Original Research ARTICLE
Affected Sib-pair Analyses Identify Signaling Networks Associated with Social Behavioral Deficits in Autism
- 1National Heart, Lung, and Blood Institute (NHLBI), United States
- 2Johns Hopkins University, United States
- 3Pediatrics/Genetic Medicine, Johns Hopkins University, United States
Autism spectrum disorders (ASDs) are characterized by deficits in three core behavioral domains: reciprocal social interactions, communication, and restricted interests and/or repetitive behaviors. Several hundreds of risk genes for autism have been identified, however, it remains a challenge to associate these genes with specific core behavioral deficits. In multiplex autism families, affected sibs often show significant differences in severity of individual core phenotypes. We hypothesize that a higher mutation burden contributes to a larger difference in the severity of specific core phenotypes between affected sibs. We tested this hypothesis on social behavioral deficits in autism. We sequenced synaptome genes (n=1,886) in affected male sib-pairs (n=274) in families from the Autism Genetics Research Exchange (AGRE) and identified rare (MAF≤1%) and predicted functional variants. We selected affected sib-pairs with a large (≥10; n=92 pairs) or a small (≤4; n=108 pairs) difference in total cumulative Autism Diagnostic Interview-Revised (ADI-R) social scores (SOCT_CS). We compared burdens of unshared variants present only in sibs with severe social deficits and found a higher burden in SOCT_CS≥10 compared to SOCT_CS≤4 (SOCT_CS≥10: 705.1±16.2; SOCT_CS≤4, 668.3±9.0; p=0.025). Unshared SOCT_CS≥10 genes only in sibs with severe social deficits are significantly enriched in the SFARI gene set. Network analyses of these genes using InWeb_IM, MSigDB, and GeNetMeta identified enrichment for PI3K-AKT-mTOR (eScore P-value=3.36E-07; n=8 genes) and NGF (eScore P-value =8.94E-07; n=9 genes) networks. These studies support a key role for these signaling networks in social behavioral deficits and present a novel approach to associate risk genes and signaling networks with core behavioral domains in autism.
Keywords: Affected sibs; autism social behavior; network analysis; InWeb_IM; MSigDB; GeNetMeta; synaptome; PI3K-AKT-mTOR; NGF signaling, Autism (ASD), affected sib pairs, social behaivor, synaptome, Network analysis
Received: 03 Jun 2019;
Accepted: 25 Oct 2019.
Copyright: © 2019 Pirooznia, Niranjan, Chen, Tunc, Goes, Avramopoulos, Huganir, Potash, Zandi and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Dr. Mehdi Pirooznia, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD 20892, Maryland, United States, firstname.lastname@example.org
Dr. Tao Wang, Johns Hopkins University, Pediatrics/Genetic Medicine, Baltimore, 21205, MD, United States, email@example.com