Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations
Summary: Alzheimer disease (AD) is the most common form of senile dementia, with high incidence late in life in many populations including Caribbean Hispanic (CH) populations. Such admixed populations, descended from more than one ancestral population, can present challenges for genetic studies, inc...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | HGG Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247723000398 |
| _version_ | 1797811083744903168 |
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| author | Andrea R.V.R. Horimoto Lisa A. Boyken Elizabeth E. Blue Kelsey E. Grinde Rafael A. Nafikov Harkirat K. Sohi Alejandro Q. Nato, Jr. Joshua C. Bis Luis I. Brusco Laura Morelli Alfredo Ramirez Maria Carolina Dalmasso Seth Temple Claudia Satizabal Sharon R. Browning Sudha Seshadri Ellen M. Wijsman Timothy A. Thornton |
| author_facet | Andrea R.V.R. Horimoto Lisa A. Boyken Elizabeth E. Blue Kelsey E. Grinde Rafael A. Nafikov Harkirat K. Sohi Alejandro Q. Nato, Jr. Joshua C. Bis Luis I. Brusco Laura Morelli Alfredo Ramirez Maria Carolina Dalmasso Seth Temple Claudia Satizabal Sharon R. Browning Sudha Seshadri Ellen M. Wijsman Timothy A. Thornton |
| author_sort | Andrea R.V.R. Horimoto |
| collection | DOAJ |
| description | Summary: Alzheimer disease (AD) is the most common form of senile dementia, with high incidence late in life in many populations including Caribbean Hispanic (CH) populations. Such admixed populations, descended from more than one ancestral population, can present challenges for genetic studies, including limited sample sizes and unique analytical constraints. Therefore, CH populations and other admixed populations have not been well represented in studies of AD, and much of the genetic variation contributing to AD risk in these populations remains unknown. Here, we conduct genome-wide analysis of AD in multiplex CH families from the Alzheimer Disease Sequencing Project (ADSP). We developed, validated, and applied an implementation of a logistic mixed model for admixture mapping with binary traits that leverages genetic ancestry to identify ancestry-of-origin loci contributing to AD. We identified three loci on chromosome 13q33.3 associated with reduced risk of AD, where associations were driven by Native American (NAM) ancestry. This AD admixture mapping signal spans the FAM155A, ABHD13, TNFSF13B, LIG4, and MYO16 genes and was supported by evidence for association in an independent sample from the Alzheimer’s Genetics in Argentina—Alzheimer Argentina consortium (AGA-ALZAR) study with considerable NAM ancestry. We also provide evidence of NAM haplotypes and key variants within 13q33.3 that segregate with AD in the ADSP whole-genome sequencing data. Interestingly, the widely used genome-wide association study approach failed to identify associations in this region. Our findings underscore the potential of leveraging genetic ancestry diversity in recently admixed populations to improve genetic mapping, in this case for AD-relevant loci. |
| first_indexed | 2024-03-13T07:17:23Z |
| format | Article |
| id | doaj.art-bc1d19b1b9194d0ba327e4e0b482b7b4 |
| institution | Directory Open Access Journal |
| issn | 2666-2477 |
| language | English |
| last_indexed | 2024-03-13T07:17:23Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj.art-bc1d19b1b9194d0ba327e4e0b482b7b42023-06-05T04:13:09ZengElsevierHGG Advances2666-24772023-07-0143100207Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populationsAndrea R.V.R. Horimoto0Lisa A. Boyken1Elizabeth E. Blue2Kelsey E. Grinde3Rafael A. Nafikov4Harkirat K. Sohi5Alejandro Q. Nato, Jr.6Joshua C. Bis7Luis I. Brusco8Laura Morelli9Alfredo Ramirez10Maria Carolina Dalmasso11Seth Temple12Claudia Satizabal13Sharon R. Browning14Sudha Seshadri15Ellen M. Wijsman16Timothy A. Thornton17Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Corresponding authorDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USADivision of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USADepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Mathematics, Statistics and Computer Science, Macalester College, Saint Paul, MN 55105, USADepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA; Division of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USADivision of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA; Biomedical and Health Informatics Program, University of Washington, Seattle, WA 98195, USADivision of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USACardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USACENECON - Center of Behavioural Neurology and Neuropsychiatry, School of Medicine, University of Buenos Aires, C1121A6B Buenos Aires, ArgentinaLaboratory of Brain Aging and Neurodegeneration-Fundación Instituto Leloir-IIBBA- National Scientific and Technical Research Council (CONICET), C1405BWE Ciudad Autónoma de Buenos Aires, ArgentinaDivision of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, 50937 Cologne, Germany; Department of Neurodegeneration and Gerontopsychiatry, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne, 50674 Cologne, Germany; Department of Psychiatry, UT Health San Antonio, San Antonio, TX 78229, USA; Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78229, USADivision of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, 50937 Cologne, Germany; Neurosciences and Complex Systems Unit (EnyS), CONICET, Hospital El Cruce, National University A. Jauretche (UNAJ), B1888AAE Florencio Varela, ArgentinaDepartment of Statistics, University of Washington, Seattle, WA 98195, USAGlenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78229, USA; Department of Population Health Sciences, University of Texas, San Antonio, TX 78229, USA; Department of Neurology, University of Texas, San Antonio, TX 78229, USADepartment of Biostatistics, University of Washington, Seattle, WA 98195, USADepartment of Neurology, University of Texas, San Antonio, TX 78229, USADepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA; Division of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA; Corresponding authorDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Statistics, University of Washington, Seattle, WA 98195, USASummary: Alzheimer disease (AD) is the most common form of senile dementia, with high incidence late in life in many populations including Caribbean Hispanic (CH) populations. Such admixed populations, descended from more than one ancestral population, can present challenges for genetic studies, including limited sample sizes and unique analytical constraints. Therefore, CH populations and other admixed populations have not been well represented in studies of AD, and much of the genetic variation contributing to AD risk in these populations remains unknown. Here, we conduct genome-wide analysis of AD in multiplex CH families from the Alzheimer Disease Sequencing Project (ADSP). We developed, validated, and applied an implementation of a logistic mixed model for admixture mapping with binary traits that leverages genetic ancestry to identify ancestry-of-origin loci contributing to AD. We identified three loci on chromosome 13q33.3 associated with reduced risk of AD, where associations were driven by Native American (NAM) ancestry. This AD admixture mapping signal spans the FAM155A, ABHD13, TNFSF13B, LIG4, and MYO16 genes and was supported by evidence for association in an independent sample from the Alzheimer’s Genetics in Argentina—Alzheimer Argentina consortium (AGA-ALZAR) study with considerable NAM ancestry. We also provide evidence of NAM haplotypes and key variants within 13q33.3 that segregate with AD in the ADSP whole-genome sequencing data. Interestingly, the widely used genome-wide association study approach failed to identify associations in this region. Our findings underscore the potential of leveraging genetic ancestry diversity in recently admixed populations to improve genetic mapping, in this case for AD-relevant loci.http://www.sciencedirect.com/science/article/pii/S2666247723000398local ancestrymulti-ethnicgene mappinghaplotypeprotectivenon-coding |
| spellingShingle | Andrea R.V.R. Horimoto Lisa A. Boyken Elizabeth E. Blue Kelsey E. Grinde Rafael A. Nafikov Harkirat K. Sohi Alejandro Q. Nato, Jr. Joshua C. Bis Luis I. Brusco Laura Morelli Alfredo Ramirez Maria Carolina Dalmasso Seth Temple Claudia Satizabal Sharon R. Browning Sudha Seshadri Ellen M. Wijsman Timothy A. Thornton Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations HGG Advances local ancestry multi-ethnic gene mapping haplotype protective non-coding |
| title | Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations |
| title_full | Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations |
| title_fullStr | Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations |
| title_full_unstemmed | Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations |
| title_short | Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations |
| title_sort | admixture mapping implicates 13q33 3 as ancestry of origin locus for alzheimer disease in hispanic and latino populations |
| topic | local ancestry multi-ethnic gene mapping haplotype protective non-coding |
| url | http://www.sciencedirect.com/science/article/pii/S2666247723000398 |
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