| 1. |
- Alaerts, Maaike, et al.
(författare)
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Detailed analysis of the serotonin transporter gene (SLC6A4) shows no association with bipolar disorder in the Northern Swedish population
- 2009
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Ingår i: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. - : John Wiley & Sons, Inc. - 1552-4841 .- 1552-485X. ; 150B:4, s. 585-592
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Tidskriftsartikel (refereegranskat)abstract
- Through active reuptake of serotonin into presynaptic neurons, the serotonin transporter (5-HTT) plays an important role in regulating serotonin concentrations in the brain, and it is the site of binding for tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Therefore it has been hypothesized that this transporter is involved in the etiology of bipolar (BP) disorder. Inconsistent association study results for the SLC6A4 gene encoding 5-HTT reported in literature emphasize the need for more systematic and detailed analyses of this candidate gene. We performed an extensive analysis of SLC6A4 on DNA of 254 BPI patients and 364 control individuals from a Northern Swedish isolated population. This analysis consisted of a HapMap LD-based association study including three widely investigated polymorphisms (5-HTTVNTR, 5-HTTLPR, and rs3813034), a copy-number variation (CNV) analysis and a mutation analysis of the complete coding sequence and the 3'-UTR of SLC6A4. No single marker showed statistically significant association with BPI, nor did any of the haplotypes. In the mutation analysis 13 novel variants were detected, including 2 amino acid substitutions M389V and 1587L, but these are probably not implicated in risk for BP. No deletions or duplications were detected in the CNV analysis. We conclude that variation in the SLC6A4 gene or its regulatory regions does not contribute to the susceptibility for BP disorder in the Northern Swedish population.
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| 2. |
- Alaerts, Maaike, et al.
(författare)
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Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population
- 2006
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Ingår i: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 16:6, s. 235-236
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Tidskriftsartikel (refereegranskat)abstract
- GPR50 is a G protein-coupled receptor, located on Xq28 and related to the melatonin receptor family. It is suggested as a functional and positional candidate gene for bipolar disorder (BP). Recently an insertion/deletion polymorphism in GPR50, Delta502-505, was found to be associated with BP in a Scottish association sample (P=0.007). When the analysis was restricted to female subjects, the association increased in significance (P=0.00023). We attempted to replicate this finding in a Northern Swedish association sample, but no significant association was detected (P=0.7, women only: P=0.65).
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| 3. |
- Alaerts, Maaike, et al.
(författare)
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Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population
- 2009
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Ingår i: Archives of General Psychiatry. - : American Medical Association. - 0003-990X .- 1538-3636. ; 66:8, s. 828-837
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Tidskriftsartikel (refereegranskat)abstract
- Context: Neuregulin 1 (NRG1), a growth factor involved in neurodevelopment, myelination, neurotransmitter receptor expression, and synaptic plasticity, first joined the list of candidate genes for schizophrenia when a 7-marker haplotype at the 5' end of the gene (Hap(ICE)) was shown to be associated with the disorder in the Icelandic population. Since then, more genetic and functional evidence has emerged, which supports a role for NRG1 in the development of schizophrenia.Objective: To determine the contribution of NRG1 to susceptibility for schizophrenia in a northern Swedish isolated population.Design: Detailed linkage disequilibrium (LD)-based patient- control association study. This is the first study to type and analyze the 7 Hap(ICE) markers and a set of 32 HapMap tagging single-nucleotide polymorphisms (SNPs) that represents variants with a minor allele frequency of at least 1% and fully characterizes the LD structure of the 5' part of NRG1.Setting: Outpatient and inpatient hospitals.Participants: A total of 486 unrelated patients with schizophrenia and 514 unrelated control individuals recruited from a northern Swedish isolated population.Main Outcome Measures: Association between markers and disease.Results: Analysis of the Hap(ICE) markers showed the association of a 7-marker and 2-microsatellite haplotype, different from the haplotypes associated in the Icelandic population and overrepresented in northern Swedish control individuals. Subsequently, a more detailed analysis that included all 37 genotyped SNPs was performed by investigating haplotypic association, dependent and independent of LD block structure. We found significant association with 5 SNPs located in the second intron of NRG1 (.007 <= P <= .04). Also, 2-, 3-, and 4-SNP windows that comprise these SNPs were associated (P < 3 x 10(-4)). One protective haplotype (0% vs 1.8%; P < 5 x 10(-5)) and 1 disease risk-causing haplotype (40.4% vs 34.9%, P=.02) were defined.Conclusion: The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.
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| 4. |
- Ceulemans, Shana, et al.
(författare)
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Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population
- 2011
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Ingår i: Bipolar Disorders. - Malden, USA : John Wiley & Sons. - 1398-5647 .- 1399-5618. ; 13:7-8, s. 614-623
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD. Methods: Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population. Results: Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10–15%) susceptibility haplotype covering the entire coding region and 3? untranslated region (UTR) of NR3C1. Conclusions: This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.
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| 5. |
- Forero, Diego A., et al.
(författare)
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A network of synaptic genes associated with schizophrenia and bipolar disorder
- 2016
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 172:1-3, s. 68-74
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Tidskriftsartikel (refereegranskat)abstract
- Identification of novel candidate genes for schizophrenia (SZ) and bipolar disorder (BP), two psychiatric disorders with large epidemiological impacts, is a key research area in neurosciences and psychiatric genetics. Previous evidence from genome-wide studies suggests an important role for genes involved in synaptic plasticity in the risk for SZ and BP. We used a convergent genomics approach, combining different lines of biological evidence, to identify genes involved in the cAMP/PKA/CREB functional pathway that could be novel candidates for BP and SZ: CREB1, CREM, GRIN2C, NPY2R, NF1, PPP3CB and PRKAR1A. These 7 genes were analyzed in a HapMap based association study comprising 48 common SNPs in 486 SZ, 351 BP patients and 514 control individuals recruited from an isolated population in Northern Sweden. Genetic analysis showed significant allelic associations of SNPs in PRKAR1A with SZ and of PPP3CB and PRKAR1A with BP. Our results highlight the feasibility and the importance of convergent genomic data analysis for the identification of candidate genes and our data provide support for the role of common inherited variants in synaptic genes and their involvement in the etiology of BP and SZ.
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| 6. |
- Hultdin, Magnus, et al.
(författare)
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Association between telomere length and V-H gene mutation status in chronic lymphocytic leukaemia : clinical and biological implications
- 2003
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Ingår i: British Journal of Cancer. - London : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 88:4, s. 593-598
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Tidskriftsartikel (refereegranskat)abstract
- The immunoglobulin V-H gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V-H genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated VH genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and VH gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between VH gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 63 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months), Furthermore, the I-g gene sequence data revealed that samples with high mutations frequency (> 6%) had long telomeres (similar to 8 kbp). Thus, both the telomere and VH gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction. (C) 2003 Cancer Research UK.
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| 7. |
- Hultdin, Magnus, et al.
(författare)
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Replication timing of human telomeric DNA and other repetitive sequences analyzed by fluorescence in situ hybridization and flow cytometry
- 2001
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Ingår i: Experimental Cell Research. - : Elsevier. - 0014-4827. ; 271, s. 223-229
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Tidskriftsartikel (refereegranskat)abstract
- The replication timing of telomeres seems to differ between species. Yeast telomeres are late replicating, whereas limited data from very few human cell lines have indicated telomere replication throughout S phase. In the present study a series of permanent cell lines and patient samples was investigated using a flow cytometric approach for telomere length determination based on in situ hybridization using peptide nucleic acid probes and DNA staining. This method permits selective analysis of cells in specific phases of the cell cycle without perturbation of the cell cycle machinery. The timing of replication of telomeric C(3)TA(2) and T(2)AG(3) repeats was found to differ between individual samples and could precede or be concomitant with the replication of bulk DNA. Replication of the T(2)AG(3) strand seemed to occur somewhat later than that of the C(3)TA(2) strand in some samples. (GTG)(n) and other repetitive sequences generally showed a replication pattern similar to that of the bulk of DNA with slightly individual differences, whereas centromeric DNA repeats consistently replicated within a short time frame in late S phase. The apparent variability in replication timing seen for telomeric DNA might suggest individual differences in firing of replication origins.
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| 8. |
- Hultdin, Magnus, et al.
(författare)
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Telomere analysis by fluorescence in situ hybridization and flow cytometry
- 1998
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Ingår i: Nucleic Acids Research. - Oxford : Oxford University Press. - 0305-1048 .- 1362-4962. ; 26:16, s. 3651-3656
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Tidskriftsartikel (refereegranskat)abstract
- Determination of telomere length is traditionally performed by Southern blotting and densitometry, giving a mean telomere restriction fragment (TRF) value for the total cell population studied. Fluorescence in situ hybridization (FISH) of telomere repeats has been used to calculate telomere length, a method called quantitative (Q)-FISH, We here present a quantitative flow cytometric approach, Q-FISHFCM, for evaluation of telomere length distribution in individual cells based on in situ hybridization using a fluorescein-labeled peptide nucleic acid (PNA) (CCCTAA)(3) probe and DMA staining with propidium iodide, A simple and rapid protocol with results within 30 h was developed giving high reproducibility, One important feature of the protocol was the use of an internal cell line control, giving an automatic compensation for potential differences in the hybridization steps. This protocol was tested successfully on cell lines and clinical samples from bone marrow, blood, lymph nodes and tonsils. A significant correlation was found between Southern blotting and Q-FISHFCM telomere length values (P = 0.002), The mean sub-telomeric DNA length of the tested cell lines and clinical samples was estimated to be 3.2 kbp, With the Q-FISHFCM method the fluorescence signal could be determined in different cell cycle phases, indicating that in human cells the vast majority of telomeric DNA is replicated early in S phase.
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| 9. |
- Karling, Pontus, et al.
(författare)
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Association between gastrointestinal symptoms and affectivity in patients with bipolar disorder
- 2016
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Ingår i: World Journal of Gastroenterology. - : Baishideng. - 1007-9327 .- 2219-2840. ; 22:38, s. 8540-8548
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To study if anxiety, depression and experience of stress are associated with gastrointestinal (GI) symptoms in patients with bipolar disorder.METHODS: A total of 136 patients with bipolar disorder (mean age 49.9 years; 61% women) and 136 controls from the general population (mean age 51.0 years; 60% women) were included in the study. GI symptoms were assessed with The Gastrointestinal Symptom Rating Scale-irritable bowel syndrome (GSRS-IBS), level of anxiety and depression with The Hospital Anxiety and Depression Scale (HADS) and stress-proneness with Perceived Stress Questionnaire. Over a ten year period, all visits in primary care were retrospectively recorded in order to identify functional GI disorders.RESULTS: In subjects with low total HADS-score, there were no significant differences in GI-symptoms between patients and controls (GSRS-IBS 7.0 vs 6.5, P = 0.513). In the patients with bipolar disorder there were significant correlations between all GSRS and HADS subscores for all symptom clusters except for "constipation" and "reflux". Factors associated to GI symptoms in the patient group were female sex (adjusted OR = 2.37, 95%CI: 1.07-5.24) and high HADS-Depression score (adjusted OR = 3.64, 95%CI: 1.07-12.4). These patients had also significantly more visits for IBS than patients with low HADS-Depression scores (29% vs 8%, P = 0.008). However, there was no significant differences in consulting behaviour for functional GI disorders between patients and controls (25% vs 17%, P = 0.108).CONCLUSION: Female patients and patients with high HADS depression score reported significantly more GI symptoms, whereas patients with low HADS scores did not differ from control subjects.
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| 10. |
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