Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome.
Détails
Télécharger: 35768638_BIB_3163D2CE1B72.pdf (1490.56 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_3163D2CE1B72
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome.
Périodique
Molecular psychiatry
Collaborateur⸱rice⸱s
Estonian Biobank Research Team
Contributeur⸱rice⸱s
Milani L., Nelis M., Mägi R., Esko T., Metspalu A.
ISSN
1476-5578 (Electronic)
ISSN-L
1359-4184
Statut éditorial
Publié
Date de publication
10/2022
Peer-reviewed
Oui
Volume
27
Numéro
10
Pages
4191-4200
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
While the recurrent 22q11.2 deletion is one of the strongest genetic risk factors for schizophrenia (SCZ), variability of its associated neuropsychiatric endophenotypes reflects its incomplete penetrance for psychosis development. To assess whether this phenotypic variability is linked to common variants associated with SCZ, we studied the association between SCZ polygenic risk score (PRS) and longitudinally acquired phenotypic information of the Swiss 22q11.2DS cohort (n = 97, 50% females, mean age 17.7 yr, mean visit interval 3.8 yr). The SCZ PRS with the best predictive performance was ascertained in the Estonian Biobank (n = 201,146) with LDpred. The infinitesimal SCZ PRS model showed the strongest capacity in discriminating SCZ cases from controls with one SD difference in SCZ PRS corresponding to an odds ratio (OR) of 1.73 (95% CI 1.57-1.90, P = 1.47 × 10 <sup>-29</sup> ). In 22q11.2 patients, random-effects ordinal regression modelling using longitudinal data showed SCZ PRS to have the strongest effect on social anhedonia (OR = 2.09, P = 0.0002), and occupational functioning (OR = 1.82, P = 0.0003) within the negative symptoms course, and dysphoric mood (OR = 2.00, P = 0.002) and stress intolerance (OR = 1.76, P = 0.0002) within the general symptoms course. Genetic liability for SCZ was additionally associated with full scale cognitive decline (β = -0.25, P = 0.02) and with longitudinal volumetric reduction of the right and left hippocampi (β = -0.28, P = 0.005; β = -0.23, P = 0.02, respectively). Our results indicate that the polygenic contribution to SCZ acts upon the threshold-lowering first hit (i.e., the deletion). It modifies the endophenotypes of 22q11.2DS and augments the derailment of developmental trajectories of negative and general symptoms, cognition, and hippocampal volume.
Mots-clé
Female, Humans, Adolescent, Male, Schizophrenia/genetics, DiGeorge Syndrome/genetics, Multifactorial Inheritance/genetics, Psychotic Disorders/genetics, Cognitive Dysfunction/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
04/07/2022 10:36
Dernière modification de la notice
23/01/2024 7:22