Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Depienne, Christel; Ciura, Sorana; Trouillard, Oriane; Bouteiller, Delphine; Leitão, Elsa; Nava, Caroline; Keren, Boris; Marie, Yannick; Guégan, Justine; Forlani, Sylvie; Brice, Alexis; Anheim, Mathieu; Agid, Yves; Krack, Paul; Damier, Philippe; Viallet, François; Houeto, Jean‐Luc; Durif, Franck; Vidailhet, Marie; Worbe, Yulia; Roze, Emmanuel; Kabashi, Edor; Hartmann, Andreas

doi:10.7916/tohm.v0.693

Cited by 15 publications

(3 citation statements)

References 67 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In PCDH10 , two rare (MAF < 1%) variants that possibly lead to a loss of protein function have been detected in GTS patients (Depienne et al, 2019). Homozygous deletion of PCDH10 has been associated with ASD, a common comorbidity of GTS (Morrow et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

Borczyk

Fichna

Piechota

et al. 2021

Preprint

View full text Add to dashboard Cite

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder from the spectrum of tic disorders (TDs). GTS and other TDs have a substantial genetic component with the heritability estimated at between 60 and 80%. Here we propose an oligogenic risk model of GTS and other TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients and their families (n=185). The model is based on the overrepresentation of putatively pathogenic coding and non-coding genetic variants in genes selected from a set of 86 genes previously suggested to be associated with GTS. Based on the variant overrepresentation (SKAT test results) between unrelated GTS patients and controls based on gnomAD database allele frequencies five genes (HDC, CHADL, MAOA, NAA11, and PCDH10) were selected for the risk model. Putatively pathogenic variants (n = 98) with the median allele frequency of ~0.04 in and near these genes were used to build an additive classifier which was then validated on the GTS patients and their families. This risk model successfully assigned individuals from 22 families to either healthy or GTS groups (AUC-ROC = 0.6, p < 0.00001). These results were additionally validated using the GTS GWAS data from the Psychiatric Genomic Consortium. To investigate the GTS genetics further we identified 32 genes from the list of 86 genes as candidate genes in 14 multiplex families, including NEGR1 and NRXN with variants overrepresented in multiple families. WGS data allowed the construction of an oligogenic risk model of GTS based on possibly pathogenic variants likely contributing to the risk of GTS and TDs. The model includes putatively deleterious rare and non-coding variants in and near GTS candidate genes that may cooperatively contribute to GTS etiology and provides a novel approach to the analysis of clinical WGS data.

show abstract

Section: Discussionmentioning

confidence: 99%

Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

Borczyk

Fichna

Piechota

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Protocadherins are believed to mediate intracellular signaling via their unique cytoplasmic tails, in conjunction with their weak adhesive properties (25). Mutations or copy number variations in PCDH10 have been linked to ASD (26,27) and comorbid disorders such as Tourette's syndrome in humans (28). Pcdh10 is predominantly expressed in the nervous system, including neurons of the olfactory system, limbic system, visual system, cerebellum and spinal cord (24,(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

Altered Socio-Affective Communication and Amygdala Development in mice with Protocadherin10-deficient Interneurons

Aerts,

Boonen,

Geenen

et al. 2024

Preprint

View full text Add to dashboard Cite

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviors. The cell adhesion molecule Protocadherin10 (Pcdh10) has been implicated in the etiology of ASD. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and has been linked to neural circuit formation. Here, we show strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex of the amygdala at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the basolateral complex at perinatal stages and genes linked to vocalization behavior were enriched in Pcdh10-expressing neurons in adult mice. To further investigate the involvement of Pcdh10 in neurodevelopment with relevance to ASD, and to assess the functional and behavioral consequences of loss of Pcdh10 in basolateral amygdala interneurons, we combined a ubiquitous and a conditional Pcdh10 knockout mouse model. Conditional knockout of Pcdh10 reduced the number of interneurons in the basolateral complex. Both models exhibited altered developmental trajectories of socio-affective communication through isolation-induced ultrasonic vocalizations in neonatal pups, characterized by increased emission rates in heterozygous pups. Furthermore, acoustic call features were affected and heterozygous conditional knockout pups emitted calls characterized by reduced peak frequencies but increased frequency modulation. Additionally, we identified distinct clusters of call subtypes with specific developmental trajectories, suggesting the vocalization repertoire is extensive and dynamic during early life. The nuanced alterations in socio-affective communication at the level of call emission rates, acoustic call features, and clustering of call subtypes were primarily seen in heterozygous pups of the conditional knockout and less prominent in the ubiquitous Pcdh10 knockout, suggesting that changes in anxiety levels associated with Gsh2-lineage interneurons might drive the observed behavioral effects. Together, this demonstrates that loss of Pcdh10 specifically in interneurons contributes to behavioral alterations in socio-affective communication with relevance to ASD.

show abstract

“…Protocadherins are believed to mediate intracellular signalling via their unique cytoplasmic tails, in conjunction with their weak adhesive properties [ 25 ]. Mutations or copy number variations in PCDH10 have been linked to ASD [ 26 , 27 ] and comorbid disorders such as Tourette’s syndrome in humans [ 28 ]. Pcdh10 is predominantly expressed in the nervous system, including neurons of the olfactory system, limbic system, visual system, cerebellum and spinal cord [ 24 , 29 – 32 ].…”

Section: Introductionmentioning

confidence: 99%

Altered socio-affective communication and amygdala development in mice with protocadherin10-deficient interneurons

Aerts,

Boonen,

Geenen

et al. 2024

Open Biol.

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviours. The cell adhesion molecule protocadherin10 ( PCDH10 ) is linked to ASD in humans. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and is important for neural circuit formation. In mice, strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex (BLC) of the amygdala was observed at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the BLC at perinatal stages and vocalization-related genes were enriched in Pcdh10 -expressing neurons in adult mice. An epitope-tagged Pcdh10 -HAV5 mouse line revealed endogenous interactions of PCDH10 with synaptic proteins in the young postnatal telencephalon. Nuanced socio-affective communication changes in call emission rates, acoustic features and call subtype clustering were primarily observed in heterozygous pups of a conditional knockout (cKO) with selective deletion of Pcdh10 in Gsh2 -lineage interneurons. These changes were less prominent in heterozygous ubiquitous Pcdh10 KO pups, suggesting that altered anxiety levels associated with Gsh2 -lineage interneuron functioning might drive the behavioural effects. Together, loss of Pcdh10 specifically in interneurons contributes to behavioural alterations in socio-affective communication with relevance to ASD.

show abstract

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Cited by 15 publications

References 67 publications

Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

Altered Socio-Affective Communication and Amygdala Development in mice with Protocadherin10-deficient Interneurons

Altered socio-affective communication and amygdala development in mice with protocadherin10-deficient interneurons

Contact Info

Product

Resources

About