umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A novel stroke susceptibility locus mapped to chromosome 9q in an extended pedigree from northern Sweden
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-5387OAI: oai:DiVA.org:umu-5387DiVA: diva2:144888
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2016-08-22Bibliographically approved
In thesis
1. Genetic studies of stroke in Northern Sweden
Open this publication in new window or tab >>Genetic studies of stroke in Northern Sweden
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stroke is a common disorder of later life with a complex etiology, including both environmental and genetic risk factors. The inherited predisposition is challenging to study due to the complexity of the stroke phenotype. Genetic studies in an isolated population have successfully identified a positional candidate gene for stroke, phosphodiesterase 4D (PDE4D).

The aim of this thesis was to identify stroke susceptibility loci and positional candidate genes, taking advantage of low genetic variation in the northern Sweden population. All stroke cases were identified in a population-based stroke registry at the northern Sweden MONICA Centre. 56 families containing multiple cases of stroke and a follow up set of an additional 53 families were used for linkage studies. For association studies, 275 cases of first ever stroke together with 550 matched community controls were included. In paper I, we used a candidate region approach to investigate the PDE4D region on chromosome 5q. Linkage was obtained with a maximum allele-sharing LOD score of 2.06; P = 0.001. However, no significant association of ischemic stroke to the previously defined at-risk allele in PDE4D was observed. We next performed a genome wide linkage scan to explore new susceptibility loci for common forms of stroke (paper II). Non-parametric multipoint linkage analysis yielded allele-sharing LOD scores > 1.2 at nine locations; 1p34, 5q13, 7q35, 9q22, 9q34, 13q32, 14q32, 18p11, 20q13. The highest allele-sharing LOD score was obtained on chromosome 18p (LOD = 2.14). Fine mapping resulted in increased allele-sharing LOD scores for chromosome 5q13 and 9q22. In the follow up analysis of the nine regions, including all 109 families, the highest allele-sharing LOD scores were obtained on chromosomes 5q, 13q and 18p although none reached the initial genome wide values. In paper III, we focused on the chromosome 5q region, and further mapping and haplotype analysis in the families was performed. A common 1 cM haplotype was found to be shared among affected members of five families. In this region only the regulatory subunit 1 of phosphatidylinositol 3-kinase (PIK3R1) gene was located. Association of three single nucleotide polymorphisms in the PIK3R1 gene to common stroke was obtained in the case-control material. Finally, in paper IV, an extended pedigree containing seven families connected to common founders eight generations back was identified by genealogical analysis, and submitted to a separate genome wide scan analysis. A significant allele-sharing LOD score of 4.66 (genome wide P < 0.001) at chromosome 9q31-33 was obtained. Haplotype analysis identified a minimal common region of 3.2 cM, which was shared by four of the seven families. These four families contained all of the primary intracerebral hemorrhagic cases present in the extended pedigree.

In conclusion we have replicated linkage of stroke susceptibility to the PDE4D region on chromosome 5q, but no significant association of ischemic stroke to PDE4D was observed. Linkage analysis of stroke did not identify any new major stroke loci, indicating that multiple minor susceptibility loci in addition to the previously known locus on chromosome 5q could contribute to the disease. In the chromosome 5q region a novel positional candidate gene for stroke was identified, the PIK3R1 gene. The PIK3R1 protein has several biological actions with potential roles in stroke susceptibility. Also a novel susceptibility locus for common forms of stroke at chromosome 9q was identified in a large pedigree, which may be of special importance for susceptibility to hemorrhagic stroke.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2006. 71 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1060
Keyword
stroke, linkage, genome wide scan, susceptibility loci, association, candidade gene, PDE4D, PIK3R1, extended pedigree
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-887 (URN)91-7264-191-6 (ISBN)
Public defence
2006-10-27, Hörsal Betula, 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2009-10-23Bibliographically approved
2. The genetic contribution to stroke in northern Sweden
Open this publication in new window or tab >>The genetic contribution to stroke in northern Sweden
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
Genetikens roll för stroke i norra Sverige
Abstract [en]

Stroke is a common multi factorial cerebrovascular disorder with a large impact on global health. It is a disorder primarily associated with old age but environmental factors, lifestyle choices and medical history are all important for the risk of developing the disorder. It is also known that heritability is important for predisposition to the disorder. The aim of this work has been to identify genetic variations that increase the risk of being affected by stroke in the population of northern Sweden, a population well apt for genetic studies due to well kept church and medical records together with limited genetic diversity.

In the first paper we used linkage analysis in families with early onset of stroke. By this approach we identified a region on chromosome 5q to be linked to an increased risk of developing stroke, a region previously identified as a susceptibility locus for stroke in the Icelandic population. In the second study we used genealogy to identify common ancestry and thereby identify common susceptibility to stroke. The seven families we connected showed significant linkage to the chromosome 9q31-33 region and four of the families shared a common haplotype over 2.1 megabases. In the third manuscript we investigated sequence variation of two candidate genes, TNFSF15 and TLR4. Sequencing of the TLR4 gene revealed previously identified variations in affected individuals from two of the families. Further SNP analysis showed five separate haplotypes among the investigated families and four haplotypes for TNFSF15. However none of these co-segregated with stroke among the investigated families. In the final paper we used a case-control stroke cohort to ascertain association for genetic variation in five genes and genetic regions previously suggested to be linked with stroke. Initial analyses showed association for the 9p21 chromosomal region and a variant in Factor 5 that showed protection against stroke, but after adjustments for common risk factors for stroke, the findings were no longer significant.

In conclusion, by studying selected families we have been able to show linkage to two chromosomal regions, 5q and 9q31-33, that indicate genetic predisposition for developing stroke. Further we have shown that family based studies are still an important tool in deciphering the underlying mechanisms for complex disease.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2010. 70 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1329
Keyword
Northern Sweden, stroke, genetics, genome wide scan, association, 5q13, 9q31-33
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-31929 (URN)978-91-7264-947-7 (ISBN)
Public defence
2010-03-19, Hörsal Betula, BY 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2010-02-26 Created: 2010-02-24 Last updated: 2010-02-26Bibliographically approved

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Janunger, TomasWiklund, Per-GunnarAndersson Escher, Stefan
By organisation
Department of Medical Biosciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 74 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf