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.
|Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol Autism 8:21|
|Peter, Beate; Wijsman, Ellen M; Nato Jr, Alejandro Q et al. (2016) Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech. PLoS One 11:e0153864|
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|Faja, Susan; Dawson, Geraldine; Aylward, Elizabeth et al. (2016) Early event-related potentials to emotional faces differ for adults with autism spectrum disorder and by serotonin transporter genotype. Clin Neurophysiol 127:2436-47|
|Truong, D T; Shriberg, L D; Smith, S D et al. (2016) Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders. Hum Genet 135:1329-1341|
|Wijsman, Ellen M (2016) Family-based approaches: design, imputation, analysis, and beyond. BMC Genet 17 Suppl 2:9|
|Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium (2015) Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci 18:199-209|
|Maier, Robert; Moser, Gerhard; Chen, Guo-Bo et al. (2015) Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder. Am J Hum Genet 96:283-94|
|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|
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