The objective of the proposed research is to translate genetic findings to a biological understanding of the contribution of non-coding RNAs to autism spectrum disorders (ASD). Genome-wide association studies (GWAS) are designed to identify novel genes and pathways that contribute to complex disorder risk. The first published ASD GWAS indicated genome-wide significant association of the rs4307059 T allele (P=10-10) at a gene-poor region of chromosome 5p14.1. These ASD-associated markers map between the genes encoding cadherin 9 and cadherin 10, but the genetic peak maps ~1 million nucleotides from either cadherin gene and there was no correlation between genotype and expression of the cadherins. We discovered a non-coding RNA that is transcribed directly under the ASD association peak on chromosome 5p14.1. Because the non- coding RNA is transcribed from the opposite (anti-sense) strand of moesin pseudogene 1 (MSNP1), we designate it MSNP1AS (moesin pseudogene 1, anti-sense). Our data indicate that expression of MSNP1AS is increased 12.7-fold in the postmortem temporal cerebral cortex of individuals with ASD compared to controls and correlates with genotype of the ASD-associated genetic markers. Over-expression of MSNP1AS in human neuronal cell lines caused significantly decreased expression of moesin, which is encoded by an X chromosome gene and influences stability of neuronal processes and immune response. These data establish that a genome-wide significant GWAS finding pointed to a non-coding RNA that is functional and dysregulated in ASD. Our preliminary data indicate that the major findings of subsequent ASD GWAS also point directly to non-coding RNAs. We hypothesize that non-coding RNAs, not the flanking protein-coding genes, contribute to ASD. We propose two complementary aims toward advancing our understanding of non-coding RNAs in ASD.
Aim 1 will determine the function of non-coding RNAs that lie directly under ASD GWAS peaks on chromosomes 5p15.2 and 20p12.1.
Aim 2 will generate RNA-Seq data from postmortem ASD brains, determine non-coding RNA transcripts with altered expression in ASD, and correlate these regions with genetic evidence for contributions to ASD. This work represents the critical 'post-GWAS'translation of genetic findings to an understanding of their biological consequences and establishes a platform for analysis of non-coding RNAs in neurodevelopmental disorders.

Public Health Relevance

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects ~1% of children. We identified a functional non-coding RNA that has both genome-wide significant association with ASD and dramatically increased expression in the brains of individuals with ASD. This research proposal will investigate the role of non-coding RNAs in ASD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Molecular Neurogenetics Study Section (MNG)
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Senthil, Geetha
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University of Southern California
Schools of Medicine
Los Angeles
United States
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DeWitt, Jessica J; Grepo, Nicole; Wilkinson, Brent et al. (2016) Impact of the Autism-Associated Long Noncoding RNA MSNP1AS on Neuronal Architecture and Gene Expression in Human Neural Progenitor Cells. Genes (Basel) 7:
Hecht, Patrick M; Ballesteros-Yanez, Inmaculada; Grepo, Nicole et al. (2015) Noncoding RNA in the transcriptional landscape of human neural progenitor cell differentiation. Front Neurosci 9:392
Wilkinson, B; Grepo, N; Thompson, B L et al. (2015) The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes. Transl Psychiatry 5:e568