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Discuss key features of polygenic and multifactorial diseases. How would you go about isolating a gene involved in polygenic inheritance? Helen Stuart Cardiff. Complex disorders Continuous traits Quantitative trait loci Linkage analysis Linkage disequilibrium Genetic heterogeneity

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  1. Discuss key features of polygenic and multifactorial diseases. How would you go about isolating a gene involved in polygenic inheritance?Helen StuartCardiff

  2. Complex disorders Continuous traits Quantitative trait loci Linkage analysis Linkage disequilibrium Genetic heterogeneity Allele-sharing methods Identical-by-descent Association studies Admixture Array chips Experimental crosses Quantitative trait loci Candidate genes Key words

  3. Definitions • Polygenic disease = A genetic disease caused by the combined actions of two or more genes. E.g. coronary heart disease, hypertension • Multifactorial disease = A disease caused by the complex interaction of many environmental and genetic susceptibility factors. E.g. diabetes mellitus, Alzheimer's disease. Aka complex disorders Note: some of the genetic factors can even be protective for the occurrence of the disease

  4. Key features • High population incidence • The disease can occur in isolation • Non-Mendelian inheritance • Low heritability • Higher recurrence risk with increased number of siblings/relatives affected • Higher recurrence risk if relative is more severely affected • Consanguinity increases probability of being affected • Sexes have different probabilities of being affected • Environmental influences can increase or decrease the risk of multifactorial diseases

  5. Medical Definition of Polygenic inheritance Inheritance in which a measurable phenotype is generated by many loci, the contributions of which are statistically independent, additive, and of about equal value.

  6. Isolation of a gene involved in polygenic inheritance • Linkage analysis • Allele-sharing methods • Association studies • Experimental crosses

  7. Isolation of a gene I:Linkage analysis • If two loci are usually inherited together, they are said to be linked (linkage disequilibrium) • Transmission within a pedigree • Quantitative trait loci (QTL) • Linkage only within some pedigrees – genetic heterogeneity

  8. Genetic (locus) heterogeneity • Genetic heterogeneity complicates the analysis of complex disorders • Different genotype > same phenotype

  9. Isolation of a gene II:Allele-sharing methods • Affected individuals inherit identical copies of a region more often than by chance • Highly polymorphic markers • Multiple families • Identical-by-descent…use lots of markers

  10. Isolation of gene III:Association studies • Compare unrelated affected and unaffected individuals within a population • Genome-wide association studies (GWAS) • Array chip (high-density SNPs) • Identify SNPs associated with a disease (QTL) • Associations because: • SNP is cause of disease • SNP is in linkage disequilibrium with the causal gene • Artefact (admixture)

  11. Isolation of gene IV:Experimental crosses • Large number of progeny • Genetic homogeneity • Only identifies QTLs that differ in parents • Effects of QTLs may change - epistasis

  12. Candidate genes • Gene expression - in the right tissues at the right time • Animal models - lack of specific gene sequence (or gene product) + phenotype of interest • Identification of human chromosomal rearrangements or mutations in these candidate genes that cause the phenotype of interest • Previous human linkage and/or linkage disequilibrium/association studies – supporting findings • Determine function of WT and mutant gene products

  13. References • Chial, H (2008) Polygenic inheritance and gene mapping. Nature Education 1(1) • Lander, E.S. and Schork, N.J. (1994) Genetic dissection of complex traits. Science 265 • Hitzemann, R. et al (2008) Quantitative trait locus analysis: multiple cross and heterogeneous stock mapping. Alcohol Research and Health 31(3) • Jorde, L.B. (2000) Linkage disequlibrium and the search for complex genes. Genome Res 10(10):1435-44

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