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Genetic mapping studies - Asthma and allergy

Genetic mapping studies - Asthma and allergy. Clinical expertise Diagnostic classification. Genetic analysis Disease modelling. Nature of disease gene projects. Hopes and aims: what does one want to find?. Development of therapies New bioactive factors or immediate drug targets

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Genetic mapping studies - Asthma and allergy

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  1. Genetic mapping studies - Asthma and allergy

  2. Clinical expertise Diagnostic classification Genetic analysis Disease modelling Nature of disease gene projects

  3. Hopes and aims: what does one want to find? • Development of therapies • New bioactive factors or immediate drug targets • New pathways or disease mechanisms • New associations for known pathways • Development of diagnostics • Specific assays for disease screening • Specific diagnostic assays for clinical use • Informative and useful new assays

  4. How to think of gene effects in multifactorial diseases? • Pedigrees and penetrance • The threshold model of susceptibility • Quantitative gene effects • Diversity of disease-associated variants

  5. Map location Expression pattern Polymorphism Tissue How to find the asthma gene?

  6. Autosomal dominant, 100% penetrance

  7. …67% penetrance…

  8. …33% penetrance

  9. Threshold model of susceptibility healthydisease gene — gene + Number of people Quantitative measure

  10. Promoter variants • altered transcription • Missense variants • altered protein function • Splice site variants • altered transcript • UTR variants • transcript instability • Nonsense variants • truncated transcript • Intron variants • regulatory elements Diversity of mutations

  11. Population simulation and disease modelling Multilocus association analysis Etc. Linkage analysis Etc. Etc. A gene mapper’s lunchbasket for an excursion to multifactorial diseases

  12. Population movement in the 1500’s Little later immigration Small permanent settlement of south and west coasts >2000 y A brief population history Rapid late population growth (10 x / 250 y)

  13. Why study a multifactorial Why study a multifactorial disease in a founder isolate? disease in a founder isolate?

  14. Kainuu Kainuu Asthma Study Asthma Study 15-20 generations 15-20 generations Department of Medical Genetics and Department of Medical Genetics and Department of Pulmonary Diseases, Department of Pulmonary Diseases, University of Helsinki and HUCH University of Helsinki and HUCH Department of Clinical Genetics, the Finnish Department of Clinical Genetics, the Finnish Family Federation (Väestöliitto) Family Federation (Väestöliitto) Kainuu Central Hospital, Kajaani Kainuu Central Hospital, Kajaani

  15. Disease gene mapping project Design of study Obtaining permissions Recruitment of families Verification of diagnoses Collection of samples Genotyping Analysis of data Identification of gene Functional analysis Utilization

  16. Candidate gene regions in asthma • Chromosome 5q31-q33 • Interleukin gene cluster —no gene implicated so far • Chromosome 11q13, FCER1B • Initial results on effect largely unconfirmed • Chromosome 16p12, IL4R • Replicated in several studies, small effect • Xq28, IL9R • Replicated in several studies, small effect • Chromosome 19p13, FCER2 • Unconfirmed • At least 12 other more or less uncertain localizations

  17. Linkage results of the genome scan for asthma with 304 autosomal and 8 X-chromosomal markers in 86 Finnish pedigrees. Laitinen et al., Nature Genetics 28:87, 2001

  18. A susceptibility gene for asthma in chromosome 7p • Genome scan in Finnish families gave significant evidence for linkage to chromosome 7 (NPL=3.9 for high IgE phenotype; NPL=3.0 for asthma) • Result replicated in French-Canadian pedigrees from Saguenay-Lac-St-Jean (NPL=2.7 for asthma) • Second replication in North Karelian pedigrees (NPL=1.9 for high IgE) Laitinen et al., Nature Genetics 28:87, 2001

  19. Association studies A:(A+C) B:(B+D) Allele-specific risk =

  20. Linkage disequilibrium mapping

  21. Key group members Asthma: Tarja Laitinen, Siru Mäkelä, Anne Polvi, Johanna Vendelin • Computational methods: Päivi Onkamo, Petteri Sevon, Vesa Ollikainen Collaborators Asthma mapping: Lauri A. Laitinen, Mark Daly, Tom Hudson, Eric Lander Computational methods: Heikki Mannila, Hannu T.T. Toivonen Gene expression: Riitta Lahesmaa Acknowledgements

  22. One day I’llmutate…

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