Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci
Abstract Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequenc...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-02-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00649-7 |
| _version_ | 1797275409266507776 |
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| author | Ece Bayram Paolo Reho Irene Litvan International LBD Genomics Consortium Jinhui Ding J. Raphael Gibbs Clifton L. Dalgard Bryan J. Traynor Sonja W. Scholz Ruth Chia |
| author_facet | Ece Bayram Paolo Reho Irene Litvan International LBD Genomics Consortium Jinhui Ding J. Raphael Gibbs Clifton L. Dalgard Bryan J. Traynor Sonja W. Scholz Ruth Chia |
| author_sort | Ece Bayram |
| collection | DOAJ |
| description | Abstract Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65–3.56, p-value = 7.0 × 10−6) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10−4). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer’s-related risk for females with LBD. |
| first_indexed | 2024-03-07T15:12:56Z |
| format | Article |
| id | doaj.art-4b0bdd16236c46ffb7fc3ff2e86da758 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-07T15:12:56Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-4b0bdd16236c46ffb7fc3ff2e86da7582024-03-05T18:03:09ZengNature Portfolionpj Parkinson's Disease2373-80572024-02-011011910.1038/s41531-024-00649-7Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk lociEce Bayram0Paolo Reho1Irene Litvan2International LBD Genomics ConsortiumJinhui Ding3J. Raphael Gibbs4Clifton L. Dalgard5Bryan J. Traynor6Sonja W. Scholz7Ruth Chia8Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California San DiegoNeurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and StrokeDepartment of Neurosciences, Parkinson and Other Movement Disorders Center, University of California San DiegoComputational Biology Group, Laboratory of Neurogenetics, National Institute on AgingComputational Biology Group, Laboratory of Neurogenetics, National Institute on AgingDepartment of Anatomy, Physiology & Genetics, Uniformed Services University of the Health SciencesDepartment of Neurology, Johns Hopkins University Medical CenterNeurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and StrokeNeuromuscular Diseases Research Section, National Institute on AgingAbstract Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65–3.56, p-value = 7.0 × 10−6) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10−4). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer’s-related risk for females with LBD.https://doi.org/10.1038/s41531-024-00649-7 |
| spellingShingle | Ece Bayram Paolo Reho Irene Litvan International LBD Genomics Consortium Jinhui Ding J. Raphael Gibbs Clifton L. Dalgard Bryan J. Traynor Sonja W. Scholz Ruth Chia Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci npj Parkinson's Disease |
| title | Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci |
| title_full | Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci |
| title_fullStr | Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci |
| title_full_unstemmed | Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci |
| title_short | Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci |
| title_sort | genetic analysis of the x chromosome in people with lewy body dementia nominates new risk loci |
| url | https://doi.org/10.1038/s41531-024-00649-7 |
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