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Published Online: 15 February 2019

A Third Linear Association Between Olduvai (DUF1220) Copy Number and Severity of the Classic Symptoms of Inherited Autism

Jonathan M. Davis, Ph.D., Ilea Heft, Ph.D., Stephen W. Scherer, Ph.D., and James M. Sikela, Ph.D. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 176, Number 8
https://doi.org/10.1176/appi.ajp.2018.18080993
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Abstract

Objective:

The authors previously reported that the copy number of sequences encoding an Olduvai protein domain subtype (CON1) shows a linear association with the severity of social deficits and communication impairment in individuals with autism. In this study, using an improved measurement method, the authors replicated this association in an independent population.

Method:

The authors obtained whole genome sequence (WGS) data and phenotype data on 215 individuals from the Autism Speaks MSSNG project. They derived copy number from WGS data using a modified sequence read-depth technique. A linear mixed-effects model was used to test the association between Olduvai CON1 copy number and symptom severity as measured by the Autism Diagnostic Interview–Revised. The authors then combined data from previous studies (N=524) for final analyses.

Results:

A significant linear association was observed between CON1 copy number and social diagnostic score (SDS) (β=0.24) and communicative diagnostic score (CDS) (β=0.23). Using the combined data, the authors present strong significant associations of CON1 dosage with SDS (β=0.18) and CDS (β=0.13). The authors also implicate Olduvai subtypes found in two genes, NBPF1 and NBPF14 (R2=6.2%). Associations were preferentially found in multiplex versus simplex families.

Conclusions:

The finding of a third dose-dependent association between Olduvai sequences and autism severity, preferentially in multiplex families, provides strong evidence that this highly duplicated and underexamined protein domain family plays an important role in inherited autism.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 176 • Number 8 • August 01, 2019
Pages: 643 - 650
PubMed: 30764650

History

Received: 28 August 2018
Revision received: 9 November 2018
Accepted: 10 December 2018
Published online: 15 February 2019
Published in print: August 01, 2019

Keywords

  1. Olduvai
  2. DUF1220
  3. Autism Symptoms
  4. Copy Number

Authors

Details

Jonathan M. Davis, Ph.D.
The Department of Biochemistry and Molecular Genetics, Human Medical Genetics and Genomics Program and Neuroscience Program, University of Colorado School of Medicine, Aurora (Davis, Heft, Sikela); the McLaughlin Centre and the Department of Molecular Genetics, University of Toronto, and the Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto (Scherer).
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Ilea Heft, Ph.D.
The Department of Biochemistry and Molecular Genetics, Human Medical Genetics and Genomics Program and Neuroscience Program, University of Colorado School of Medicine, Aurora (Davis, Heft, Sikela); the McLaughlin Centre and the Department of Molecular Genetics, University of Toronto, and the Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto (Scherer).
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Stephen W. Scherer, Ph.D.
The Department of Biochemistry and Molecular Genetics, Human Medical Genetics and Genomics Program and Neuroscience Program, University of Colorado School of Medicine, Aurora (Davis, Heft, Sikela); the McLaughlin Centre and the Department of Molecular Genetics, University of Toronto, and the Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto (Scherer).
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James M. Sikela, Ph.D. [email protected]
The Department of Biochemistry and Molecular Genetics, Human Medical Genetics and Genomics Program and Neuroscience Program, University of Colorado School of Medicine, Aurora (Davis, Heft, Sikela); the McLaughlin Centre and the Department of Molecular Genetics, University of Toronto, and the Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto (Scherer).
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Notes

Send correspondence to Dr. Sikela ([email protected]).

Competing Interests

Dr. Sikela is an inventor on U.S. patent no. 9,988,681, related to autism. Dr. Scherer has served on scientific advisory boards or committees for Population Bio, Inc., and Deep Genomics. The other authors report no financial relationships with commercial interests.

Funding Information

Supported by NIH grant R01 MH108684 (to Dr. Sikela) and Pilot Award 309230 from the Simons Foundation Autism Research Initiative (to Dr. Sikela).

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