title: Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.
abstract: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders, characterized by impairment in communication and social interactions, and by repetitive behaviors. ASDs are highly heritable, and estimates of the number of risk loci range from hundreds to >1000. We considered 7 extended families (size 12-47 individuals), each with ≥3 individuals affected by ASD. All individuals were genotyped with dense SNP panels. A small subset of each family was typed with whole exome sequence (WES). We used a 3-step approach for variant identification. First, we used family-specific parametric linkage analysis of the SNP data to identify regions of interest. Second, we filtered variants in these regions based on frequency and function, obtaining exactly 200 candidates. Third, we compared two approaches to narrowing this list further. We used information from the SNP data to impute exome variant dosages into those without WES. We regressed affected status on variant allele dosage, using pedigree-based kinship matrices to account for relationships. The p value for the test of the null hypothesis that variant allele dosage is unrelated to phenotype was used to indicate strength of evidence supporting the variant. A cutoff of p = 0.05 gave 28 variants. As an alternative third filter, we required Mendelian inheritance in those with WES, resulting in 70 variants. The imputation- and association-based approach was effective. We identified four strong candidate genes for ASD (SEZ6L, HISPPD1, FEZF1, SAMD11), all of which have been previously implicated in other studies, or have a strong biological argument for their relevance.
authors.affiliation: Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Nicola H
authors.initials: NH
authors.lastname: Chapman
authors.affiliation: Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Alejandro Q
authors.initials: AQ
authors.lastname: Nato
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.affiliation: Department of Psychiatry, University of California, San Francisco, CA, USA.
authors.forename: Katy
authors.initials: K
authors.lastname: Ankenman
authors.affiliation: Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Harkirat
authors.initials: H
authors.lastname: Sohi
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.|Center on Child Development and Disability, University of Washington, Seattle, WA, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Munson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Patowary
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Archer
authors.affiliation: Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Elizabeth M
authors.identifier: http://orcid.org/0000-0002-2725-6669
authors.initials: EM
authors.lastname: Blue
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.|Center on Child Development and Disability, University of Washington, Seattle, WA, USA.
authors.forename: Sara Jane
authors.initials: SJ
authors.lastname: Webb
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.|Department of Psychiatry, School of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Coon
authors.affiliation: Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.|Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Brkanac
authors.affiliation: Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, USA. wijsman@u.washington.edu.|Department of Biostatistics, University of Washington, Seattle, WA, USA. wijsman@u.washington.edu.|Department of Genome Sciences, University of Washington, Seattle, WA, USA. wijsman@u.washington.edu.|University of Washington, University of Washington Tower, T15, 4333 Brooklyn Ave, NE, BOX 359460, Seattle, WA, 98195-9460, USA. wijsman@u.washington.edu.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Wijsman
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D059472:Exome; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D005136:Eye Proteins; C000595492:FEZF1 protein, human; D008565:Membrane Proteins; D012097:Repressor Proteins; C584612:SAMD11 protein, human; C421964:SEZ6L protein, human; D014157:Transcription Factors; D017856:Phosphotransferases (Phosphate Group Acceptor); C562140:PPIP5K2 protein, human