| 1. |
- Alaerts, Maaike, et al.
(författare)
-
Detailed analysis of the serotonin transporter gene (SLC6A4) shows no association with bipolar disorder in the Northern Swedish population
- 2009
-
Ingår i: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. - : John Wiley & Sons, Inc. - 1552-4841 .- 1552-485X. ; 150B:4, s. 585-592
-
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.
|
|
| 2. |
- Alaerts, Maaike, et al.
(författare)
-
Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population
- 2009
-
Ingår i: Archives of General Psychiatry. - : American Medical Association. - 0003-990X .- 1538-3636. ; 66:8, s. 828-837
-
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.
|
|
| 3. |
- Chowdhury, Mohammed Gofran, et al.
(författare)
-
Experimentally validated CFD simulations predicting wind effects on photovoltaic modules mounted on inclined surfaces
- 2018
-
Ingår i: Sustainable Energy Technologies and Assessments. - : ELSEVIER SCIENCE BV. - 2213-1388 .- 2213-1396. ; 30, s. 201-208
-
Tidskriftsartikel (refereegranskat)abstract
- Computational Fluid Dynamics (CFD) and wind tunnel experiments were used to study wind flow over PV modules attached to inclined surfaces. Wind velocities were investigated at various positions on a WA module, for five wind speeds varying from 1 to 5 m s(-1). After validation the CFD model was used to study the effects air gaps and wall cavities under the module have on the airflow over the module. Data were measured for two air gaps, 3.5 cm and 5.5 cm thick, and for three cavity depths ranging from 0 cm to 9 cm. The 3.5 cm air gap resulted in lower near-surface wind speeds over the PV module. This will result in less wind-generated cooling of the module, and consequently, in a lower electrical performance. The wall cavities did not affect the magnitude of the wind speed over the module but generated an increased deflection of the wind towards the lateral sides of the module. They also created clockwise and anti-clockwise eddies next to the PV setup and in the cavity itself. The study shows that in CFD simulations for PV applications, even small irregularities in the PV setup should be included in the model to predict reliable results.
|
|
| 4. |
- Goossens, Dirk, et al.
(författare)
-
Simultaneous mutation and copy number variation (CNV) detection by multiplex PCR-based GS-FLX sequencing.
- 2009
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 30:3, s. 472-6
-
Tidskriftsartikel (refereegranskat)abstract
- We evaluated multiplex PCR amplification as a front-end for high-throughput sequencing, to widen the applicability of massive parallel sequencers for the detailed analysis of complex genomes. Using multiplex PCR reactions, we sequenced the complete coding regions of seven genes implicated in peripheral neuropathies in 40 individuals on a GS-FLX genome sequencer (Roche). The resulting dataset showed highly specific and uniform amplification. Comparison of the GS-FLX sequencing data with the dataset generated by Sanger sequencing confirmed the detection of all variants present and proved the sensitivity of the method for mutation detection. In addition, we showed that we could exploit the multiplexed PCR amplicons to determine individual copy number variation (CNV), increasing the spectrum of detected variations to both genetic and genomic variants. We conclude that our straightforward procedure substantially expands the applicability of the massive parallel sequencers for sequencing projects of a moderate number of amplicons (50-500) with typical applications in resequencing exons in positional or functional candidate regions and molecular genetic diagnostics.
|
|
| 5. |
- Johnstone, Mandy, et al.
(författare)
-
Copy number variations in DISC1 and DISC1-interacting partners in major mental illness
- 2015
-
Ingår i: Molecular neuropsychiatry. - : S. Karger AG. - 2296-9209. ; 1:3, s. 175-190
-
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.
|
|
| 6. |
- Moens, Lotte N, et al.
(författare)
-
Sequencing of DISC1 Pathway Genes Reveals Increased Burden of Rare Missense Variants in Schizophrenia Patients from a Northern Swedish Population
- 2011
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8, s. e23450-
-
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.
|
|
| 7. |
- Momozawa, Yukihide, et al.
(författare)
-
Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease
- 2011
-
Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 43:1, s. 43-47
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.
|
|
| 8. |
|
|
| 9. |
- Rischer, Heiko, et al.
(författare)
-
Gene-to-metabolite networks for terpenoid indole alkaloid biosynthesis in Catharanthus roseus cells
- 2006
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 103:14, s. 5614-5619
-
Tidskriftsartikel (refereegranskat)abstract
- Rational engineering of complicated metabolic networks involved in the production of biologically active plant compounds has been greatly impeded by our poor understanding of the regulatory and metabolic pathways underlying the biosynthesis of these compounds. Whereas comprehensive genome-wide functional genomics approaches can be successfully applied to analyze a select number of model plants, these holistic approaches are not yet available for the study of nonmodel plants that include most, if not all, medicinal plants. We report here a comprehensive profiling analysis of the Madagascar periwinkle (Catharanthus roseus), a source of the anticancer drugs vinblastine and vincristine. Genome-wide transcript profiling by cDNA-amplified fragment-length polymorphism combined with metabolic profiling of elicited C. roseus cell cultures yielded a collection of known and previously undescribed transcript tags and metabolites associated with terpenoid indole alkaloids. Previously undescribed gene-to-gene and gene-to-metabolite networks were drawn up by searching for correlations between the expression profiles of 417 gene tags and the accumulation profiles of 178 metabolite peaks. These networks revealed that the different branches of terpenoid indole alkaloid biosynthesis and various other metabolic pathways are subject to differing hormonal regulation. These networks also served to identify a select number of genes and metabolites likely to be involved in the biosynthesis of terpenoid indole alkaloids. This study provides the basis for a better understanding of periwinkle secondary metabolism and increases the practical potential of metabolic engineering of this important medicinal plant.
|
|
| 10. |
- Sutrala, Smitha R, et al.
(författare)
-
Gene copy number variation in schizophrenia
- 2007
-
Ingår i: Schizophrenia Research. - Amsterdam : Elsevier. - 0920-9964 .- 1573-2509. ; 96:1-3, s. 93-99
-
Tidskriftsartikel (refereegranskat)abstract
- The possibility that gene copy number variations play a role in the development of complex disorders is a topic of considerable interest. Recent reports have highlighted the large number of such variations that exist and that their occurrence varies considerably between populations. A recent report has suggested that copy number variations in four genes (GRIK3, EFNA5, AKAP5 and CACNG2) may be associated with schizophrenia. One problem with this area of study is the validation of high throughput methods such as comparative genomic hybridisation, as the latter inevitably generates false positives. We have used two contrasting methodologies to determine the validity of the findings reported above which if true would have major implications for the pathogenesis of schizophrenia. Samples from a UK population were tested using a method of allele quantification by DNA pooling and samples from Belgium and northern Sweden were tested using Multiplex Amplicon Quantification (MAQ). Both methods were used to test DNA samples used in the original investigation. No copy number variations were found for any of the genes in any samples. Our data suggests that more reliable methods need to be used to validate the existence of CNVs before full scale association studies are carried out.
|
|
