Involvement of the 14-3-3 gene family in autism spectrum disorder and schizophrenia: genetics, transcriptomics and functional analyses

  • The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.

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Author:Bàrbara Torrico, Ester Antón-GalindoORCiD, Noèlia Fernàndez-CastilloORCiDGND, Eva Rojo-FrancàsORCiD, Sadaf Ghorbani, Laura Pineda-CireraORCiD, Amaia HervásORCiD, Isabel Rueda, Estefanía MorenoORCiD, Janice M. FullertonORCiD, Vicent Casadó, Jan K. BuitelaarORCiDGND, Nanda Rommelse, Barbara FrankeORCiDGND, Andreas ReifORCiDGND, Andreas Geburtig-ChiocchettiORCiDGND, Christine M. FreitagORCiDGND, Rune KleppeORCiD, Jan HaavikORCiD, Claudio TomaORCiD, Bru CormandORCiD
Parent Title (English):Journal of Clinical Medicine
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/06/13
Date of first Publication:2020/06/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/08/28
Tag:14-3-3 gene family; YWHAE; YWHAZ; autism; common variants; rare variants; schizophrenia; transcriptomics
Page Number:21
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0