title: Rare-variant extensions of the transmission disequilibrium test: application to autism exome sequence data.
abstract: Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zongxiao
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gao
authors.initials: G
authors.lastname: Wang
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Hooker
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Kan
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Nik
authors.initials: N
authors.lastname: Krumm
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: sleal@bcm.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D000483:Alleles; D001321:Autistic Disorder / Q000235:genetics*; D003198:Computer Simulation; D059472:Exome; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D010641:Phenotype; D017422:Sequence Analysis, DNA