title: Identification of rare variants from exome sequence in a large pedigree with autism.
abstract: We carried out analyses with the goal of identifying rare variants in exome sequence data that contribute to disease risk for a complex trait. We analyzed a large, 47-member, multigenerational pedigree with 11 cases of autism spectrum disorder, using genotypes from 3 technologies representing increasing resolution: a multiallelic linkage marker panel, a dense diallelic marker panel, and variants from exome sequencing. Genome-scan marker genotypes were available on most subjects, and exome sequence data was available on 5 subjects. We used genome-scan linkage analysis to identify and prioritize the chromosome 22 region of interest, and to select subjects for exome sequencing. Inheritance vectors (IVs) generated by Markov chain Monte Carlo analysis of multilocus marker data were the foundation of most analyses. Genotype imputation used IVs to determine which sequence variants reside on the haplotype that co-segregates with the autism diagnosis. Together with a rare-allele frequency filter, we identified only one rare variant on the risk haplotype, illustrating the potential of this approach to prioritize variants. The associated gene, MYH9, is biologically unlikely, and we speculate that for this complex trait, the key variants may lie outside the exome.
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Marchani
authors.forename: N H
authors.initials: NH
authors.lastname: Chapman
authors.forename: C Y K
authors.initials: CY
authors.lastname: Cheung
authors.forename: K
authors.initials: K
authors.lastname: Ankenman
authors.forename: I B
authors.initials: IB
authors.lastname: Stanaway
authors.forename: H H
authors.initials: HH
authors.lastname: Coon
authors.forename: D
authors.initials: D
authors.lastname: Nickerson
authors.forename: R
authors.initials: R
authors.lastname: Bernier
authors.forename: Z
authors.initials: Z
authors.lastname: Brkanac
authors.forename: E M
authors.initials: EM
authors.lastname: Wijsman
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020409:Molecular Motor Proteins / Q000235:genetics*; D009010:Monte Carlo Method; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains