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L29 - Disease Mapping (Study Design Categories (Association Studies -…

- - - - Family Based Association
        
        Uses Transmission disequilibrium Test (TDT)*
        
        Collect affected child and their parents
        
        Compare the distribution of the transmitted allele to the distribution of the non transmitted allele from parents
        
        Disadvantage
        
        Heterozygosity
        
        Requires at least one parent to be heterozygous (In order to determine if recombinant or linked) at the marker being tested, therefore power of this approach is significantly lower*
        
        Advantage
        
        Resistant to Bias
        
        Resistant to potential bias from
        population stratification
        
        Transmission Disequilibrium Test
        
        Analyses transmission of alleles to progreny from heterozygous parents
        
        1.Test if there is deviation from Mendelian segregation ratios.
        
        If there is no association (i.e. disequilibrium caused by linkage)
        
        Then 50% transmission rate of either allele
        
        If there is association
        
        Then one allele will be inherited >50% of the time
        
        If there is transmission distortion (linkage disequlibrium)
        
        Suggests an aetilogicassociation between gene variant and disease
      - Population Based Association Study
        
        May use a Case and Control study Design
        
        Collect affected subjects (cases) and compare genetic variation with unaffected subjects (controls).
        
        Compare frequency of genetic components between two groups.
        
        Advantages
        
        Powerful
        
        Quite powerful to detect
        relatively small genotypic effects,
        even in modest samples of
        cases and controls (ex. 100-500
        of each)
        
        Easy
        
        To collect the cases and
        controls or general population
        samples*
        
        Disadvantage
        
        Requires Population stratification
        
        If there are underlying differences between the cases and controls that are unrelated to disease risk, false positive results are more likely.
        
        Spurious Association resulting from stratification is caused by;
        
        Unequal proportions of individuals from sub-populations found between case and controls
        
        Individuals from sub-populations have differen allelic freuqencies at the locus
        
        Population Stratification
        
        To avoid population stratification and limit confounding
        
        Family based controls
        
        e.g. TDT looks at number of parents heterozygous for an allele that pass that allele to affected offspring compared with the non-disease allele. This is equivalent to a population based association study, just within a family context
        
        ‘Genetic control’: extra genotyping
        
        Look for evidence of background population substructure and account for it.
      - Association - allelic linkage
        
        The reason why we can rely upon population based association studies to determine linkage between marker and disease causing gene
        Markers remain in linkage disequilibrium with mutation over the course of many generations - even tracing back to the original mutation event.
        So long as the marker is very close to the disease-causing variant, it is likely that it will remain linked over generations
        
        Mapping with Linkage Disequilibrium
        
        Population based
        
        Look for variant allele in LD with disease
        
        If most affected individuals in a population share the same mutant allele, then LD can be used to locate the chromosomal region harbouring the mutant allele
        
        Markers proximal to the disease allele enjoy higher rates of linkage disequilibrium than marker alleles located distally
        
        Mapping
        
        The correlation (i.e. LD) is based on founder effect:
        
        The disease allele originates from mutation on a certain ancestral chromosome.
        
        From this ancient mutation, the majority of disease alleles existing presently are derivatives of that original mutation*
        
        The marker itself is NOT the reason for the
        disease, it is important simply because it's located nearby the suspected gene
        Proximity translates to correlation between the marker allele/haplotype and the disease gene
    - - Case-Control Designs
      - Cohort Studies
      - Parents + affected child trios
      - May be more appropriate for complex diseases
  - - - Very effective for diseases abiding to Mendelian patterns
      - Large Families
      - Sibling Pairs - or other family pairs
- - - - Linkage Analysis (Linkage Mapping)
        
        Yields broad chromosome region harbouring many genes
        
        Resolution drawn from assessing meioses (recomb. events) in families
        
        Effective as requires few markers, limited in finding specific variants
        Combined with gene sequencing, it is a formidable tool
        
        Differences
        
        Linkage is resulted from recombination events in the last 2-3 generations, LD is resulted from much earlier, ancestral recombination events
        
        Linkage measures co-segregation in a pedigree, LD measures co segregation in a population (essentially a very huge pedigree)
        
        Linkage is usually detected for markers reasonably close to the disease gene (1 Mb?), LD is detected for markers** even closer (10
        20 kB)**
        
        Linkage is good for Mendelian diseases, LD better for complex disease?*
      - Association Analysis (Linkage Disequilibrium Mapping)
        
        Yields fine scale resolution of genetic variants
        
        Resolution comes from analysis of ancestral recombination events (meioses)
        
        Effective in finding specific variants, limited in requiring many markers