The role of large pedigrees in an era of high-throughput sequencing

Wijsman, Ellen M.

doi:10.1007/s00439-012-1190-2

Cited by 89 publications

(94 citation statements)

References 89 publications

(116 reference statements)

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“…More recently, family-based designs have been recommended for association studies concerned with parent-of-origin effects and the control of population stratification [40]. Pedigrees have also been recommended as an efficient design, both for identifying rare disease-risk alleles in association analyses and for initial sequencing of selected affected family members [12,60].…”

Section: Introductionmentioning

confidence: 99%

On the use of dense SNP marker data for the identification of distant relative pairs

Sun

Jobling

Taliun

et al. 2016

Theoretical Population Biology

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There has been recent interest in the exploitation of readily available dense genome scan marker data for the identification of relatives. However, there are conflicting findings on how informative these data are in practical situations and, in particular, sets of thinned markers are often used with no concrete justification for the chosen spacing. We explore the potential usefulness of dense single nucleotide polymorphism (SNP) arrays for this application with a focus on inferring distant relative pairs. We distinguish between relationship estimation, as defined by a pedigree connecting the two individuals of interest, and estimation of general relatedness as would be provided by a kinship coefficient or a coefficient of relatedness. Since our primary interest is in the former case, we adopt a pedigree likelihood approach. We consider the effect of additional SNPs and data on an additional typed relative, together with choice of that relative, on relationship inference. We also consider the effect of linkage disequilibrium. When overall relatedness, rather than the specific relationship, would suffice, * Theoretical Population Biology. In Press. http://dx.doi.org/10.1016/j.tpb.2015.10 † Corresponding author. E-mail address: Nuala.Sheehan@leicester.ac.uk 1 we propose an approximate approach that is easy to implement and appears to compete well with a popular moment-based estimator and a recent maximum likelihood approach based on chromosomal sharing. We conclude that denser marker data are more informative for distant relatives. However, linkage disequilibrium cannot be ignored and will be the main limiting factor for applications to real data.

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Section: Introductionmentioning

confidence: 99%

On the use of dense SNP marker data for the identification of distant relative pairs

Sun

Jobling

Taliun

et al. 2016

Theoretical Population Biology

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“…Pedigrees have become especially relevant in the detection of rare variant effects on diseases because pedigrees are well-suited for the study of rare variation. 9 Under the hypothesis that multiple rare and common variants contribute to complex disease, projects such as the Alzheimer's Disease Sequencing Project, the San Antonio Mexican American Family Studies, and the Jackson Heart Study have all undertaken deep whole-genome sequencing of members of clinically ascertained pedigrees. Projects such as these could particularly benefit directly from verification and detection of distant relatedness in PADRE.…”

Section: Discussionmentioning

confidence: 99%

“…6 Genetic relationships identified in population studies can be leveraged for improved haplotype phase inference, detection of population structure, genotype imputation, and study designs such as identical-by-descent (IBD) mapping and tests to detect multiple rare and common variants that contribute to disease. [7][8][9][10][11][12][13] The identification of relatives also plays an important role in forensics in criminal investigations, 14 identification of victims of mass disaster, 15 and discovery of family history.…”

Section: Introductionmentioning

confidence: 99%

PADRE: Pedigree-Aware Distant-Relationship Estimation

Staples

Witherspoon

Jorde

et al. 2016

The American Journal of Human Genetics

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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.

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“…several allelic variants exist at the same locus each with different penetrances, can reduce the power of linkage analysis to map the disease gene. This problem can be diminished using large pedigrees, which can each be more homogeneous with respect to genetic variation than unrelated individuals or a sample of many small pedigrees [48,49] . Admittedly, the GENEHUNTER software was originally designed for the analysis of small to moderately sized pedigrees (2 n -f ≤ 20 with n non-founders and f founders in a pedigree).…”

Section: Discussionmentioning

confidence: 99%

Fast Linkage Analysis with MOD Scores Using Algebraic Calculation

Brügger

Strauch²

2014

Hum Hered

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Objective: As the mode of inheritance is often unknown for complex diseases, a MOD-score analysis, in which the parametric LOD score is maximized with respect to the trait-model parameters, can be a powerful approach in genetic linkage analysis. Because the calculation of the disease-locus likelihood is the most time-consuming step in a MOD-score analysis, we aimed to optimize this part of the calculation to speed up linkage analysis using the GENEHUNTER-MODSCORE software package. Methods: Our new algorithm is based on minimizing the effective number of inheritance vectors by collapsing them into classes. To this end, the disease-locus-likelihood contribution of each inheritance vector is represented and stored in its algebraic form as a symbolic sum of products of penetrances and disease-allele frequencies. Simulations were used to assess the speedup of our new algorithm. Results: We were able to achieve speedups ranging from 1.94 to 11.52 compared to the original GENEHUNTER-MODSCORE version, with higher speedups for larger pedigrees. When calculating p values, the speedup ranged from 1.69 to 10.36. Conclusion: Computation times for MOD-score analysis, involving the evaluation of many tested sets of trait-model parameters and p value calculation, have been prohibitively high so far. With our new algebraic algorithm, such an analysis is now feasible within a reasonable amount of time.

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The role of large pedigrees in an era of high-throughput sequencing

Cited by 89 publications

References 89 publications

On the use of dense SNP marker data for the identification of distant relative pairs

On the use of dense SNP marker data for the identification of distant relative pairs

PADRE: Pedigree-Aware Distant-Relationship Estimation

Fast Linkage Analysis with MOD Scores Using Algebraic Calculation

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