| 1. |
- Wikgren, Mikael, 1981-, et al.
(författare)
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Short Telomeres in Depression and the General Population Are Associated with a Hypocortisolemic State
- 2012
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Ingår i: Biological Psychiatry. - New York : Elsevier. - 0006-3223 .- 1873-2402. ; 71:4, s. 294-300
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Tidskriftsartikel (refereegranskat)abstract
- Background The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls. Methods Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires. Results TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, short TL was associated with a hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control subjects but more pronounced among patients. This state, which was overrepresented among patients, was characterized by high familial loading of affective disorders among patients (p = .001) and high C-reactive protein levels among control subjects (p = .040). TL was also inversely associated with stress measured with the Perceived Stress Questionnaire (rs = −.258, p = .003). Conclusions Short TL is associated with depression and hypocortisolism. Because hypocortisolism has been shown to develop from chronic stress exposure, our findings corroborate the concept of TL as a cumulative measure of stress and provide novel insights into the detrimental role of stress in depressive illness and the general population.
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| 2. |
- 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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| 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. |
- Johnstone, Mandy, et al.
(författare)
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Copy number variations in DISC1 and DISC1-interacting partners in major mental illness
- 2015
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Ingår i: Molecular neuropsychiatry. - : S. Karger AG. - 2296-9209. ; 1:3, s. 175-190
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Tidskriftsartikel (refereegranskat)abstract
- Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.
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| 7. |
- 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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| 8. |
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| 9. |
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| 10. |
- 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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