Chapter 062. Principles of Human Genetics (Part 28)

Allelic Association, Linkage Disequilibrium, and HaplotypesAllelic 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) 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 issignificantly increased or decreased in individuals affected by a particular diseasein comparison to controls. Linkage and association differ in several aspects. Genetic linkage isdemonstrable 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 includeunrelated affected individuals and matched controls, or as family-based studiesthat compare the frequencies of alleles transmitted or not transmitted to affectedchildren. Allelic association studies are particularly useful for identifyingsusceptibility genes in complex diseases. When alleles at two loci occur morefrequently in combination than would be predicted (based on known allelefrequencies and recombination fractions), they are said to be in linkagedisequilibrium . In Fig. 62-13, a mutation, Z, has occurred at a susceptibility locuswhere the normal allele is Y. The mutation is in close proximity to a genetic polymorphism with allele Aor B. With time, the chromosomes carrying the A and Z alleles accumulate andrepresent 10% of the chromosomes in the population. The fact that the disease susceptibility gene, Z, is found preferentially, orexclusively, 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 associationwith the Z allele. This model implies that it may be possible in the future to identify Zdirectly to provide a more accurate prediction of disease susceptibility. Evidencefor linkage disequilibrium can be helpful in mapping disease genes because itsuggests 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 commoncomplex disorders remains a great challenge. In many instances, these are low-penetrance alleles, i.e., variations that individually only have a subtle effect ondisease development, and they can only be identified by unbiased genome-wideassociation studies. Most variants are in noncoding or regulatory sequences but do not alterprotein structure. The analysis of complex disorders is further complicated byethnic differences in disease prevalence, differences in allele frequencies in knownsusceptibility 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 forthe characterization of complex disorders more realistic. Adjacent SNPs areinherited together as blocks, and these blocks can be identified by genotypingselected marker SNPs, so-called Tag SNPs, thereby reducing cost and workload(Fig. 62-8). The availability of this information permits the characterization of a limitednumber of SNPs to identify the set of haplotypes present in an individual, e.g., incases and controls. This, in turn, permits genome-wide association studies by searching forassociations of certain haplotypes with a disease phenotype of interest, an essentialstep for unraveling the genetic factors contributing to complex disorders.