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Structural Decomposition of Genetic Diversity in Families with Alcoholism

Genotype-to-Phenotype Research Strategies

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.

COGA Study: Affected versus Unaffected Sibs

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(Xi,Xj) between feature vectors Xi, Xj made up by the allelic patterns of individuals i, j with respect to n loci L1, L2, .. Ln. 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", irrespective 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.

Genetic Diversity

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").

References

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Stassen HH, Szegedi A, Scharfetter C: Modeling Activation of Inflammatory Response System. A Molecular-Genetic Neural Network Analysis. BMC Proceedings 2007, 1 (Suppl 1): S61, 1-6
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alcohol dependence
Fig. 10: Very similar NPL score characteristics for multiplex nuclear families ascertained in 2 independent waves ("Wave-I", "Wave-II") through index-cases with a diagnosis of alcohol dependence indicate reproducibility of vulnerability and protection loci.
Please note: important here is not the absolute size of the locus contributions when comparing the 2 populations ascertained through index cases with a diagnosis of alcohol dependence, but the fact that the signals are showing up at the same genomic locations (green marks).
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