Glutamatergic Signalling and Autism: A Family Based Association Study on the Glutamatergic Neurotransmitter System

Friday, May 13, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
A. Yousaf1, H. S. Bour1, D. Haslinger1, E. Duketis1, T. Jarczok1, M. Sachse1, A. Voran2, M. Biscaldi3, S. Kupferschmid4, M. Schulte-Rüther5, F. Degenhardt6,7, S. Herms6,7,8, S. Cichon6,7,8,9, I. Koch10, R. J. Anney11,12, A. Chiocchetti1 and C. M. Freitag1, (1)Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Johann Wolfgang Goethe-University Frankfurt/Main, Frankfurt, Germany, (2)Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Homburg, Germany, (3)Department of Child and Adolescent Psychiatry, University Hospital Freiburg, Freiburg, Germany, (4)University Hospital of Child and Adolescent Psychiatry, University of Bern, Bern, Switzerland, (5)Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital RWTH Aachen, Aachen, Germany, (6)Institute of Human Genetics, University of Bonn, Bonn, Germany, (7)Department of Genomics, University of Bonn, Bonn, Germany, (8)Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland, (9)Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany, (10)Molecular Bioinformatics, Institute of Computer Science, Johann Wolfgang Goethe-University Frankfurt am Main, Frankfurt, Germany, (11)Trinity College Dublin, Dublin, Ireland, (12)Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University,, Cardiff, United Kingdom

Common single nucleotide polymorphisms (SNPs) can explain up to 50% of ASD risk. In a previous study we showed that common functional SNPs of genes implicated in Fragile X Syndrome (FXS) are associated with ASD risk (Waltes et al., 2014). Interestingly, the FXS associated protein FMRP is regulated by the glutamatergic system, a pathomechanism discussed for ASD.


Here we tested if functional common SNPs of glutamatergic genes are also associated with ASD risk or ASD specific symptoms in two large ASD family cohorts (Autism Genome Project/AGP set, N=2734 families; German data set N=578 families). Since the genetic architecture between individuals with High IQ (HIQ= IQ>70) and Low IQ (LIQ= IQ≤70) differs (Vieland et al., 2010), we also split the two cohorts into high and low functioning (HIQ, LIQ) individuals.


207 functional SNPs of 124 glutamatergic genes with a minor allele frequency over 5% were tested using Plink v 1.9 (DFAM) in the cohort with HIQ, LIQ and the combined cohorts, respectively. Phenotype association was tested using logistic ordinal regression correcting for gender, IQ and clinical site. Phenotype measures were taken from the Autism Diagnostic Interview-Revised (ADI-R) scores for Social Interaction (Domain A), Verbal Communication (B1-B4; verbal individuals only), Non-Verbal Communication (Domain B2;B3; all individuals), Repetitive Behavior (Domain C) and Abnormal Development (Domain D). Variants significant in both cohorts with effect sizes in the same direction were considered as replicated. Similarly, genes with any nominal significant variant in both cohorts were considered as replicated hits.


We identified nominal significant associations of variants rs7206796 and rs3790112 (GNAO1) as well as rs3742926 (AKAP6) in both the German and the AGP LIQ cohort. In addition, significant but not overlapping SNPs of AKAP2 were identified (LIQ only). rs2178865 (GRIK1) was associated with Abnormal Development, and rs731826 (AKT1S1) was associated with Non Verbal Communication in the HIQ cohorts. In addition, we report 24 genes that are nominally associated with ADI-R scores in both cohorts. Genes that were involved in all five phenotypes tested were strongly related to the TOR Pathway (e.g. genes MTOR and TSC2) or the second messenger system (e.g. G-proteins GNAS, phospholipases PLCB, protein phosphatases PPP1CA). A subset of genes was specific to each phenotype or significant in one of the subgroups (HIQ and LIQ) only. For example AKAP13 or RPS6K are associated with Verbal Communication in Low Functioning Individuals.


We suggest that variants of genes that are associated with glutamate signaling, and specifically the mTOR pathway are modulators of ASD symptoms. Genes such as TSC1 or RPS6K are known to mediate glutamatergic signaling through mTOR, whereas AKAP proteins are important interactors of glutamate receptors (Sanderson et al., 2011). Both, the mTOR pathways and AKAP proteins have previously been associated with ASD (Chen et al ., 2014; Poelmans et al., 2013). Further functional analyses of glutamatergic variants are thus recommended to elucidate ASD etiology.

See more of: Genetics
See more of: Genetics