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| PMID |
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| TITLE |
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| Testing the performance of polygenic scores for multiple traits to explain cerebral palsy in two independent cohorts. |
|
| ABSTRACT |
|
| BACKGROUND |
NlmCategory: BACKGROUND |
| Cerebral palsy (CP) is a complex neurodevelopmental disorder with both environmental and genetic contributors. Rare genetic variants explain a substantial proportion of CP, but the contribution of common variants remains unclear. We evaluated whether polygenic scores for CP and related traits explain the aetiology of CP. |
| METHODS |
NlmCategory: METHODS |
| Cerebral palsy (CP) is a complex neurodevelopmental disorder with both environmental and genetic contributors. Rare genetic variants explain a substantial proportion of CP, but the contribution of common variants remains unclear. We evaluated whether polygenic scores for CP and related traits explain the aetiology of CP. We analysed two independent target cohorts: a case-control cohort including people with a confirmed clinical diagnosis of CP from the Australian CP Biobank and population-based controls; and MyCode, a United States healthcare cohort with CP status identified by electronic health records. Only participants of European genetic ancestry were included. CP polygenic scores were constructed using a publicly available discovery genome-wide association meta-analysis of Finnish and UK cohorts (n = 624, n = 495,687) and applied to the target cohorts for out-of-sample prediction. Additional polygenic scores were generated from publicly available genome-wide association studies for seven CP-related traits. Predictive performance was assessed using logistic regression, area under the receiver operating characteristic curve, and variance in CP liability explained. |
| FINDINGS |
NlmCategory: RESULTS |
| Cerebral palsy (CP) is a complex neurodevelopmental disorder with both environmental and genetic contributors. Rare genetic variants explain a substantial proportion of CP, but the contribution of common variants remains unclear. We evaluated whether polygenic scores for CP and related traits explain the aetiology of CP. We analysed two independent target cohorts: a case-control cohort including people with a confirmed clinical diagnosis of CP from the Australian CP Biobank and population-based controls; and MyCode, a United States healthcare cohort with CP status identified by electronic health records. Only participants of European genetic ancestry were included. CP polygenic scores were constructed using a publicly available discovery genome-wide association meta-analysis of Finnish and UK cohorts (n = 624, n = 495,687) and applied to the target cohorts for out-of-sample prediction. Additional polygenic scores were generated from publicly available genome-wide association studies for seven CP-related traits. Predictive performance was assessed using logistic regression, area under the receiver operating characteristic curve, and variance in CP liability explained. The Australian cohort included 525 cases and 20,410 controls, and MyCode 322 cases and 1610 age-matched controls. The combined model of all eight polygenic scores significantly discriminated CP status, explaining 1·3% of CP liability in the Australian cohort (90% CI lower bound 0·82%, padj<0·0001), and 0·78% in MyCode (90% CI lower bound 0·35%, padj<0·0001). CP-specific polygenic scores demonstrated minimal predictive signal, likely reflecting limited GWAS power. Polygenic scores for known CP predisposing factors (birth weight, gestational duration, stroke) showed modest predictive performance, with some cohort differences. Results were similar when the Australian cohort was stratified by monogenic CP diagnosis. |
| INTERPRETATION |
NlmCategory: CONCLUSIONS |
| Cerebral palsy (CP) is a complex neurodevelopmental disorder with both environmental and genetic contributors. Rare genetic variants explain a substantial proportion of CP, but the contribution of common variants remains unclear. We evaluated whether polygenic scores for CP and related traits explain the aetiology of CP. We analysed two independent target cohorts: a case-control cohort including people with a confirmed clinical diagnosis of CP from the Australian CP Biobank and population-based controls; and MyCode, a United States healthcare cohort with CP status identified by electronic health records. Only participants of European genetic ancestry were included. CP polygenic scores were constructed using a publicly available discovery genome-wide association meta-analysis of Finnish and UK cohorts (n = 624, n = 495,687) and applied to the target cohorts for out-of-sample prediction. Additional polygenic scores were generated from publicly available genome-wide association studies for seven CP-related traits. Predictive performance was assessed using logistic regression, area under the receiver operating characteristic curve, and variance in CP liability explained. The Australian cohort included 525 cases and 20,410 controls, and MyCode 322 cases and 1610 age-matched controls. The combined model of all eight polygenic scores significantly discriminated CP status, explaining 1·3% of CP liability in the Australian cohort (90% CI lower bound 0·82%, padj<0·0001), and 0·78% in MyCode (90% CI lower bound 0·35%, padj<0·0001). CP-specific polygenic scores demonstrated minimal predictive signal, likely reflecting limited GWAS power. Polygenic scores for known CP predisposing factors (birth weight, gestational duration, stroke) showed modest predictive performance, with some cohort differences. Results were similar when the Australian cohort was stratified by monogenic CP diagnosis. Our findings demonstrate a measurable polygenic contribution to CP and shared genetic influences with predisposing factors, including those traditionally considered environmental, and comorbidities. Common variants appear to contribute broadly to CP susceptibility, highlighting a multifactorial landscape relevant for earlier diagnosis and intervention. |
| FUNDING |
NlmCategory: BACKGROUND |
| Cerebral palsy (CP) is a complex neurodevelopmental disorder with both environmental and genetic contributors. Rare genetic variants explain a substantial proportion of CP, but the contribution of common variants remains unclear. We evaluated whether polygenic scores for CP and related traits explain the aetiology of CP. We analysed two independent target cohorts: a case-control cohort including people with a confirmed clinical diagnosis of CP from the Australian CP Biobank and population-based controls; and MyCode, a United States healthcare cohort with CP status identified by electronic health records. Only participants of European genetic ancestry were included. CP polygenic scores were constructed using a publicly available discovery genome-wide association meta-analysis of Finnish and UK cohorts (n = 624, n = 495,687) and applied to the target cohorts for out-of-sample prediction. Additional polygenic scores were generated from publicly available genome-wide association studies for seven CP-related traits. Predictive performance was assessed using logistic regression, area under the receiver operating characteristic curve, and variance in CP liability explained. The Australian cohort included 525 cases and 20,410 controls, and MyCode 322 cases and 1610 age-matched controls. The combined model of all eight polygenic scores significantly discriminated CP status, explaining 1·3% of CP liability in the Australian cohort (90% CI lower bound 0·82%, padj<0·0001), and 0·78% in MyCode (90% CI lower bound 0·35%, padj<0·0001). CP-specific polygenic scores demonstrated minimal predictive signal, likely reflecting limited GWAS power. Polygenic scores for known CP predisposing factors (birth weight, gestational duration, stroke) showed modest predictive performance, with some cohort differences. Results were similar when the Australian cohort was stratified by monogenic CP diagnosis. Our findings demonstrate a measurable polygenic contribution to CP and shared genetic influences with predisposing factors, including those traditionally considered environmental, and comorbidities. Common variants appear to contribute broadly to CP susceptibility, highlighting a multifactorial landscape relevant for earlier diagnosis and intervention. Cerebral Palsy Alliance Research Foundation, NICHD, NHMRC, MRFF, QIMR Berghofer. |
| Copyright © 2026 The Author(s). Published by Elsevier B.V. All rights reserved. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2025/11/24 |
| revised |
2026/02/24 |
| accepted |
2026/02/25 |
| medline |
2026/04/11 00:32 |
| pubmed |
2026/03/16 00:30 |
| entrez |
2026/03/15 23:58 |
| pmc-release |
2026/03/14 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Thomas JT |
|
Thomas |
Jodi T |
JT |
|
Brain and Mental Health Program, QIMR Berghofer, Brisbane, QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia. |
| Berry ASF |
|
Berry |
Alexander S F |
ASF |
|
Department of Developmental Medicine, Geisinger College of Health Sciences, Lewisburg, PA, USA. |
| Oetjens MT |
|
Oetjens |
Matthew T |
MT |
|
Department of Developmental Medicine, Geisinger College of Health Sciences, Lewisburg, PA, USA. |
| Berry JG |
|
Berry |
Jesia G |
JG |
|
School of Medicine and Robinson Research Institute, College of Health, Adelaide University, Adelaide, SA, Australia. |
| MacLennan AH |
|
MacLennan |
Alastair H |
AH |
|
School of Medicine and Robinson Research Institute, College of Health, Adelaide University, Adelaide, SA, Australia. |
| Gordon SD |
|
Gordon |
Scott D |
SD |
|
Brain and Mental Health Program, QIMR Berghofer, Brisbane, QLD, Australia. |
| Hale AT |
|
Hale |
Andrew T |
AT |
|
Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA; Neuroscience Institute, University of Cape Town, Cape Town, South Africa. |
| Olsen CM |
|
Olsen |
Catherine M |
CM |
|
Population Health Program, QIMR Berghofer, Brisbane, QLD, Australia. |
| Whiteman DC |
|
Whiteman |
David C |
DC |
|
Population Health Program, QIMR Berghofer, Brisbane, QLD, Australia. |
| Torene RI |
|
Torene |
Rebecca I |
RI |
|
Department of Developmental Medicine, Geisinger College of Health Sciences, Lewisburg, PA, USA. |
| Ledbetter DH |
|
Ledbetter |
David H |
DH |
|
Institute for Pediatric Rare Diseases, College of Medicine, Florida State University, Tallahassee, FL, USA. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Brain and Mental Health Program, QIMR Berghofer, Brisbane, QLD, Australia. |
| van Eyk CL |
|
van Eyk |
Clare L |
CL |
|
School of Medicine and Robinson Research Institute, College of Health, Adelaide University, Adelaide, SA, Australia. |
| Gecz J |
|
Gecz |
Jozef |
J |
|
School of Medicine and Robinson Research Institute, College of Health, Adelaide University, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia. |
| Myers SM |
|
Myers |
Scott M |
SM |
|
Department of Developmental Medicine, Geisinger College of Health Sciences, Lewisburg, PA, USA. |
| Mitchell BL |
|
Mitchell |
Brittany L |
BL |
|
Brain and Mental Health Program, QIMR Berghofer, Brisbane, QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia. |
| Corbett MA |
|
Corbett |
Mark A |
MA |
|
School of Medicine and Robinson Research Institute, College of Health, Adelaide University, Adelaide, SA, Australia. Electronic address: mark.corbett@adelaide.edu.au. |
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| INVESTIGATORS |
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| JOURNAL |
|
| VOLUME: 126 |
| ISSUE: |
| TITLE: EBioMedicine |
| ISOABBREVIATION: EBioMedicine |
| YEAR: 2026 |
| MONTH: Apr |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 2352-3964 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: EBioMedicine |
| COUNTRY: Netherlands |
| ISSNLINKING: 2352-3964 |
| NLMUNIQUEID: 101647039 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GRANTID |
AGENCY |
COUNTRY |
| R01 HD104938 |
NICHD NIH HHS |
United States |
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| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| Cerebral palsy |
| Genome wide association study |
| Hypoxic ischaemic encephalopathy |
| Intellectual disability |
| Non-progressive movement disorder |
| Polygenic |
| Stroke |
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| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Humans |
|
| Cerebral Palsy |
etiology |
| Multifactorial Inheritance |
etiology |
| Genome-Wide Association Study |
etiology |
| Female |
etiology |
| Male |
etiology |
| Genetic Predisposition to Disease |
etiology |
| Case-Control Studies |
etiology |
| Australia |
etiology |
| Cohort Studies |
etiology |
| Polymorphism, Single Nucleotide |
etiology |
| Adult |
etiology |
| Phenotype |
etiology |
| ROC Curve |
etiology |
| Middle Aged |
etiology |
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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| OTHER ID's |
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