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J Neural Transm (Vienna). 2018 Feb;125(2):259-271. doi: 10.1007/s00702-017-1813-9. Epub 2017 Nov 16.

Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities.

Author information

1
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence Frankfurt, University Hospital Frankfurt, Goethe University, Deutschordenstraße 50, 60258, Frankfurt am Main, Germany. andreas.chiocchetti@kgu.de.
2
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence Frankfurt, University Hospital Frankfurt, Goethe University, Deutschordenstraße 50, 60258, Frankfurt am Main, Germany.
3
Department of Child and Adolescent Psychiatry, University Hospital Freiburg, 79106, Freiburg, Germany.
4
Institute of Human Genetics, University of Bonn, 53113, Bonn, Germany.
5
Department of Genomics, University of Bonn, 53113, Bonn, Germany.
6
Division of Medical Genetics, Department of Biomedicine, University of Basel, 4003, Basel, Switzerland.
7
Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, 52428, Juelich, Germany.
8
Molecular Bioinformatics, Institute of Computer Science, Johann Wolfgang Goethe-University Frankfurt am Main, 60323, Frankfurt am Main, Germany.
9
Division of Molecular Genome Analysis and Division of Cancer Genome Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.

Abstract

The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR < 0.79, p < 0.04) of the AKAP13 rs745191-T allele in both LIQ cohorts, but not in the much larger HIQ cohorts. At the phenotypic level, we nominally replicated associations of CAMK2A-rs2241694 with non-verbal communication in both combined LIQ and HIQ ASD cohorts. Variants PLD1-rs2124147 and ADCY1-rs2461127 were nominally associated with impaired non-verbal abilities and AKAP2-rs3739456 with repetitive behaviour in both LIQ cohorts. All four LIQ-associated genes are involved in G-protein coupled signal transduction, a downstream pathway of metabotropic glutamate receptor activation. We conclude that functional common variants of glutamatergic genes do not have a strong impact on ASD, but seem to moderately affect ASD risk and phenotypic expression. Since most of our nominally replicated hits were identified in the LIQ cohort, further investigation of the glutamatergic system in this subpopulation might be warranted.

KEYWORDS:

ADI-R phenotypes; Association study; Genetic architecture; IQ

PMID:
29147782
DOI:
10.1007/s00702-017-1813-9

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