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| PMID |
|
|
| TITLE |
|
| Parkinson's Disease Polygenic Risk Score and Neurological Involvement in Carriers of the FMR1 Premutation Allele: A Case for Genetic Modifier. |
|
| ABSTRACT |
|
| BACKGROUND |
NlmCategory: BACKGROUND |
| Premutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers. |
| METHODS |
NlmCategory: METHODS |
| Premutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers. The Genome-wide SNP genotyping and clinical data on neurological status were obtained from 250 unrelated affected and non-affected male and female adult carriers of the premutation. The medians for the Parkinson's Disease Polygenic Risk Score (PD PRS) were compared between the groups of asymptomatic and neurologically affected carriers, and the association of PD PRS with neurological involvement in context with the other known risk factors was explored by fitting univariate and multiple logistic regression models. |
| RESULTS |
NlmCategory: RESULTS |
| Premutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers. The Genome-wide SNP genotyping and clinical data on neurological status were obtained from 250 unrelated affected and non-affected male and female adult carriers of the premutation. The medians for the Parkinson's Disease Polygenic Risk Score (PD PRS) were compared between the groups of asymptomatic and neurologically affected carriers, and the association of PD PRS with neurological involvement in context with the other known risk factors was explored by fitting univariate and multiple logistic regression models. There was a significant difference between the medians from the asymptomatic versus neurologically affected (FXTAS+) groups (p = 0.009). The FXTAS+ status was significantly associated with age at testing (p < 0.001), gender (p = 0.026), and with PD PRS (p = 0.021). The contribution of PD PRS remained significant after adjusting for age and gender (p = 0.044). |
| CONCLUSIONS |
NlmCategory: CONCLUSIONS |
| Premutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers. The Genome-wide SNP genotyping and clinical data on neurological status were obtained from 250 unrelated affected and non-affected male and female adult carriers of the premutation. The medians for the Parkinson's Disease Polygenic Risk Score (PD PRS) were compared between the groups of asymptomatic and neurologically affected carriers, and the association of PD PRS with neurological involvement in context with the other known risk factors was explored by fitting univariate and multiple logistic regression models. There was a significant difference between the medians from the asymptomatic versus neurologically affected (FXTAS+) groups (p = 0.009). The FXTAS+ status was significantly associated with age at testing (p < 0.001), gender (p = 0.026), and with PD PRS (p = 0.021). The contribution of PD PRS remained significant after adjusting for age and gender (p = 0.044). We have obtained the first evidence for the relationship between PD PRS and the risk of FXTAS or lesser neurological involvements in the FMR1 premutation carriers. This suggests the role of Parkinson's disease polygenic variants as genetic modifiers of the risk of late onset neurological changes in these carriers. |
| © 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. |
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| DATE PUBLISHED |
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|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| revised |
2024/10/09 |
| received |
2024/07/15 |
| accepted |
2024/11/12 |
| medline |
2024/11/26 12:32 |
| pubmed |
2024/11/26 12:31 |
| entrez |
2024/11/26 07:32 |
| pmc-release |
2024/11/26 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Loesch DZ |
|
Loesch |
Danuta Z |
DZ |
|
School of Psychology and Public Health, La Trobe University, Bundoora, Victoria, Australia. |
| Chafota F |
|
Chafota |
Freddy |
F |
|
Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Bui MQ |
|
Bui |
Minh Q |
MQ |
|
Centre for Epidemiology and Biostatistics, School of Global and Population Health, University of Melbourne, Victoria, Australia. |
| Storey E |
|
Storey |
Elsdon |
E |
|
Department of Medicine (Neuroscience), Monash University, Alfred Hospital Campus, Melbourne, Australia. |
| Atkinson A |
|
Atkinson |
Anna |
A |
|
School of Psychology and Public Health, La Trobe University, Bundoora, Victoria, Australia. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Gordon SD |
|
Gordon |
Scott D |
SD |
|
Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Rentería ME |
|
Rentería |
Miguel E |
ME |
|
Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Hagerman RJ |
|
Hagerman |
Randi J |
RJ |
|
Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Health, Sacramento, California, USA. |
| Tassone F |
|
Tassone |
Flora |
F |
|
School of Medicine and MIND Institute, University of California Davis Medical Center, Davis, California, USA. |
|
| INVESTIGATORS |
|
|
| JOURNAL |
|
| VOLUME: 12 |
| ISSUE: 11 |
| TITLE: Molecular genetics & genomic medicine |
| ISOABBREVIATION: Mol Genet Genomic Med |
| YEAR: 2024 |
| MONTH: Nov |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 2324-9269 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Mol Genet Genomic Med |
| COUNTRY: United States |
| ISSNLINKING: 2324-9269 |
| NLMUNIQUEID: 101603758 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
|
| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| HD 036071 |
Eunice Kennedy Shriver National Institute of Child Health and Human Development |
|
| IDDRC P50 HD103526 |
Eunice Kennedy Shriver National Institute of Child Health and Human Development |
|
| APP1172990 |
National Health and Medical Research Council |
|
| CF06/0269 |
National Health and Medical Research Council |
|
|
National Institute of Child Health and Human Development |
|
| F20231230 |
Rebecca L Cooper Medical Research Foundation |
|
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| FMR1/CGG repeats |
| FXTAS |
| Parkinson's risk score |
| fragile X premutation |
| neurological status |
| premutation carriers |
| regression analysis |
| whole genome screening |
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Humans |
|
| Fragile X Mental Retardation Protein |
genetics |
| Male |
genetics |
| Female |
genetics |
| Parkinson Disease |
genetics |
| Aged |
genetics |
| Middle Aged |
genetics |
| Heterozygote |
genetics |
| Fragile X Syndrome |
pathology |
| Tremor |
pathology |
| Ataxia |
pathology |
| Alleles |
pathology |
| Multifactorial Inheritance |
pathology |
| Genes, Modifier |
pathology |
| Adult |
pathology |
| Aged, 80 and over |
pathology |
| Polymorphism, Single Nucleotide |
pathology |
| Genetic Risk Score |
pathology |
|
| SUPPLEMENTARY MESH |
|
| SUPPLMESHNAME |
SUPPLMESHTYPE |
| Fragile X Tremor Ataxia Syndrome |
Disease |
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 139135-51-6 |
Fragile X Mental Retardation Protein |
| 0 |
FMR1 protein, human |
|
| OTHER ID's |
|
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|
