Genetic analyses in multiplex families confirms chromosome 5q35 as a risk locus for Alzheimer’s Disease in individuals of African Ancestry
Year: 2023
Type: article
Study design: Observational Study
Abstract: There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0.01), functional potential of coding and noncoding variants, co-segregation with AD and presence in multi-ancestry ADSP release 3 WGS data. We identified a significant linkage signal on chromosome 5q35 (HLOD=3.3) driven by nine families. Haplotype segregation analysis in the family with highest LOD score identified a 3'UTR variant in INSYN2B with the most functional evidence. Four other linked AA families harbor within-family shared variants located in INSYN2B's promoter or enhancer regions. This AA family-based finding shows the importance of diversifying population-level genetic data to better understand the genetic determinants of AD on a global scale.
Source: Neurobiology of Aging
Authors: Karen Nuytemans, Farid Rajabli, Melissa Jean-Francois, Jiji Thulaseedhara Kurup, Larry D. Adams, Takiyah D. Starks, Patrice L. Whitehead, Brian W. Kunkle, Allison Caban-Holt, Jonathan L. Haines, Michael L. Cuccaro, Jeffery M. Vance, Goldie S. Byrd, Gary W. Beecham, Christiane Reitz, Margaret A. Pericak-Vance
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,200
Awards: Neuroanatomical associations with the factor structure underlying neuropsychiatric symptoms in Alzheimer's disease, Replication and Extension of ADSP Discoveries in African-Americans, Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS), Additional Sequencing Cohorts for the Alzheimer's Disease Sequencing Project, Using RDoC Negative and Positive Valence Paradigms to Investigate the Mechanisms of Neuropsychiatric Symptoms (NPS) in Alzheimer's Disease and Related Dementias, The Origins of Alzheimer Disease in Individuals of African Ancestry, G9000269964, G9000273041, National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS), The Origins of Alzheimer Disease in African Americans, Genetic and neuroanatomical basis of neuropsychiatric symptoms in Alzheimer's disease in populations of diverse ancestry, Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP), National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W4388039264