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
Genetic studies of stroke in Northern Sweden
Umeå University, Faculty of Medicine, Medical Biosciences.
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 [en]
stroke, linkage, genome wide scan, susceptibility loci, association, candidade gene, PDE4D, PIK3R1, extended pedigree
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-887ISBN: 91-7264-191-6 (print)OAI: oai:DiVA.org:umu-887DiVA: diva2:144889
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
List of papers
1. Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.
Open this publication in new window or tab >>Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.
Show others...
2005 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 36, no 8, 1666-1671 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Recent Icelandic studies have demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke. Using a candidate region approach, we wanted to test the validity of these findings in a different population from northern Sweden. METHODS: A total of 56 families with 117 affected individuals were included in the linkage study. Genotyping was performed with polymorphic microsatellite markers with an average distance of 4.5 cM on chromosome 5. In the association study, 275 cases of first-ever stroke were included together with 550 matched community controls. Polymorphisms were tested individually for association of PDE4D to stroke. RESULTS: Maximum allele-sharing lod score in favor of linkage was observed at marker locus D5S424 (lod score=2.06; P=0.0010). Conditional logistic regression calculations revealed no significant association of ischemic stroke to the defined at-risk allele in PDE4D (odds ratio, 1.1; 95% confidence interval, 0.84 to 1.45). A protective effect may though be implied for 2 of the polymorphisms analyzed in PDE4D. CONCLUSIONS: Using a candidate region approach in a set of stroke families from northern Sweden, we have replicated linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q. Association studies in an independent nested case-control sample from the same geographically located population suggested that different alleles confer susceptibility/protection to stroke in the Icelandic and the northern Swedish populations.

Keyword
3';5'-Cyclic-Nucleotide Phosphodiesterase/*genetics, Algorithms, Alleles, Case-Control Studies, Cerebrovascular Accident/genetics, Chromosome Mapping, Chromosomes; Human; Pair 5, Diabetes Complications/genetics, Exons, Family Health, Gene Frequency/*genetics, Genetic Markers, Genetic Predisposition to Disease, Genotype, Humans, Iceland, Ischemia, Linkage (Genetics), Linkage Disequilibrium, Lod Score, Microsatellite Repeats, Models; Statistical, Odds Ratio, Polymorphism; Genetic, Regression Analysis, Risk Factors, Sweden
Identifiers
urn:nbn:se:umu:diva-14817 (URN)10.1161/01.STR.0000174188.04716.8d (DOI)16020760 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2017-12-14Bibliographically approved
2. Genome-wide linkage scan of common stroke in families from northern Sweden.
Open this publication in new window or tab >>Genome-wide linkage scan of common stroke in families from northern Sweden.
Show others...
2007 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 38, no 1, 34-40 p.Article in journal (Other academic) Published
Keyword
Aged, Chromosome Mapping/*methods, Chromosomes; Human; Pair 13/genetics, Chromosomes; Human; Pair 18/genetics, Chromosomes; Human; Pair 5/genetics, DNA Mutational Analysis, Female, Gene Frequency/genetics, Genetic Predisposition to Disease/epidemiology/*genetics, Genetic Screening, Genetic Variation/genetics, Genome; Human/*genetics, Humans, Male, Middle Aged, Stroke/epidemiology/*genetics, Sweden/epidemiology
Identifiers
urn:nbn:se:umu:diva-11537 (URN)10.1161/01.STR.0000251643.37454.16 (DOI)17122438 (PubMedID)
Available from: 2009-01-13 Created: 2009-01-13 Last updated: 2017-12-14Bibliographically approved
3. Variation in the regulatory subunit p85alpha of Phosphatidylinositol 3-kinase, PIK3R1, is associated with common forms of stroke
Open this publication in new window or tab >>Variation in the regulatory subunit p85alpha of Phosphatidylinositol 3-kinase, PIK3R1, is associated with common forms of stroke
Show others...
(English)Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-5386 (URN)
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2016-08-22Bibliographically approved
4. A novel stroke susceptibility locus mapped to chromosome 9q in an extended pedigree from northern Sweden
Open this publication in new window or tab >>A novel stroke susceptibility locus mapped to chromosome 9q in an extended pedigree from northern Sweden
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-5387 (URN)
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2016-08-22Bibliographically approved

Open Access in DiVA

fulltext(785 kB)1052 downloads
File information
File name FULLTEXT01.pdfFile size 785 kBChecksum SHA-1
14e77337dc55d6d3103e046b5b79bbc50cd1bf39cbf1abf7e6764d895e7eb9fc94fb43ef
Type fulltextMimetype application/pdf

By organisation
Medical Biosciences
Medical Genetics

Search outside of DiVA

GoogleGoogle Scholar
Total: 1052 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 675 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