Genetics of Asthma: A Review: Asthma: Description Positional Cloning Approach

Two types of linkage analysis, parametric and nonparametric, are available.
1. Parametric Linkage Analysis: This is the classic approach and often the unqualified term “linkage analysis” is used to describe this approach. Extended pedigrees are the best substrate for this approach. A model of inheritance is proposed (hence the term “parametric”). First, the likelihood of observing the segregation pattern of two loci assuming the null hypothesis of no genetic linkage between the two is calculated. Next the likelihoods for each of several alternative hypotheses, each assuming different extents of crossing over, are calculated and compared to the likelihood of a null hypothesis. The “odds ratio” is a ratio of the likelihood of a hypothesis of linkage to the likelihood of a hypothesis of no linkage. Odds ratio of >1,000:1, also expressed as a “LOD” (logarithm of the odds) >3.0, is taken as evidence for linkage in mendelian disorders. At this level of significance, there is a 5% chance of a false-positive linkage. It has been suggested that for complex diseases, higher LOD scores (>3.3) should be used to define significant linkage.39 A major problem in parametric linkage analysis is that a model of inheritance needs to be proposed and the result is dependent on the model. Because, in complex diseases like asthma the mode of inheritance is not clear, parametric linkage analysis is often difficult.

2. Nonparametric Linkage Analysis or Allele-Sharing Methods: These are not dependent on assuming a genetic model of inheritance and are therefore better suited for analysis of complex diseases. The tradeoff is that allele-sharing methods are often less powerful than a correctly specified linkage model and analysis.26 The affected sib-pair analysis is the most commonly used allele-sharing method. Here families with at least two affected siblings are chosen. If the disease is linked to a certain marker, then the affected siblings will inherit identical alleles of the marker more often than expected by chance alone. The excess allele-sharing can be measured by a x2 test. It is suggested that a p value >2.2X10 (corresponding to a LOD score of 3.6) be used to define significant linkage with this type of analysis of complex genetic diseases.
Going from map position to the gene still remains a daunting task. Genetic mapping permits localization to a region in the range of 2 to 5 megabases (Mb).40 Even with fine mapping, resolution of