Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis
BackgroundThe UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1067954/full |
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| author | Arianna Manini Arianna Manini Valeria Casiraghi Valeria Casiraghi Alberto Brusati Alberto Brusati Alessio Maranzano Alessio Maranzano Francesco Gentile Francesco Gentile Eleonora Colombo Ruggero Bonetti Ruggero Bonetti Silvia Peverelli Sabrina Invernizzi Davide Gentilini Davide Gentilini Stefano Messina Federico Verde Federico Verde Barbara Poletti Isabella Fogh Claudia Morelli Vincenzo Silani Vincenzo Silani Antonia Ratti Antonia Ratti Nicola Ticozzi Nicola Ticozzi |
| author_facet | Arianna Manini Arianna Manini Valeria Casiraghi Valeria Casiraghi Alberto Brusati Alberto Brusati Alessio Maranzano Alessio Maranzano Francesco Gentile Francesco Gentile Eleonora Colombo Ruggero Bonetti Ruggero Bonetti Silvia Peverelli Sabrina Invernizzi Davide Gentilini Davide Gentilini Stefano Messina Federico Verde Federico Verde Barbara Poletti Isabella Fogh Claudia Morelli Vincenzo Silani Vincenzo Silani Antonia Ratti Antonia Ratti Nicola Ticozzi Nicola Ticozzi |
| author_sort | Arianna Manini |
| collection | DOAJ |
| description | BackgroundThe UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other clinical features and ALS phenotypic variability is controversial.MethodsGenotype data of the UNC13A rs12608932 SNP (A–major allele; C–minor allele) was obtained from a cohort of 972 ALS patients. Demographic and clinical variables were collected, including cognitive and behavioral profiles, evaluated through the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) – Italian version and the Frontal Behavioral Inventory (FBI); upper and lower motor neuron involvement, assessed by the Penn Upper Motor Neuron Score (PUMNS) and the Lower Motor Neuron Score (LMNS)/Medical Research Council (MRC) scores, respectively; the ALS Functional Rating Scale Revised (ALSFRS-R) score at evaluation and progression rate; age and site of onset; survival. The comparison between the three rs12608932 genotypes (AA, AC, and CC) was performed using the additive, dominant, and recessive genetic models.ResultsThe rs12608932 minor allele frequency was 0.31 in our ALS cohort, in comparison to 0.33–0.41 reported in other Caucasian ALS populations. Carriers of at least one minor C allele (AC + CC genotypes) had a shorter median survival than patients with the wild-type AA genotype (−11.7 months, p = 0.013), even after adjusting for age and site of onset, C9orf72 mutational status and gender. Patients harboring at least one major A allele (AA + AC genotypes) and particularly those with the wild-type AA genotype showed a significantly higher PUMNS compared to CC carriers (p = 0.015 and padj = 0.037, respectively), thus indicating a more severe upper motor neuron involvement. Our analysis did not detect significant associations with all the other clinical parameters considered.ConclusionOverall, our findings confirm the role of UNC13A as a determinant of survival in ALS patients and show the association of this locus also with upper motor neuron involvement. |
| first_indexed | 2024-04-10T18:51:41Z |
| format | Article |
| id | doaj.art-ab3bde1bf5394265b98be74e3d334377 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-04-10T18:51:41Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-ab3bde1bf5394265b98be74e3d3343772023-02-01T07:26:13ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652023-02-011510.3389/fnagi.2023.10679541067954Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosisArianna Manini0Arianna Manini1Valeria Casiraghi2Valeria Casiraghi3Alberto Brusati4Alberto Brusati5Alessio Maranzano6Alessio Maranzano7Francesco Gentile8Francesco Gentile9Eleonora Colombo10Ruggero Bonetti11Ruggero Bonetti12Silvia Peverelli13Sabrina Invernizzi14Davide Gentilini15Davide Gentilini16Stefano Messina17Federico Verde18Federico Verde19Barbara Poletti20Isabella Fogh21Claudia Morelli22Vincenzo Silani23Vincenzo Silani24Antonia Ratti25Antonia Ratti26Nicola Ticozzi27Nicola Ticozzi28Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyNeurology Residency Program, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Medical Biotechnology and Molecular Medicine, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Brain and Behavioral Sciences, Università degli Studi di Pavia, Pavia, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyNeurology Residency Program, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyNeurology Residency Program, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyNeurology Residency Program, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Brain and Behavioral Sciences, Università degli Studi di Pavia, Pavia, ItalyBioinformatics and Statistical Genomics Unit, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyMaurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, United KingdomDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Medical Biotechnology and Molecular Medicine, Università degli Studi di Milano, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, ItalyBackgroundThe UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other clinical features and ALS phenotypic variability is controversial.MethodsGenotype data of the UNC13A rs12608932 SNP (A–major allele; C–minor allele) was obtained from a cohort of 972 ALS patients. Demographic and clinical variables were collected, including cognitive and behavioral profiles, evaluated through the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) – Italian version and the Frontal Behavioral Inventory (FBI); upper and lower motor neuron involvement, assessed by the Penn Upper Motor Neuron Score (PUMNS) and the Lower Motor Neuron Score (LMNS)/Medical Research Council (MRC) scores, respectively; the ALS Functional Rating Scale Revised (ALSFRS-R) score at evaluation and progression rate; age and site of onset; survival. The comparison between the three rs12608932 genotypes (AA, AC, and CC) was performed using the additive, dominant, and recessive genetic models.ResultsThe rs12608932 minor allele frequency was 0.31 in our ALS cohort, in comparison to 0.33–0.41 reported in other Caucasian ALS populations. Carriers of at least one minor C allele (AC + CC genotypes) had a shorter median survival than patients with the wild-type AA genotype (−11.7 months, p = 0.013), even after adjusting for age and site of onset, C9orf72 mutational status and gender. Patients harboring at least one major A allele (AA + AC genotypes) and particularly those with the wild-type AA genotype showed a significantly higher PUMNS compared to CC carriers (p = 0.015 and padj = 0.037, respectively), thus indicating a more severe upper motor neuron involvement. Our analysis did not detect significant associations with all the other clinical parameters considered.ConclusionOverall, our findings confirm the role of UNC13A as a determinant of survival in ALS patients and show the association of this locus also with upper motor neuron involvement.https://www.frontiersin.org/articles/10.3389/fnagi.2023.1067954/fullamyotrophic lateral sclerosisUNC13Aallelesgenotypemotor neuronsbehavioral symptoms |
| spellingShingle | Arianna Manini Arianna Manini Valeria Casiraghi Valeria Casiraghi Alberto Brusati Alberto Brusati Alessio Maranzano Alessio Maranzano Francesco Gentile Francesco Gentile Eleonora Colombo Ruggero Bonetti Ruggero Bonetti Silvia Peverelli Sabrina Invernizzi Davide Gentilini Davide Gentilini Stefano Messina Federico Verde Federico Verde Barbara Poletti Isabella Fogh Claudia Morelli Vincenzo Silani Vincenzo Silani Antonia Ratti Antonia Ratti Nicola Ticozzi Nicola Ticozzi Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis Frontiers in Aging Neuroscience amyotrophic lateral sclerosis UNC13A alleles genotype motor neurons behavioral symptoms |
| title | Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis |
| title_full | Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis |
| title_fullStr | Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis |
| title_full_unstemmed | Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis |
| title_short | Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis |
| title_sort | association of the risk factor unc13a with survival and upper motor neuron involvement in amyotrophic lateral sclerosis |
| topic | amyotrophic lateral sclerosis UNC13A alleles genotype motor neurons behavioral symptoms |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1067954/full |
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