Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations
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
Affiliations
Andrea R.V.R. Horimoto
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Corresponding author
Lisa A. Boyken
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
Elizabeth E. Blue
Division of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
Kelsey E. Grinde
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Mathematics, Statistics and Computer Science, Macalester College, Saint Paul, MN 55105, USA
Rafael A. Nafikov
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Division of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA
Harkirat K. Sohi
Division of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA; Biomedical and Health Informatics Program, University of Washington, Seattle, WA 98195, USA
Alejandro Q. Nato, Jr.
Division 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, USA
Joshua C. Bis
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
Luis I. Brusco
CENECON - Center of Behavioural Neurology and Neuropsychiatry, School of Medicine, University of Buenos Aires, C1121A6B Buenos Aires, Argentina
Laura Morelli
Laboratory of Brain Aging and Neurodegeneration-Fundación Instituto Leloir-IIBBA- National Scientific and Technical Research Council (CONICET), C1405BWE Ciudad Autónoma de Buenos Aires, Argentina
Alfredo Ramirez
Division 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, USA
Maria Carolina Dalmasso
Division 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, Argentina
Seth Temple
Department of Statistics, University of Washington, Seattle, WA 98195, USA
Claudia Satizabal
Glenn 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, USA
Sharon R. Browning
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
Sudha Seshadri
Department of Neurology, University of Texas, San Antonio, TX 78229, USA
Ellen M. Wijsman
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Division of Medical Genetics/Department of Medicine, University of Washington, Seattle, WA 98195, USA; Corresponding author
Timothy A. Thornton
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Statistics, University of Washington, Seattle, WA 98195, USA
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.
