University of Illinois at Chicago (UIC) Autism Centers of Excellence (ACE) Exome Sequencing Analysis

Autism spectrum disorder (ASD) is highly heritable with recent sibling recurrence risk estimates of 19% overall and 26% in males. The heritable phenotype of hyperserotonemia, or elevated levels of platelet serotonin (5HT), in ~35% of people with ASD is a well-established biomarker. The efficacy of drugs like risperidone and potent serotonin transporter inhibitors at treating behaviors related to Insistence on Sameness, along with evidence of the contribution of hyperserotonemia to autism susceptibility collectively support the hypothesis that dysfunction in the 5HT system is a significant etiological target for investigation of the genetic component to autism. ASD genetic architecture is complex; common variants of large effect do not contribute substantially to overall ASD risk, but there are clearly common variants with small effects and rare genetic/genomic variation of larger effect among ASD genetic risk factors. The NIH ARRA Autism Sequencing Consortium, including Dr. Sutcliffe and Dr. Cook among others, has initiated exome sequencing studies to identify more of the rare variants contributing to ASD. Data from our group and others reveal numerous rare de novo and inherited sequence mutations, and the number of de novo and other functional mutations that are found to affect molecules encoding 5HT signaling and its regulation further reinforces our hypothesis that regulation of serotonin levels is important in autism genetic susceptibility. Integrin receptor signaling pathways were prominently featured among identified de novo mutations, thus defining a set of interrelated gene networks that control 5HT signaling. We propose to extend our findings to date by conducting exome sequencing on ACE subjects, for whom we also have 5HT biochemical data, to identify rare variants (including CNVs) in 5HT-related gene networks. In total we propose to have exome sequencing completed on 523 samples. The purpose of the proposed research is two-fold: 1) we will conduct more extensive investigations to determine the support for the hypothesis that genetic variation at genes regulating platelet serotonin levels affect susceptibility to ASD and 2) we will combine the exome sequence data from these studies with sequence data for autism being accumulated in a variety of other research projects to further the goal of identifying and characterizing the genetic component to ASD.

• Study Design:
  • Family/Twin/Trios
• Study Type:
  • Parent-Offspring Trios
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 589
• Subject Sample Telemetry Report (SSTR)

1. Family-based association design;
2. Probands met ADI and ADOS algorithm criteria for Autism or ASD as well as a best estimate diagnosis of either Autism or ASD; and,
3. At enrollment, no known genetic disorders.

The individuals in this study are part of the UIC ACE: Translational Studies of Insistence on Sameness in Autism study. Neuroimaging, Genomics, and extensive Phenotypic data are available through the National Database for Autism Research (NDAR; http://ndar.nih.gov) for the study participants.

The UIC ACE is NDAR collection #1 (https://ndar.nih.gov/data_from_labs.html?id=1&showSingle=true).

• Primary Phenotype: Autistic Disorder
• Developmental Disabilities

• BioProject
• PubMed
• Sequence Read Archive
• BioSample
• MeSH
• PMC

• Principal Investigator
  • Edwin Cook, MD. University of Illinois at Chicago (UIC), Chicago, IL, USA.
• Funding Sources
  • P50 HD055751. National Institutes of Health, Bethesda, MD, USA.
  • 1X01HG007235. National Institutes of Health, Bethesda, MD, USA.
• Sequencing Center
  • Center for Inherited Disease Research (CIDR). Johns Hopkins University, Baltimore, MD, USA.
• Funding Source for Sequencing
  • HHSN268201200008I. National Institutes of Health, Bethesda, MD, USA.