The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders.
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3) 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 14-3-3 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 14-3-3 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 = 6.6 107), 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 ; Fundació La Marató de TV3 (092010), Fundación Alicia Koplowitz, AGAUR (2017SGR738, 2017SGR1497), the Spanish Ministerio de Economía y Competitividad with FEDER funds (SAF2015-68341-R, SAF2017-87629-R, RTI2018-100968-B-I00) and the Australian National Medical and Health Research Council (NHMRC) Project Grant 1063960 and 1066177, and Program Grant 1037196. The research leading to these results also received funding from the European Union H2020 Program (H2020/2014-2020) under grant agreements 667302 (CoCA) and 643051 (MiND). B. Torrico was supported by AGAUR (Generalitat de Catalunya), E. Antón-Galindo by the Ministerio de Economía y Competitividad (Spanish Government), N. Fernàndez-Castillo by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and L. Pineda-Cirera by the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/ 03867). C. Toma was supported by the European Union (Marie Curie, PIEF-GA-2009-254930) and currently is a recipient of a 'Ramón y Cajal' fellowship (RyC2018-024106-I) from the Spanish MINECO
