| 1. |
- van West, Dirk, et al.
(författare)
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Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression
- 2006
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 31:3, s. 620-627
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5' region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5' region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.
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| 2. |
- Cammaerts, Sophia, et al.
(författare)
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Schizophrenia-Associated MIR204 Regulates Noncoding RNAs and Affects Neurotransmitter and Ion Channel Gene Sets
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells. Analysis of the consequences of the altered miR-204 expression on the transcriptome of these cells uncovered a new mode of action for miR-204, being the regulation of noncoding RNAs (ncRNAs), including several miRNAs, such as MIR296. Furthermore, pathway analysis showed downstream effects of miR-204 on neurotransmitter and ion channel related gene sets, potentially mediated by miRNAs regulated through miR-204.
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| 3. |
- Moens, Lotte N, et al.
(författare)
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PCM1 and schizophrenia : a replication study in the Northern Swedish population
- 2010
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Ingår i: American Journal of Medical Genetics. - : Wiley. - 0148-7299 .- 1096-8628. ; 153B:6, s. 1240-1243
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies implicated centrosomal dysfunction as a source of various neuropsychiatric disorders, including schizophrenia (SZ). Two recent reports [Gurling et al., 2006; Datta et al., 2008. Mol Psychiatry] described an association between polymorphisms in the PCM1 gene and SZ in a UK/Scottish population. In this study, we aimed to replicate these findings in a Northern Swedish association sample of 486 research subjects with SZ and 512 unrelated control individuals. We genotyped 12 previously described SNP markers and carried out haplotype analyses using the same multi-marker haplotypes previously reported. Though we could not replicate the association with SNPs rs445422 and rs208747, we did observe a significant protective association with intronic SNP rs13276297. Furthermore, we performed a meta-analysis comprising 1,794 SZ patients and 1,553 controls, which confirmed the previously reported association with rs445422 and rs208747. These data provide further evidence that PCM1-though certainly not a major risk factor in the Northern Swedish population-cannot be ruled out as a contributor to SZ risk and/or protection, and deserves further replication in larger populations to elucidate its role in disease etiology.
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| 4. |
- Moens, Lotte N, et al.
(författare)
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Sequencing of DISC1 Pathway Genes Reveals Increased Burden of Rare Missense Variants in Schizophrenia Patients from a Northern Swedish Population
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8, s. e23450-
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence - both genetic and functional - indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P = 0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P = 0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that similar to 90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- Mendlewicz, Julien, et al.
(författare)
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Expanded RED products and loci containing CAG/CTG repeats on chromosome 17 (ERDA1) and chromosome 18 (CTG18.1) in trans-generational pairs with bipolar affective disorder
- 2004
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Ingår i: American Journal of Medical Genetics. - Hoboken : John Wiley & Sons. - 0148-7299 .- 1096-8628. ; 128B:1, s. 71-75
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to further test if expanded CAG repeats detected by the repeat expansion detection (RED) method in bipolar affective disorder (BPAD) are correlated with ERDA1 (17q21.3) and/or CTG18.1 (18q21.1) loci expansions, and changes of phenotype severity in successive generations (anticipation). The sample was designed to analyze ERDA1 and CTG18.1 expansions in trans-generational pairs of affected individuals (parent-offspring pairs: G1 and G2). Clinical and genetic information was available on 95 two-generations pairs. We found in our sample no one patient.
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| 8. |
- Van Den Bogaert, Ann, et al.
(författare)
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No allelic association or interaction of three known functional polymorphisms with bipolar disorder in a northern Swedish isolated population
- 2006
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Ingår i: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 16:5, s. 209-212
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Tidskriftsartikel (refereegranskat)abstract
- Most genetic association studies in bipolar disorder have focussed on genes involved in major neurotransmitter systems or brain development. Functional polymorphisms in the serotonin transporter (5-HTTLPR), catechol-O-methyltransferase (Val158Met) and dopamine D3 receptor (Ser9Gly) genes have all been associated with bipolar disorder. We aimed at investigating whether these functional variants contribute to the genetic etiology of bipolar disorder in a northern Swedish isolated population. Moreover, we wanted to gain information about the synergistic contribution of these functional variants. Neither of these functional polymorphisms was associated with bipolar disorder in the northern Swedish patient-control sample nor did we find evidence of gene-gene interaction. Together, our data suggest that these functional variants are not involved in the etiology of bipolar disorder in the northern Swedish population nor did gene-gene interaction analysis support a central role of these variants in bipolar disorder.
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| 9. |
- Van Den Eede, Filip, et al.
(författare)
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Single nucleotide polymorphism analysis of corticotropin-releasing factor-binding protein gene in bipolar disorder
- 2007
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Ingår i: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 17:5, s. 304-307
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Tidskriftsartikel (refereegranskat)abstract
- Corticotropin-releasing factor-binding protein regulates the availability of free corticotropin-releasing factor and is a functional candidate gene for affective disorders. The aim of this study was to examine the association between polymorphisms in CRF-BP gene and bipolar disorder in an isolated Swedish population. One hundred and eighty-two patients with bipolar I disorder and 333 controls from Northern Sweden were included in the study. Five single nucleotide polymorphisms and a deletion polymorphism in the CRF-BP gene were genotyped. The haplotype block structure of the gene was considered and the expectation maximization algorithm was adopted to estimate the haplotype frequencies. As a result, there were no significant associations of the different polymorphisms in the CRF-BP gene with bipolar disorder. In conclusion, this study in an isolated Swedish population does not support a role for the CRF-BP gene in the vulnerability for bipolar disorder.
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| 10. |
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