This is an application for a 5-year competing continuation of an ongoing longitudinal (R01) study of autistic social impairment in sibling pairs. Given recent findings regarding the genetic and neurobiologic architecture of autism, it has become clear that a more precise characterization of heritable quantitative components of the autism phenome might accelerate the discovery of specific genetic and neurobiologic causes of autism. This study will involve quantitative phenotyping of 5576 subjects (from 1295 clinically ascertained families of children with and without autism spectrum disorders (ASD). It will include: assessment of parents and affected individuals in extended pedigrees;examination of whether patterns of distribution of quantitative autistic traits in families vary as a function of gender, ethnicity, simplex versus multiplex versus """"""""complex"""""""" autism, or other phenotypic covariates;longer-term follow-up of existing longitudinal study subjects to better elucidate the developmental course of autistic social impairment over time;and examination among sib-pairs of novel quantitative endophenotypes (motor, somatosensory, and electrophysiologic) that may relate both to severity of autistic social impairment and to core genetic and neurobiologic determinants of autism. In this application, we have attempted to be responsive to the problem that previous family-genetic studies of autism have often under-represented minority and disadvantaged populations, for whom specific liabilities to autism (if present) would be overlooked in existing studies and data sets. In addition to enhanced phenotypic characterization of this large clinically-ascertained sibling sample, 475 of the families will be genotyped (parents and sibling sets) by either of two ongoing national linkage studies of autism (the Autism Genetic Resource Exchange and the Simons Simplex Collection). In addition to implications for the genetics and neurobiology of autism, the findings from the study will enhance methods for measuring subtle effects of treatment, will identify intervals in the lifespan when interventions might have particular influence on social development, and will elucidate the manner in which functional disability incurred by a wide range of non-ASD child psychiatric conditions, including ADHD can be exacerbated when superimposed (as is common) by the co-occurrence of sub clinical autistic traits.

Public Health Relevance

Autism and related disorders affect 1 out of every 150 children in the US and result in profound social impairment throughout life. This study examines how autistic social impairments change over the course of childhood, how they are transmitted across generations, and which normal developmental processes they disrupt. The results of the study will aid in the search for the genes and neural abnormalities that cause autism, will enhance methods for measuring subtle but important effects of intervention, and will identify intervals in the lifespan when interventions might have their greatest impact on social development in affected children.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042541-09
Application #
8111217
Study Section
Special Emphasis Panel (ZRG1-HOP-T (04))
Program Officer
Kau, Alice S
Project Start
2002-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$548,446
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sysoeva, Olga V; Constantino, John N; Anokhin, Andrey P (2018) Event-related potential (ERP) correlates of face processing in verbal children with autism spectrum disorders (ASD) and their first-degree relatives: a family study. Mol Autism 9:41
Page, Joshua; Constantino, John Nicholas; Zambrana, Katherine et al. (2016) Quantitative autistic trait measurements index background genetic risk for ASD in Hispanic families. Mol Autism 7:39
Lowe, Jennifer K; Werling, Donna M; Constantino, John N et al. (2015) Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8. Am J Psychiatry 172:266-75
Frazier, Thomas W; Ratliff, Kristin R; Gruber, Chris et al. (2014) Confirmatory factor analytic structure and measurement invariance of quantitative autistic traits measured by the social responsiveness scale-2. Autism 18:31-44
De Alwis, Duneesha; Agrawal, Arpana; Reiersen, Angela M et al. (2014) ADHD symptoms, autistic traits, and substance use and misuse in adult Australian twins. J Stud Alcohol Drugs 75:211-21
Lyall, Kristen; Constantino, John N; Weisskopf, Marc G et al. (2014) Parental social responsiveness and risk of autism spectrum disorder in offspring. JAMA Psychiatry 71:936-42
Kamio, Y; Inada, N; Moriwaki, A et al. (2013) Quantitative autistic traits ascertained in a national survey of 22 529 Japanese schoolchildren. Acta Psychiatr Scand 128:45-53
Messinger, Daniel; Young, Gregory S; Ozonoff, Sally et al. (2013) Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. J Am Acad Child Adolesc Psychiatry 52:300-308.e1
Hilton, Claudia List; Zhang, Yi; Whilte, Megan R et al. (2012) Motor impairment in sibling pairs concordant and discordant for autism spectrum disorders. Autism 16:430-41
Frazier, Thomas W; Youngstrom, Eric A; Speer, Leslie et al. (2012) Validation of proposed DSM-5 criteria for autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 51:28-40.e3

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