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| 13. |
- Hughes, T., et al.
(författare)
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Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder
- 2018
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis pvalues: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3's association with bipolar disorder.
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| 18. |
- Aas, M, et al.
(författare)
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Telomere length is associated with childhood trauma in patients with severe mental disorders
- 2019
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 97-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced telomere length (TL) and structural brain abnormalities have been reported in patients with schizophrenia (SZ) and bipolar disorder (BD). Childhood traumatic events are more frequent in SZ and BD than in healthy individuals (HC), and based on recent findings in healthy individuals could represent one important factor for TL and brain aberrations in patients. The study comprised 1024 individuals (SZ [n = 373]; BD [n = 249] and HC [n = 402]). TL was measured by quantitative polymerase chain reaction (qPCR), and childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Diagnosis was obtained by the Structured Clinical Interview (SCID) for the diagnostic and statistical manual of mental disorders-IV (DSM-IV). FreeSurfer was used to obtain regional and global brain volumes from T1-weighted magnetic resonance imaging (MRI) brain scans. All analyses were adjusted for current age and sex. Patients had on average shorter TL (F = 7.87, p = 0.005, Cohen’s d = 0.17) and reported more childhood trauma experiences than HC (χ2 = 148.9, p < 0.001). Patients with a history of childhood sexual, physical or emotional abuse had shorter TL relative to HC and to patients without a history of childhood abuse (F = 6.93, p = 0.006, Cohen’s d = 0.16). After adjusting for childhood abuse, no difference in TL was observed between patients and HC (p = 0.12). There was no statistically significant difference in reported childhood abuse exposure or TL between SZ and BD. Our analyses revealed no significant associations between TL and clinical characteristics or brain morphometry. We demonstrate shorter TL in SZ and BD compared with HC and showed that TL is sensitive to childhood trauma experiences. Further studies are needed to identify the biological mechanisms of this relationship.
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| 20. |
- Athanasiu, L., et al.
(författare)
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A genetic association study of CSMD1 and CSMD2 with cognitive function
- 2017
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 61, s. 209-216
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Tidskriftsartikel (refereegranskat)abstract
- The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n = 670). Replication testing of SNPs with p-value < 0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n =1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n = 1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMDI SNP rs2740931 and performance in immediate episodic memory (p-value = 5 Chi 10(-6), minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p <= 1.2 Chi 10(-5)). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n = 3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease. (C) 2016 The Authors. Published by Elsevier Inc.
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