Our unique resource of extended pedigrees with autism spectrum disorder (ASD) will allow us to make important contributions to genetic studies of ASD. We will sequence family members from the most informative pedigrees to study genetic variation contributing to ASD and related phenotypes. We will work to discover new variation, and also use the resource to characterize variants in conjunction with existing whole exome data available through our collaborations. We will test findings in up to 10 other families available from the Autism Genome Project (AGP) network of collaborators. We will also make the resource available to the broader scientific community. Extended families offer an excellent opportunity to identify and study genetic variation, giving a complementary approach to ongoing studies of simplex and small multiplex families. The current collection of families represents some of the largest pedigrees with ASD in the world. We have already detected significant linkage evidence in some of these families with clinical diagnosis and also with related phenotypes, including gender;Full Scale IQ;discrepancy between verbal and nonverbal IQ;language delay, Insistence on Sameness, Repetitive Sensory-Motor Actions (RSMA), overall clinical severity, and regressive onset (all derived from the ADI);head circumference;and the Broader Autism Phenotype. Sequence data in these extended families will result in highly accurate and extensive genetic information. We will identify familial variation in these data, and predict potentially deleterious variants using new informatics approaches. We will refine information about risk by comparing to ongoing sequence projects. We will also use the ongoing sequence projects to help prioritize the familial variant discovery, and choose the best for replication efforts in other AGP families. Finally, we will investigate sequence variants found by simplex/small family sequencing to determine specificity and penetrance in our extended families. Our proposed project will benefit from the continued collaboration of excellent molecular, analytic, and clinical expertise in the Autism Genome Project to enable the most effective use of this unique resource.
Autism Spectrum Disorder (ASD) imposes an enormous psychological and economic burden on affected individuals, their families, and society. We will sequence family members in a unique resource of up to 40 of the world's largest extended ASD families to study genetic variation contributing to ASD. The planned studies are ideally timed to complement and enhance findings from ongoing sequence studies of ASD in cases and small families.
|Hu, Hao; Coon, Hilary; Li, Man et al. (2016) VARPRISM: incorporating variant prioritization in tests of de novo mutation association. Genome Med 8:91|
|Bakian, Amanda V; Bilder, Deborah A; Coon, Hilary et al. (2015) Spatial relative risk patterns of autism spectrum disorders in Utah. J Autism Dev Disord 45:988-1000|
|Chapman, Nicola H; Nato Jr, Alejandro Q; Bernier, Raphael et al. (2015) Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes. Hum Genet 134:1055-68|
|Pinto, Dalila; Delaby, Elsa; Merico, Daniele et al. (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 94:677-94|
|Bowton, E; Saunders, C; Reddy, I A et al. (2014) SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking. Transl Psychiatry 4:e464|
|De Rubeis, Silvia; He, Xin; Goldberg, Arthur P et al. (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209-15|
|Hu, Hao; Roach, Jared C; Coon, Hilary et al. (2014) A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data. Nat Biotechnol 32:663-9|
|Buxbaum, Joseph D; Bolshakova, Nadia; Brownfeld, Jessica M et al. (2014) The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses. Mol Autism 5:34|
|Liu, Li; Sabo, Aniko; Neale, Benjamin M et al. (2013) Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. PLoS Genet 9:e1003443|
|Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381:1371-9|
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