Characterization of autism spectrum disorder caused by alterations in complex genomic regions : molecular and pathophysiological mechanisms

Costa Roger, Mar

Characterization of autism spectrum disorder caused by alterations in complex genomic regions : molecular and pathophysiological mechanisms

Document Type

Doctoral thesis
Published Version

Author

Costa Roger, Mar

Director

Cuscó Martí, Ivon
Pérez Jurado, Luis Alberto

Publication Date

2021-05-14

Pages

233 p.

License

Citation

Costa Roger, M. Characterization of autism spectrum disorder caused by alterations in complex genomic regions : molecular and pathophysiological mechanisms. 2021. handle: http://hdl.handle.net/10803/671770

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders, the etiology of which is unknown in the majority of cases. Little is known about complex genomic regions containing part of the missing heritability. In this thesis, we have assessed three complex genomic regions including the well-known 7q11.23 locus and unexplored 8p23.1 and 17q21.31 loci bearing common inversions. We have performed genomic and transcriptomic analyses to unravel common pathophysiological mechanisms in ASD patients with several susceptibility variants (Dup7, inv8p23.1 and inv17q21.31) and also in idiopathic patients considering a multiple-hit model. By using these strategies, we have uncovered several pathways and GO categories, including cholesterol biosynthesis, actin cytoskeletal dynamics, glutamate receptor signaling and immune-inflammatory pathways, that could partially contribute to the underlying molecular mechanism of ASD. Lastly, our data supports the implication of previously ASD-related genes and points out the potential role of novel ASD candidate genes such as NR4A3, SLC12A6 or DUSP6.
El Trastorn de l’Espectre Autista (TEA) és un grup de trastorns del neuro-desenvolupament, l’etiologia dels quals és desconeguda en la majoria dels casos. Se sap poc sobre les regions genòmiques complexes que podrien contenir part de l’heretabilitat perduda. En aquesta tesi, hem estudiat tres regions complexes incloent el conegut 7q11.23 locus, i els inexplorats 8p23.1 i 17q21.31 loci que contenen inversions. Hem realitzat anàlisis genòmics i transcriptòmics trobar mecanismes fisiopatològics comuns en pacients TEA amb diverses variants de susceptibilitat (Dup7, inv8p23.1 i inv17q21.31) i també en pacients idiopàtics considerant un model de multiple-hit. Hem descobert vies i categories d’ontologia gènica, com la síntesi de colesterol, la dinàmica del citoesquelet d’actina, la senyalització dels receptors de glutamat i vies immune-inflamatòries, que podrien contribuir parcialment al mecanisme fisiopatològic del TEA. Per últim, les nostres dades donen suport a la implicació de gens prèviament relacions amb TEA i assenyalen el rol potencial de nous gens candidats com NR4A3, SLC12A6 o DUSP6.