PADRE: Pedigree-Aware Distant-Relationship Estimation

Abstract

Accurate estimation of shared ancestry is an important component of many genetic studies; current prediction tools accurately estimate pairwise genetic relationships up to the ninth degree. Pedigree-aware distant-relationship estimation (PADRE) combines relationship likelihoods generated by estimation of recent shared ancestry (ERSA) with likelihoods from family networks reconstructed by pedigree reconstruction and identification of a maximum unrelated set (PRIMUS), improving the power to detect distant relationships between pedigrees. Using PADRE, we estimated relationships from simulated pedigrees and three extended pedigrees, correctly predicting 20% more fourth- through ninth-degree simulated relationships than when using ERSA alone. By leveraging pedigree information, PADRE can even identify genealogical relationships between individuals who are genetically unrelated. For example, although 95% of 13(th)-degree relatives are genetically unrelated, in simulations, PADRE correctly predicted 50% of 13(th)-degree relationships to within one degree of relatedness. The improvement in prediction accuracy was consistent between simulated and actual pedigrees. We also applied PADRE to the HapMap3 CEU samples and report new cryptic relationships and validation of previously described relationships between families. PADRE greatly expands the range of relationships that can be estimated by using genetic data in pedigrees.

Keywords: genetic analysis; pedigree reconstruction; relatedness estimation.

Figure 1

Pedigree Structure Used to Simulate Ninth-Degree Pedigrees 100 ninth-degree pedigrees, each with different genotypes, were generated with A2 and B2 related as ninth-degree relatives. The same pedigree structures for samples A1–A13 and B1–B13 were also used to generate 100 pedigrees, each with different genotypes, where A2 and B2 were fourth-, fifth-, sixth-, seventh-, eighth-, and ninth-degree relatives. The number of ancestral relatives was adjusted to account for the different degree of relatedness.

Figure 2

Comparison of PADRE versus ERSA Accuracy in Simulated Data by Degree of Relationships (A) The observed accuracy in the pedigree predictions increases as additional first- and second-degree relatives are added. (B) Power of PADRE and ERSA alone to detect simulated relationships as additional first- and second-degree relatives were added to the pedigree. The ERSA results fluctuate slightly because additional pairwise estimates are added as more individuals are included, as described with the generation of the simulations.

Figure 3

PADRE and ERSA Prediction Accuracy on Simulated Pedigrees Where All Individuals Have Been Genotyped PADRE more accurately predicts fifth- through tenth-degree relationships relative to ERSA and frequently identifies 11^th- through 13^th-degree relatives who were undetectable in ERSA.

Figure 4

Percentage of Relationships Correctly Predicted by PADRE to Within ± One Degree in Real Pedigrees of European Ancestry and Simulated Pedigrees Relationship detection accuracy was broadly consistent between the real and simulated pedigrees. Because the real pedigrees included two or fewer first- or second-degree relatives, PADRE’s estimated relationship detection accuracy for pedigrees with three or more sampled relatives is based solely on simulated data.

Figure 5

A Graph of PADRE-Estimated Relationships among the CEU Samples with a Bonferroni-Adjusted Threshold of α = 0.05/9,090 = 5.5 × 10⁻⁶ Each node corresponds to a PRIMUS reconstructed network number, and an edge between nodes indicates a significant relationship predicted by PADRE using pairwise relationship likelihoods obtained by ERSA. The number next to each edge indicates the degree of relationship connecting a founder in the reconstructed pedigree of each network. This type of network graph is the standard output of PADRE.

Figure 6

An Example of Four Distantly Related HapMap3 CEU Pedigrees with Relationships Predicted by PADRE Although the trios and the full-sibling relationship between NA12813 and NA07045 have been previously reported, PADRE is able to identify statistically significant relationships connecting these distantly related pedigrees. The related pairs of founders are marked with the dotted lines, and the degree of relationship is labeled next to the line.