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This article is part of the supplement: Genetic Analysis Workshop 17: Unraveling Human Exome Data

Open Access Proceedings

Identity-by-descent filtering as a tool for the identification of disease alleles in exome sequence data from distant relatives

Nirmala Akula1*, Sevilla Detera-Wadleigh1, Yin Yao Shugart2, Michael Nalls3, Jo Steele1 and Francis J McMahon1

Author Affiliations

1 Mood and Anxiety Section, Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA

2 Unit of Statistical Genomics, National Institute of Mental Health, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA

3 Molecular Genetics Section, Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA

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BMC Proceedings 2011, 5(Suppl 9):S76  doi:10.1186/1753-6561-5-S9-S76

Published: 29 November 2011

Abstract

Large-scale, deep resequencing may be the next logical step in the genetic investigation of common complex diseases. Because each individual is likely to carry many thousands of variants, the identification of causal alleles requires an efficient strategy to reduce the number of candidate variants. Under many genetic models, causal alleles can be expected to reside within identity-by-descent (IBD) regions shared by affected relatives. In distant relatives, IBD regions constitute a small portion of the genome and can thus greatly reduce the search space for causal alleles. However, the effectiveness of this strategy is unknown. We test the simulated mini-exome data set in extended pedigrees provided by Genetic Analysis Workshop 17. At the fourth- and fifth-degree level of relatedness, case-case pairs shared between 1% and 9% of the genome identical by descent. As expected, no genes were shared identical by descent by all case subjects, but 43 genes were shared by many case subjects across at least 50 replicates. We filtered variants in these genes based on population frequency, function, informativeness, and evidence of association using the family-based association test. This analysis highlighted five genes previously implicated in triglyceride, lipid, and cholesterol metabolism. Comparison with the list of true risk alleles revealed that strict IBD filtering followed by association testing of the rarest alleles was the most sensitive strategy. IBD filtering may be a useful strategy for narrowing down the list of candidate variants in exome data, but the optimal degree of relatedness of affected pairs will depend on the genetic architecture of the disease under study.