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

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

Ablation of Mrds1/Ofcc1 Induces Hyper-γ-Glutamyl Transpeptidasemia without Abnormal Head Development and Schizophrenia-Relevant Behaviors in Mice

Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as “the Japan Mouse Clinic”. No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia