Affected Sib-Pair Analyses Identify Signaling Networks Associated With Social Behavioral Deficits in Autism

Mehdi Pirooznia, Tejasvi Niranjan, Yun Ching Chen, Ilker Tunc, Fernando S. Goes, Dimitrios Avramopoulos, James B. Potash, Richard L. Huganir, Peter P. Zandi, Tao Wang

Research output: Contribution to journalArticlepeer-review


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, molecular signatures database (MSigDB), and GeNetMeta identified enrichment for phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) (Enrichment Score [eScore] p value = 3.36E−07; n = 8 genes) and Nerve growth factor (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.

Original languageEnglish (US)
Article number1186
JournalFrontiers in Genetics
StatePublished - Nov 27 2019


  • GeNetMeta
  • InWeb_IM
  • NGF signaling
  • affected sibs
  • autism social behavior
  • network analysis
  • synaptome

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Affected Sib-Pair Analyses Identify Signaling Networks Associated With Social Behavioral Deficits in Autism'. Together they form a unique fingerprint.

Cite this