Structural Decomposition of Genetic Diversity in Families with Alcoholism

In the case of genetically complex disorders, like alcohol dependence, the standard phenotype-to-genotype research strategy may not readily lead to the detection of "signals" if the contributions of single loci are small, and if there exist significant interactions between loci. In contrast, the genotype-to-phenotype strategy has its main focus on oligogenic, interacting models that evaluate the within-family similarities of high-dimensional genetic feature vectors. In this approach, the power of detecting "signals" increases with the genetic variation that arises from the existence of various alleles at the different loci, and that is expected to be greatest when there are many alleles at a locus, all at equal frequency. Using genotypes of 280 marker loci on the 22 autosomes of 105 alcohol-dependent probands, their affected and unaffected sibs, as well as their parents, we iteratively constructed a genetic similarity function that enabled us to quantify the inter-individual genetic distances d(x_i,x_j) between feature vectors x_i, x_j made up by the allelic patterns of individuals i, j with respect to n loci l₁, l₂, .. l_n. Based on this similarity function, we investigated the sib-sib similarities which are expected to deviate from "0.5" in affected sib pairs if the region of interest contains markers close to disease-causing genes. The reference value "0.5" was derived by evaluating the parent-offspring similarities which are always "0.5", irrespectively of the status of affectedness of parents and offspring. Additionally, we determined the eigenvectors that optimally represented the genetic variation ("diversity") associated with the feature vectors. It turned out that (1) typically 3-4 eigenvectors explained two thirds of the genetic variation inherent to the 8-20 polymorphic markers of each autosome, and (2) several marker configurations on chromosomes 1, 3, 7, 15 and 17 reproducibly discriminated (p < 0.01) probands and unaffected sibs on the one hand, and affected and unaffected sibs on the other ("affected vs unaffected"), while no such differences were found between probands and affected sibs ("affected vs affected").

Figure 1a: Vulnerability-related (negative signs) and protective loci (positive signs) on chromosome 1 as derived from the COGA wave-I training samples through a multivariate sib-pair method. The contribution of each marker locus to the oligogenic model of ethnicity-independent vulnerability to alcohol dependence is plotted along the y-axis, while the chromosome 1 genomic region is plotted along the x-axis.

Figure 1b: Vulnerability-related (negative signs) and protective loci (positive signs) on chromosome 1 as derived from the COGA wave-II test samples through a multivariate sib-pair method. The contribution of each marker locus to the oligogenic model of ethnicity-independent vulnerability to alcohol dependence is plotted along the y-axis, while the chromosome 1 genomic region is plotted along the x-axis.

References

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