Cargando…
Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome
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 var...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9718680/ https://www.ncbi.nlm.nih.gov/pubmed/35768638 http://dx.doi.org/10.1038/s41380-022-01674-9 |
_version_ | 1784843142736904192 |
---|---|
author | Alver, Maris Mancini, Valentina Läll, Kristi Schneider, Maude Romano, Luciana Mägi, Reedik Dermitzakis, Emmanouil T. Eliez, Stephan Reymond, Alexandre |
author_facet | Alver, Maris Mancini, Valentina Läll, Kristi Schneider, Maude Romano, Luciana Mägi, Reedik Dermitzakis, Emmanouil T. Eliez, Stephan Reymond, Alexandre |
author_sort | Alver, Maris |
collection | PubMed |
description | 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(−29)). 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. |
format | Online Article Text |
id | pubmed-9718680 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97186802022-12-04 Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome Alver, Maris Mancini, Valentina Läll, Kristi Schneider, Maude Romano, Luciana Mägi, Reedik Dermitzakis, Emmanouil T. Eliez, Stephan Reymond, Alexandre Mol Psychiatry Article 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(−29)). 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. Nature Publishing Group UK 2022-06-29 2022 /pmc/articles/PMC9718680/ /pubmed/35768638 http://dx.doi.org/10.1038/s41380-022-01674-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Alver, Maris Mancini, Valentina Läll, Kristi Schneider, Maude Romano, Luciana Mägi, Reedik Dermitzakis, Emmanouil T. Eliez, Stephan Reymond, Alexandre Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome |
title | Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome |
title_full | Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome |
title_fullStr | Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome |
title_full_unstemmed | Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome |
title_short | Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome |
title_sort | contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9718680/ https://www.ncbi.nlm.nih.gov/pubmed/35768638 http://dx.doi.org/10.1038/s41380-022-01674-9 |
work_keys_str_mv | AT alvermaris contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT mancinivalentina contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT lallkristi contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT schneidermaude contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT romanoluciana contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT magireedik contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT dermitzakisemmanouilt contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT eliezstephan contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome AT reymondalexandre contributionofschizophreniapolygenicburdentolongitudinalphenotypicvariancein22q112deletionsyndrome |