsatellite markers on a wide 45 cM region of chromosome 1q. The results were analyzed separately for families originating from an internal isolate of Finland and for families from the rest of Finland, as well as for all families jointly. We used traditional two-point linkage analysis, SimWalk2 multipoint analysis and a novel gamete-competition association/linkage method. Evidence for linkage was obtained for one locus in the combined sample (Z(max) = 2.71, D1S2709) and in the nuclear families from outside the internal isolate (Z(max) = 3.21, D1S2709). In the families from the internal isolate the strongest evidence for linkage was obtained with markers located 22 cM centromeric from this marker (Z(max) = 2.30, D1S245). Multipoint analysis also indicated these loci. Some evidence for association with several markers was observed using the gamete-competition method. Interestingly, the strongest evidence for linkage in the combined study sample was obtained for marker D1S2709, which is an intragenic marker of the DISC1 gene, previously suggested as a susceptibility gene for schizophrenia. These results are consistent with the presence of susceptibility gene(s) in this chromosomal region, a result also implied in other recent family studies of schizophrenia.
Human Molecular Genetics 08/2001; 10(15):1611-7. · 7.64 Impact Factor
-
C Johansson,
C Smedh,
T Partonen,
P Pekkarinen, T Paunio,
J Ekholm,
L Peltonen,
D Lichtermann,
J Palmgren,
R Adolfsson,
M Schalling
[show abstract]
[hide abstract]
ABSTRACT: 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.
Neurobiology of Disease 05/2001; 8(2):351-7. · 5.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder in childhood that is caused by mutations in the gene encoding lysosomal palmitoyl protein thioesterase (PPT). INCL is characterized by massive and selective loss of cortical neurons. Here we have analyzed the intracellular processing and localization of adenovirus-mediated PPT in mouse primary neurons and NGF-induced PC-12 cells. The neuronal processing of PPT was found to be similar to that observed in peripheral cells, and a significant amount of the PPT enzyme was secreted in the primary neurons. Immunofluorescence analysis of the neuronal cells infected with wild-type PPT showed a granular staining pattern in the cell soma and neuronal shafts. Interestingly, PPT was also found in the synaptic ends of the neuronal cells and the staining pattern of the enzyme colocalized to a significant extent with the synaptic markers SV2 and synaptophysin. These in vitro data correspond with the distribution of endogeneous PPT in mouse brain and suggest that PPT may not solely be a lysosomal hydrolase. The specific targeting of PPT into the neuritic shafts and nerve terminals indicates that PPT may be associated with the maintenance of synaptic function. Furthermore, since a substantial amount of PPT is secreted by neurons, it is tempting to speculate that the enzyme could also have an extracellular substrate.
Molecular Genetics and Metabolism 03/2000; 69(2):123-9. · 3.19 Impact Factor
