Association and epistatic analysis of white matter related genes across the continuum schizophrenia and autism spectrum disorders: The joint effect of NRG1-ErbB genes

Abstract

Background

Schizophrenia-spectrum disorders (SSD) and Autism spectrum disorders (ASD) are neurodevelopmental disorders that share clinical, cognitive, and genetic characteristics, as well as particular white matter (WM) abnormalities. In this study, we aimed to investigate the role of a set of oligodendrocyte/myelin-related (OMR) genes and their epistatic effect on the risk for SSD and ASD.

Methods

We examined 108 SNPs in a set of 22 OMR genes in 1749 subjects divided into three independent samples (187 SSD trios, 915 SSD cases/control, and 91 ASD trios). Genetic association and gene-gene interaction analyses were conducted with PLINK and MB-MDR, and permutation procedures were implemented in both.

Results

Some OMR genes showed an association trend with SSD, while after correction, the ones that remained significantly associated were MBP, ERBB3, and AKT1. Significant gene-gene interactions were found between (i) NRG1*MBP (perm p-value = 0.002) in the SSD trios sample, (ii) ERBB3*AKT1 (perm p-value = 0.001) in the SSD case-control sample, and (iii) ERBB3*QKI (perm p-value = 0.0006) in the ASD trios sample.

Discussion

Our results suggest the implication of OMR genes in the risk for both SSD and ASD and highlight the role of NRG1 and ERBB genes. These findings are in line with the previous evidence and may suggest pathophysiological mechanisms related to NRG1/ERBBs signalling in these disorders.

Keywords:

• White matter
• oligodendrocyte
• myelin
• schizophrenia
• autism spectrum disorders
• gene–gene interaction

Acknowledgements

We are deeply grateful to all the participants whose generosity made this work possible. We also sincerely acknowledge the psychiatrists, psychologists, and mental health staff from all clinical and research centers who collaborated in this study. We also thank Anna Valldeperas for her assistance with the molecular laboratory tasks.

Disclosure statement

All authors report no conflict of interest.

Additional information

Funding

This study was supported by: i) Eranet Neuron Consortium “AUSZ: from Autism to SchiZophrenia: study of the genetic mechanisms underlying brain dysfunction and structural phenotypes in schizophrenia and autistic spectrum disorders” (ANR-2010-NEUR-002-01, PIM2010ERN-00642), ii) Fondation de France (Engt n°15142, 2011) and by GDR 3557, iii) the Comissionat per a Universitats i Recerca del DIUE of the Generalitat de Catalunya (Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), 2017SGR1577 and 2017SGR1271); iv) travel grant from Aarhus University graduate school to C Prats; v) Ajuts de Personal Investigador Predoctoral en Formació (APIF-IBUB-Universitat de Barcelona) to C Prats, and vi) the Spanish Ministry of Economy and Competitivity, Instituto de Salud Carlos III through the project PI18/01535 and the Miguel Servet contract CP20/00072 to M Fatjó-Vilas (co-funded by European Regional Development Fund (ERDF)/European Social Fund “Investing in your future”).