The term autism-spectrum disorders (ASD) exemplifies the tremendous heterogeneity in this developmental disorder at both the phenotypic and underlying genetic levels. It has repeatedly been observed that ASD disproportionately affects males (B) relative to females (@). Although many hypotheses attempt to explain this bias, no clear answers have emerged because of inconsistent and incomplete phenotyping and small sample sizes. We propose to leverage the interdisciplinary strengths and recruiting power of our network to study sex- specific differences by deep phenotyping and genotyping of ASD participants. We will recruit a sex-balanced cohort of ASD (N=125 B N=125 @) and matched typically developing (TD) comparison participants (N=125 B, N=125 @), as well as a set of unaffected siblings (US;N=63 @, N=62 B). We will quantitatively phenotype multiple behavioral domains and measure several key ASD-related neural systems at the level of brain structure (sMRI), connectivity (DTI and fMRI), function (task based and resting state fMRI), and temporal dynamics (EEG). Additionally, we will measure copy number variation (CNV) and single nucleotide variation (SNV) for these participants and their parents, allowing us to test sex- and circuit-specific genotype-phenotype hypotheses for five candidate ASD genes and ultimately extend our methods to a search for novel sex-specific and high-risk genes.
Our Specific Aims are to: 1) Identify sex differences in brain structure, function, connectivity, and temporal dynamics in ASD. 2) Characterize associations between DNA sequence and copy number variants and brain structure and function in @ASD and @TD versus BASD and BTD. 3) Relate brain differences in structure, function, and temporal dynamics to heterogeneity in ASD behavior and genetics. We hypothesize that advanced network methods can aid in understanding the tremendous heterogeneity in ASD by connecting different levels of phenotype with genetic variation. We will therefore combine multiple levels of biology and endophenotypes - SNVs, CNVs, behavioral metrics, and resting state imaging and electrophysiology measures - into one framework across affected and unaffected siblings and controls using an integrated network analysis, iWGCNA.
Project Narrative In this project, we will pool together our interdisciplinary expertise and recruitment efforts across four leading Centers for the study of autism spectrum disorder (Yale, UCLA, Harvard, and University of Washington) in an effort to: 1) Identify difference between boys and girls in brain mechanisms underlying autism spectrum disorder;2) Search for relationships between brain mechanisms and underlying genetic differences;3) Discover the brain and genetic mechanisms underlying heterogeneity in the presentation and severity of autism spectrum disorder in boys and girls.
|Rosenblau, Gabriela; Korn, Christoph W; Pelphrey, Kevin A (2018) A Computational Account of Optimizing Social Predictions Reveals That Adolescents Are Conservative Learners in Social Contexts. J Neurosci 38:974-988|
|Neuhaus, Emily; Beauchaine, Theodore P; Bernier, Raphael A et al. (2018) Child and family characteristics moderate agreement between caregiver and clinician report of autism symptoms. Autism Res 11:476-487|
|Hull, Jocelyn V; Dokovna, Lisa B; Jacokes, Zachary J et al. (2018) Corrigendum: Resting-State Functional Connectivity in Autism Spectrum Disorders: A Review. Front Psychiatry 9:268|
|Hudac, Caitlin M; DesChamps, Trent D; Arnett, Anne B et al. (2018) Early enhanced processing and delayed habituation to deviance sounds in autism spectrum disorder. Brain Cogn 123:110-119|
|Hernandez, L M; Krasileva, K; Green, S A et al. (2017) Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism. Mol Psychiatry 22:1134-1139|
|Pelphrey, Kevin (2017) Charting a Course for Autism Biomarkers. Biol Psychiatry 82:155-156|
|Jack, Allison; Keifer, Cara M; Pelphrey, Kevin A (2017) Cerebellar contributions to biological motion perception in autism and typical development. Hum Brain Mapp 38:1914-1932|
|Chen, Christina; Van Horn, John Darrell; GENDAAR Research Consortium (2017) Developmental neurogenetics and multimodal neuroimaging of sex differences in autism. Brain Imaging Behav 11:38-61|
|Dvornek, Nicha C; Ventola, Pamela; Pelphrey, Kevin A et al. (2017) Identifying Autism from Resting-State fMRI Using Long Short-Term Memory Networks. Mach Learn Med Imaging 10541:362-370|
|Lei, Jiedi; Sukhodolsky, Denis G; Abdullahi, Sebiha M et al. (2017) Brief report: Reduced anxiety following Pivotal Response Treatment in young children with Autism Spectrum Disorder. Res Autism Spectr Disord 43-44:1-7|
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