Year: 2024
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION: Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. HIGHLIGHTS: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE-𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.14221
Authors: Tamil Iniyan Gunasekaran, Dolly Reyes‐Dumeyer, Kelley M. Faber, Alison Goate, Brad Boeve, Carlos Cruchaga, Margaret Pericak‐Vance, Jonathan L. Haines, Roger Rosenberg, Debby Tsuang, Diones Rivera Mejia, Martin Medrano, Rafael A. Lantigua, Robert A. Sweet, David A. Bennett, Robert S. Wilson, Camille Alba, Clifton Dalgard, Tatiana Foroud, Badri N. Vardarajan, Richard Mayeux
Institutions: Columbia University, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, Icahn School of Medicine at Mount Sinai, Mayo Clinic, Washington University in St. Louis, University of Miami, Dr. John T. Macdonald Foundation, Case Western Reserve University, The University of Texas Southwestern Medical Center, University of Washington, Universidad Nacional Pedro Henríquez Ureña, Pontificia Universidad Católica Madre y Maestra, NewYork–Presbyterian Hospital, University of Pittsburgh, Rush University Medical Center, Uniformed Services University of the Health Sciences
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
Awards: G1057078313, Gene discovery in multi-ethnic late-onset Alzheimer's disease families, G1269895679, G1309605592, G3089426657, Genetic Modifiers of Alzheimer Disease in PSEN1 Mutation Carriers in Puerto Rico, G3487525919, G3703765782, G4000272535, G4037773979, Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious Order, G4194673809, G44059850, G695519849, G747802087, The Origins of Alzheimer Disease in Individuals of African Ancestry, Genetic Epidemiology of Alzheimer's Disease in Hispanics, G9000003172, G9000122267, G9000172347, G9000183948, G9000269964, G9000273041, G9000276988, G9000332506, Genomic Characterization of Alzheimer Disease Risk in Admixed Populations with Native American and Southern European Genetic Ancestry, Mount Sinai Alzheimer's Disease Research Center, G950304953
OpenAlex ID: W4402282403