title: Intellectual disability is associated with increased runs of homozygosity in simplex autism.
abstract: Intellectual disability (ID), often attributed to autosomal-recessive mutations, occurs in 40% of autism spectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runs of homozygosity (ROH) in simplex ASD-affected families consisting of a proband diagnosed with ASD and at least one unaffected sibling. In these families, probands with an IQ ≤ 70 show more ROH than their unaffected siblings, whereas probands with an IQ > 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do support an association between ROH burden and autism diagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autism candidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autism or (2) a gene that is within an autism ROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecture for participants with autism and co-occurring intellectual disability and that this architecture could involve a role for recessively inherited loci for this autism subgroup.
authors.affiliation: Laboratory for Molecular Medicine, Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02912, USA.
authors.forename: Ece D
authors.initials: ED
authors.lastname: Gamsiz
authors.forename: Emma W
authors.initials: EW
authors.lastname: Viscidi
authors.forename: Abbie M
authors.initials: AM
authors.lastname: Frederick
authors.forename: Shailender
authors.initials: S
authors.lastname: Nagpal
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.forename: Michael T
authors.initials: MT
authors.lastname: Murtha
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Triche
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.forename: Sorin
authors.initials: S
authors.lastname: Istrail
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Eric M
authors.initials: EM
authors.lastname: Morrow
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D030342:Genetic Diseases, Inborn / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005828:Genetics, Population / Q000379:methods; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007361:Intelligence Tests; D008297:Male; D010375:Pedigree; D010641:Phenotype; D012737:Sex Factors