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Mapping genetic diseases in northern Sweden
Umeå University, Faculty of Medicine, Medical Biosciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The population of northern Sweden has previously been shown to be well suited for the mapping of monogenic diseases. In this thesis we have tested the hypothesis that this population could also be used for efficient identification of risk genes for common diseases. In Paper I we have hypothesised that despite the admixture of Swedish, Finnish and Sami, the northern Swedish population consists of sub-populations geographically restricted by the main river valleys running through the region. This geographic isolation, in combination with founder effects and genetic drift, could represent a unique resource for genetic studies. On the other hand, it also underlines the importance of accounting for this e.g. in genetic association studies. To test this hypothesis, we studied the patterns of marriage within and between river valley regions and compared allelic frequencies of genetic markers between these regions. The tendency to find a spouse and live in the river valley where one was born is strong, and allelic frequencies of genetic markers vary significantly between adjacent regions. These data support our hypothesis that the river valleys are home to distinct sub-populations and that this is likely to affect mapping of genetic diseases in these populations. In Paper II, we tested the applicability of the population in mapping HSAN V, a monogenic disease. This disease was identified in only three consanguineous individuals suffering from a severe loss of deep pain perception and an impaired perception of heat. A genome-wide scan combined with sequencing of candidate genes resulted in the identification of a causative point mutation in the nerve growth factor beta (NGFB) gene. In Paper III, a large family with multiple members affected by familial forms of type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis (AITD) was studied. This syndrome was mapped to the IDDM12 region on 2q33, giving positive lodscores when conditioning on HLA haplotype. The linkage to HLA and to the IDDM12 region thus confirmed previous reports of linkage and/or association of T1DM and AITD to these loci and provided evidence that the same genetic factors may be mediating these diseases. This also supported the feasibility of mapping complex diseases in northern Sweden by the use of familial forms of these diseases. In Paper IV, we applied the same approach to study type 2 diabetes mellitus (T2DM). A non-parametric genome-wide scan was carried out on a family material from northern Sweden, and linkage was found to the calpain-10 locus, a previously described T2DM-susceptibility gene on 2q37. Together, these findings demonstrate that selecting for familial forms of even complex diseases, and choosing families from the same geographical region can efficiently reduce the genetic heterogeneity of the disease and facilitate the identification of risk genes for the disease.

Place, publisher, year, edition, pages
2005. , 38 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 946
Keyword [en]
Genetics, isolated populations, linkage disequilibrium, linkage analysis, genome-wide scan, hereditary sensory and autonomic neuropathy, type 1 diabetes mellitus, type 2 diabetes mellitus, autoimmune thyroid disease
Keyword [sv]
Genetik
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-499ISBN: 91-7305-836-X (print)OAI: oai:DiVA.org:umu-499DiVA: diva2:143620
Public defence
2005-05-13, A5, 6A, Umeå University, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2005-04-15 Created: 2005-04-15 Last updated: 2009-10-12Bibliographically approved
List of papers
1. The population structure of northern Sweden and its implications for mapping genetic diseases
Open this publication in new window or tab >>The population structure of northern Sweden and its implications for mapping genetic diseases
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4490 (URN)
Available from: 2005-04-15 Created: 2005-04-15 Last updated: 2016-06-20Bibliographically approved
2. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
Open this publication in new window or tab >>A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
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2004 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, no 8, 799-805 p.Article in journal (Refereed) Published
Abstract [en]

Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

Keyword
Adolescent, Adult, Animals, Cattle, Child, Child; Preschool, DNA Mutational Analysis, Female, Guinea Pigs, Humans, Male, Mice, Nerve Growth Factor/*genetics, Pain/*genetics, Pain Insensitivity; Congenital/*genetics, Pedigree, Protein Structure; Secondary, Rats
Identifiers
urn:nbn:se:umu:diva-14121 (URN)10.1093/hmg/ddh096 (DOI)14976160 (PubMedID)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2017-12-14Bibliographically approved
3. The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease
Open this publication in new window or tab >>The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease
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2003 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 1, 81-84 p.Article in journal (Refereed) Published
Abstract [en]

We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

Place, publisher, year, edition, pages
Nature Publishing Group, 2003
Keyword
type 1 diabetes mellitus, autoimmune thyroid disease, CTLA4, HLA, linkage
National Category
Biochemistry and Molecular Biology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-4492 (URN)10.1038/sj.ejhg.5200903 (DOI)12529710 (PubMedID)
Available from: 2005-04-15 Created: 2005-04-15 Last updated: 2017-12-14Bibliographically approved
4. Polymorphisms in the calpain-10 gene show linkage to type 2 diabetes in a population from northern Sweden
Open this publication in new window or tab >>Polymorphisms in the calpain-10 gene show linkage to type 2 diabetes in a population from northern Sweden
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4493 (URN)
Available from: 2005-04-15 Created: 2005-04-15 Last updated: 2016-06-20Bibliographically approved

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Citation style
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