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16.11.2017 | Psychiatry and Preclinical Psychiatric Studies - Original Article

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

verfasst von: Andreas G. Chiocchetti, Afsheen Yousaf, Hannah S. Bour, Denise Haslinger, Regina Waltes, Eftichia Duketis, Tomas Jarczok, Michael Sachse, Monica Biscaldi, Franziska Degenhardt, Stefan Herms, Sven Cichon, Jörg Ackermann, Ina Koch, Sabine M. Klauck, Christine M. Freitag

Erschienen in: Journal of Neural Transmission | Ausgabe 2/2018

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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.

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Titel: Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities
verfasst von: Andreas G. Chiocchetti
Afsheen Yousaf
Hannah S. Bour
Denise Haslinger
Regina Waltes
Eftichia Duketis
Tomas Jarczok
Michael Sachse
Monica Biscaldi
Franziska Degenhardt
Stefan Herms
Sven Cichon
Jörg Ackermann
Ina Koch
Sabine M. Klauck
Christine M. Freitag
Publikationsdatum: 16.11.2017
Verlag: Springer Vienna
Erschienen in: Journal of Neural Transmission / Ausgabe 2/2018
Print ISSN: 0300-9564
Elektronische ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-017-1813-9

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