The impact of population admixture on traditional linkage analysis.

Families of admixed ancestry are routinely excluded from traditional (Log of the Odds [LOD] score) linkage analysis or are analyzed as being derived from a homogeneous population using the proband's ethnicity. Using traditional linkage analysis with these families can cause complications due to the mixing of different disease rates and allele frequencies that occurs. The presence of admixture violates the key assumptions of Hardy-Weinberg Equilibrium (HWE) and Linkage Equilibrium (LE) invoked in the current methods of linkage analysis. If one or more of these assumptions are violated, incorrect inference for linkage could result. Through simulation, we investigated the effect of admixture of two populations on the LOD score under various conditions, using prostate cancer as our underlying disease model. Four-generation homogeneous and admixed families were simulated with 27 markers and two linked, bi-allelic disease loci. Two different types of admixture were tested: admixture within a family unit and a mixture of homogeneous families within a data set. All mixing was done at the founder level in three different proportions: 30/70, 50/50 and 70/30. We observed that the LOD scores under both models of admixture were closest to the homogeneous family scores of the population having the highest mixing proportion. Random sampling of families or ascertainment of families with disease affection status did not affect this observation, nor did the mode of inheritance (dominant/recessive) or sample size. Thus, the presence of families of mixed population ancestry impacts linkage analysis in terms of the LOD score and the estimate of the recombination fraction.

Barnholtz-Sloan JS ，de Andrade M ，Chakraborty R 《ETHNICITY & DISEASE》

Admixture effects in the traditional linkage analysis of admixed families.

Barnholtz-Sloan JS ，de Andrade M ，Dyer TD ，Chakraborty R ... -  《ETHNICITY & DISEASE》

Effect of heterogeneity and assumed mode of inheritance on lod scores.

Heterogeneity is a major factor in many common, complex diseases and can confound linkage analysis. Using computer-simulated heterogeneous data we tested what effect unlinked families have on a linkage analysis when heterogeneity is not taken into account. We created 60 data sets of 40 nuclear families each with different proportions of linked and unlinked families and with different modes of inheritance. The ascertainment probability was 0.05, the disease had a penetrance of 0.6, and the recombination fraction for the linked families was zero. For the analysis we used a variety of assumed modes of inheritance and penetrances. Under these conditions we looked at the effect of the unlinked families on the lod score, the evaluation of the mode of inheritance, and the estimate of penetrance and of the recombination fraction in the linked families. 1. When the analysis was done under the correct mode of inheritance for the linked families, we found that the mode of inheritance of the unlinked families had minimal influence on the highest maximum lod score (MMLS) (i.e., we maximized the maximum lod score with respect to penetrance). Adding sporadic families decreased the MMLS less than adding recessive or dominant unlinked families. 2. The mixtures of dominant linked families with unlinked families always led to a higher MMLS when analyzed under the correct (dominant) mode of inheritance than when analyzed under the incorrect mode of inheritance. In the mixtures with recessive linked families, assuming the correct mode of inheritance generally led to a higher MMLS, but we observed broad variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Durner M ，Greenberg DA 《american journal of medical genetics》

Detection of linkage under heterogeneity: comparison of the two-locus vs. admixture models.

Goldin LR 《GENETIC EPIDEMIOLOGY》

Power to detect linkage with heterogeneity in samples of small nuclear families.

Levinson DF 《american journal of medical genetics》