Asthma and atopy are complex phenotypes that are influenced by both genetic and environmental factors. A review of nearly 500 papers on disease association studies identified 25 genes that have been associated with an asthma or atopy phenotype in six or more populations. An additional 54 genes have been associated in 2-5 populations. Here, we discuss the methods that have been used to identify susceptibility genes for common diseases and overview the status of asthma genetic research. Finally, current challenges and future directions are discussed.
To avoid problems related to unknown population substructure, association studies may be conducted in founder populations. In such populations, however, the relatedness among individuals may be considerable. Neglecting such correlations among individuals can lead to seriously spurious associations. Here, we propose a method for case-control association studies of binary traits that is suitable for any set of related individuals, provided that their genealogy is known. Although we focus here on large inbred pedigrees, this method may also be used in outbred populations for case-control studies in which some individuals are relatives. We base inference on a quasi-likelihood score (QLS) function and construct a QLS test for allelic association. This approach can be used even when the pedigree structure is far too complex to use an exact-likelihood calculation. We also present an alternative approach to this test, in which we use the known genealogy to derive a correction factor for the case-control association chi2 test. We perform analytical power calculations for each of the two tests by deriving their respective noncentrality parameters. The QLS test is more powerful than the corrected chi2 test in every situation considered. Indeed, under certain regularity conditions, the QLS test is asymptotically the locally most powerful test in a general class of linear tests that includes the corrected chi2 test. The two methods are used to test for associations between three asthma-associated phenotypes and 48 SNPs in 35 candidate genes in the Hutterites. We report a highly significant novel association (P=2.10-6) between atopy and an amino acid polymorphism in the P-selectin gene, detected with the QLS test and also, but less significantly (P=.0014), with the transmission/disequilibrium test.
Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.
Hundreds of genetic association studies on asthma-related phenotypes have been conducted in different populations. To date, variants in 64 genes have been reported to be associated with asthma or related traits in at least one study. Of these, 33 associations were replicated in a second study, 9 associations were not replicated either in a second study or a second sample in the same study, and 22 associations were reported in just a single published study. These results suggest the potential for a great amount of heterogeneity underlying asthma. However, many of these studies are methodologically limited and their interpretation hampered by small sample sizes. ReviewTwo general approaches have been widely used to study the genetics of asthma: genome-wide linkage studies followed by positional cloning and candidate gene association studies. The results of linkage studies for asthma have been described in detail elsewhere [1][2][3]; this review focuses on the published candidate gene association studies for asthma.Candidate gene approach: basic principles and potential problems "Candidate genes" are selected because their biological function suggests that they could play a role in the pathophysiology of asthma (such as genes encoding cytokines and their receptors, chemokines and their receptors, transcription factors, IgE receptor, etc.). Association studies between variation in these candidate genes and asthmarelated phenotypes are mostly conducted in unrelated case and unrelated control samples by comparing allele or genotype frequencies between samples. Association studies with candidate genes are appealing because they are hypothesis-driven and can identify genetic variation that has relatively modest effects on susceptibility [4]. Compared with linkage analysis, case-control studies are much simpler to perform and less costly because they do not require the collection of families. However, the interpretation of association studies is not always straightforward (for example, see ref.[5]). In particular, there are a large number of negative association studies with candidate genes that are never reported. Because the reported p-values are rarely adjusted for the total number of studies performed (both reported and unreported), the type I error rate in the reported studies is actually higher than the nominal level.A statistically significant association between a variant in a candidate gene and a disease phenotype can have three possible explanations. (1) The marker allele truly affects gene function by altering the amino-acid sequence or by modifying splicing, transcriptional properties, or mRNA stability, and thereby directly affects disease risk. (2) The marker allele is in linkage disequilibrium (LD) with the true disease-causing variant. LD, or allelic association, is the nonrandom association of alleles at linked loci in populations, and will usually only be detected over small distances (≤ 60 approximated kb) [6,7], although LD over longer distances has been observed. Thus, the marker allele must ...
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