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ERBB4 polymorphism and family history of psychiatric disorders on age-related cortical changes in healthy children

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Abstract

Genetic variations in ERBB4 were associated with increased susceptibility for schizophrenia (SCZ) and bipolar disorders (BPD). Structural imaging studies showed cortical abnormalities in adolescents and adults with SCZ or BPD. However, less is known about subclinical cortical changes or the influence of ERBB4 on cortical development. 971 healthy children (ages 3–20 years old; 462 girls and 509 boys) were genotyped for the ERBB4-rs7598440 variants, had structural MRI, and cognitive evaluation (NIH Toolbox ®). We investigated the effects of ERBB4 variants and family history of SCZ and/or BPD (FH) on cortical measures and cognitive performances across ages 3–20 years using a general additive model. Variations in ERBB4 and FH impact differentially the age-related cortical changes in regions often affected by SCZ and BPD. The ERBB4-TT-risk genotype children with no FH had subtle cortical changes across the age span, primarily located in the left temporal lobe and superior parietal cortex. In contrast, the TT-risk genotype children with FH had more pronounced age-related changes, mainly in the frontal lobes compared to the non-risk genotype children. Interactive effects of age, FH and ERBB4 variations were also found on episodic memory and working memory, which are often impaired in SCZ and BPD. Healthy children carrying the risk-genotype in ERBB4 and/or with FH had cortical measures resembling those reported in SCZ or BPD. These subclinical cortical variations may provide early indicators for increased risk of psychiatric disorders and improve our understanding of the effect of the NRG1–ERBB4 pathway on brain development.

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Acknowledgments

We thank all of the children and their families that have participated in our study, the physicians who referred some of the participants and all the clinical and technical staff from the research teams in the PING consortium. Data collection and sharing for this project was performed by the Pediatric Imaging, Neurocognition, and Genetics (PING) consortium. PING is co-funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development (RC2DA029475). PING data are disseminated by the PING Coordinating Center at the Center for Human Development, University of California, San Diego.

Additional Grant Support from the National Institutes of Health: 2 K24-DA016170, U54NS56883, G12-MD007601.

Financial disclosures

Vanessa Douet, Linda Chang, Kristin Lee, and Thomas Ernst declare no conflicts of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all patients for being included in the study.

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  1. Department of Medicine, John A. Burns School of Medicine, University of Hawaii and The Queen’s Medical Center, 1356 Lusitana Street, UH Tower, Room 716, Honolulu, HI, 96813, USA

    Vanessa Douet, Linda Chang, Kristin Lee & Thomas Ernst

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  1. Vanessa Douet
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  2. Linda Chang
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  3. Kristin Lee
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For the Pediatric Imaging, Neurocognition, and Genetics (PING) Consortium

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Correspondence to Vanessa Douet.

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Data used in preparation of this article were obtained from the Pediatric Imaging, Neurocognition and Genetics Study (PING) database (http://ping.chd.ucsd.edu). As such, the investigators within PING contributed to the design and implementation of PING and/or provided data, but did not participate in analysis or writing of this report. A complete listing of PING investigators can be found at https://ping-dataportal.ucsd.edu/sharing/Authors10222012.pdf.

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Douet, V., Chang, L., Lee, K. et al. ERBB4 polymorphism and family history of psychiatric disorders on age-related cortical changes in healthy children. Brain Imaging and Behavior 9, 128–140 (2015). https://doi.org/10.1007/s11682-015-9363-y

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