Chapter 062. Principles of Human Genetics (Part 28)

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Allelic Association, Linkage Disequilibrium, and Haplotypes Allelic association refers to a situation in which the frequency of an allele is significantly increased or decreased in individuals affected by a particular disease in comparison to controls. Linkage and association differ in several aspects. Genetic linkage is demonstrable in families or sibships. Association studies, on the other hand, compare a population of affected individuals with a control population. Association studies can be performed as case-control studies that include unrelated affected individuals and matched controls, or as family-based studies that compare the frequencies of alleles transmitted or not transmitted to affected children. ...

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Chapter 062. Principles of Human Genetics (Part 28) Allelic Association, Linkage Disequilibrium, and Haplotypes Allelic association refers to a situation in which the frequency of an allele is significantly increased or decreased in individuals affected by a particular disease in comparison to controls. Linkage and association differ in several aspects. Genetic linkage is demonstrable in families or sibships. Association studies, on the other hand, compare a population of affected individuals with a control population.
Association studies can be performed as case-control studies that include unrelated affected individuals and matched controls, or as family-based studies that compare the frequencies of alleles transmitted or not transmitted to affected children. Allelic association studies are particularly useful for identifying susceptibility genes in complex diseases. When alleles at two loci occur more frequently in combination than would be predicted (based on known allele frequencies and recombination fractions), they are said to be in linkage disequilibrium . In Fig. 62-13, a mutation, Z, has occurred at a susceptibility locus where the normal allele is Y. The mutation is in close proximity to a genetic polymorphism with allele A or B. With time, the chromosomes carrying the A and Z alleles accumulate and represent 10% of the chromosomes in the population. The fact that the disease susceptibility gene, Z, is found preferentially, or exclusively, in association with the A allele illustrates linkage disequilibrium. Though not all chromosomes carrying the A allele carry the disease gene, the A allele is associated with an increased risk because of its possible association with the Z allele.
This model implies that it may be possible in the future to identify Z directly to provide a more accurate prediction of disease susceptibility. Evidence for linkage disequilibrium can be helpful in mapping disease genes because it suggests that the two loci, in this case A and Z, are tightly linked. Figure 62-13 Detecting the genetic factors contributing to the pathogenesis of common complex disorders remains a great challenge. In many instances, these are low-
penetrance alleles, i.e., variations that individually only have a subtle effect on disease development, and they can only be identified by unbiased genome-wide association studies. Most variants are in noncoding or regulatory sequences but do not alter protein structure. The analysis of complex disorders is further complicated by ethnic differences in disease prevalence, differences in allele frequencies in known susceptibility genes among different populations, locus and allelic heterogeneity, gene-gene and gene-environment interactions, and the possibility of phenocopies. The HapMap Project is now making genome-wide association studies for the characterization of complex disorders more realistic. Adjacent SNPs are inherited together as blocks, and these blocks can be identified by genotyping selected marker SNPs, so-called Tag SNPs, thereby reducing cost and workload (Fig. 62-8). The availability of this information permits the characterization of a limited number of SNPs to identify the set of haplotypes present in an individual, e.g., in cases and controls. This, in turn, permits genome-wide association studies by searching for associations of certain haplotypes with a disease phenotype of interest, an essential step for unraveling the genetic factors contributing to complex disorders.