| 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. |
- Chen, Long Long, et al.
(författare)
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Genomics of severe and treatment-resistant obsessive–compulsive disorder treated with deep brain stimulation : a preliminary investigation
- 2024
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Ingår i: American Journal of Medical Genetics Part B. - : John Wiley & Sons. - 1552-4841 .- 1552-485X.
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.
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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. |
- Sjöberg, Rickard L., et al.
(författare)
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Adolescent girls and criminal activity : Role of MAOA-LPR genotype and psychosocial factors
- 2007
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Ingår i: American Journal of Medical Genetics Part B. - Uppsala Univ, Cent Hosp Vasteras 1, Clin Res Ctr, S-72189 Vasteras, Sweden. Uppsala Univ, Dept Neurosci, Pharmacol Unit, S-75105 Uppsala, Sweden. : Wiley. - 1552-4841 .- 1552-485X. ; 144:2, s. 159-164
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings among boys show that interactions between a polymorphism in the monoamine oxidase A gene promoter region (MAOA-LPR) and psychosocial factors predict criminal activity. The objective of this study was to investigate whether this finding could be extended to adolescent girls. One hundred nineteen female adolescents were recruited among respondents to a cross-sectional study of the total population of 16- and 19-year old girls. These girls constituted a randomly selected sub-sample from groups representing different degrees of risk behavior. The subjects filled in a questionnaire and were interviewed and genotyped with regard to MAOA-LPR. The results indicate that the long, (4-repeat) allele confer an increased risk for criminal behavior in the presence of psychosocial risk. Among girls without social risk, MAOA-LPR genotype was of no importance for criminal behavior. The present results suggest that previous observations on adolescent males, which demonstrate that the short MAOA-LPR genotype and psychosocial adversity interact to predict criminal activity, may not be applicable to females.
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| 5. |
- Van Den Bossche, Maarten J., et al.
(författare)
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Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders
- 2012
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Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 159B:4, s. 465-475
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Tidskriftsartikel (refereegranskat)abstract
- The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7?kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 1726 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular.
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| 6. |
- Van Den Bossche, Maarten J., et al.
(författare)
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Rare copy number variants in neuropsychiatric disorders : Specific phenotype or not?
- 2012
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Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 159B:7, s. 812-822
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Tidskriftsartikel (refereegranskat)abstract
- From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on additional genetic and environmental factors. Our results also suggest that the neurodevelopmental component is larger in the etiology of schizophrenia and intellectual disability than in mood disorders. Finally, our data suggest that deletions are in general more pathogenic than duplications. Given the high frequency of the examined CNVs (12%) in patients of different neuropsychiatric disorders, screening of large cohorts with an affordable and feasible method like the MAQ assays used in this study is likely to result in important progress in unraveling the genetic factors leading to an increased susceptibility for several psychiatric disorders.
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| 7. |
- Åberg, Karolina, et al.
(författare)
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Human QKI, a New Candidate Gene for Schizophrenia Involved in Myelination
- 2005
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Ingår i: American journal of medical genetics. Part B, Neuropsychiatric genetics. - Malden : Wiley. - 1552-4841 .- 1552-485X. ; 141B:1, s. 84-90
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 Mb region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.
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| 8. |
- Jönsson, E G, et al.
(författare)
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Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: Association study and meta-analysis
- 2003
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Ingår i: American Journal of Medical Genetics. - : Wiley. - 0148-7299 .- 1096-8628. ; 119B:1, s. 28-34
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Tidskriftsartikel (refereegranskat)abstract
- An association has been reported between a dopamine D(2) receptor gene (DRD2) Ser311Cys variant and schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 173) and control subjects (n = 236) were assessed for the DRD2 Ser311Cys variant. Schizophrenic patients displayed higher Cys311 allele frequencies than control subjects (4.0 vs. 0.8%, chi(2) = 9.49, df = 1, P = 0.002; odds ratio (OR) 4.93, 95% confidence interval (95% CI) 1.61-15.12). The association was detected only in men. The results were supported by a meta-analysis of all published case-control studies comprising a total of 9,152 subjects (chi(2) = 11.37, df = 1, P < 0.001; OR 1.43, 95% CI 1.16-1.78). The present results support the involvement of the DRD2 gene in the pathogenesis of schizophrenia. Copyright 2003 Wiley-Liss, Inc.
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| 9. |
- 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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