Comprehensive Analysis of Genetic Contributions to Alzheimer’s Disease and Frontotemporal Dementia in Admixed Latin American Populations
Journal
Alzheimer's & Dementia
ISSN
1552-5260
Date Issued
2024-12
Author(s)
Juliana Acosta‐Uribe
Stefanie Danielle Pina Escudero
J. Nicholas Cochran
Jared W Taylor
Caroline Warly Solsberg
Diana Matallana
Leonel Tadao Takada
Martin Alejandro Bruno
Alexandra R. Levine
Dawwod S. George
Francisco Lopera
José Alberto Ávila Funes
Lina Maria Zapata‐Restrepo
Luis Ignacio Brusco
Nilton Custodio
Teresita Ramos Franco
Bárbara Bruna
Daniela P Ponce
Nancy Gelvez
Greizy Lopez
Luisa Gomez
Carlos Felipe Buitrago
Pablo A Reyes
Dafne Estefania Durón
Caroline Pantazis
Marcelo Adrian Maito
Shireen Javandel
Maria Eugenia Godoy
Maria Beatriz Bistue Millon
Dan Vitale
Mike A Nalls
Andrew Singleton
Bruce L. Miller
Agustín Ibáñez
Kenneth S. Kosik
Jennifer S. Yokoyama
Rosa Montesinos
Elisa de Paula França Resende
Type
journal-article
Abstract
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Most research initiatives have emerged from high‐income countries (HIC), leaving a gap in understanding the disease’s genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC’s unique genetics and socioeconomic factors to identify specific Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort’s unique genetic architecture. We conducted ancestry analysis and searched for disease‐causing variants with mendelian inheritance, genome‐wide association studies (GWAS), rare variant enrichment, and evaluation of Polygenic Risk Scores (PRS).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We recruited and genotyped an initial cohort of 1046 participants with AD, 423 with FTD, and 855 healthy controls (HC) between 2020 and 2023. Analysis is ongoing, and we expect to sequence ∼600 additional samples in the coming months. Ancestry analysis revealed tri‐continental admixture, except for Brazil, which showed an additional Asian component (Figure 1). Top candidate gene rare variant enrichment associations (SKAT p < 0.05) were <jats:italic>TREM2</jats:italic> for FTD and <jats:italic>ABCA7</jats:italic> and <jats:italic>ABCA1</jats:italic> for AD. GWAS identified a robust association with the <jats:italic>APOE</jats:italic> locus on chromosome 19 in AD vs. HC.. We tested an AD PRS developed in European populations by Bellenguez et al (2020). on our cohort using 83 single‐nucleotide polymorphisms.. The PRS modestly distinguishes between all patients and HC (p = 2.4 × 10^‐12), AD vs. HC (p = 2.2 × 10^‐12), and even FTD vs. HC (p = 4.3 × 10^‐5), albeit with modest separation between groups, as expected for its application in a genetically admixed population.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings represent a pivotal step in understanding the genetic landscape of AD and FTD in admixed populations. They underscore the importance of including diverse populations in genetic research, paving the way for future studies. These findings have the potential to inform more personalized approaches to the diagnosis and treatment of neurodegenerative diseases in diverse global populations, as well as identify novel targets for therapeutic development.</jats:p></jats:sec>
Subjects
aged
;
alzheimer disease
;
apolipoproteins e
;
atp binding cassette transporter 1
;
atp-binding cassette transporters
;
cohort studies
;
exome sequencing
;
female
;
frontotemporal dementia
;
genetic predisposition to disease
;
genome-wide association study
;
genotype
;
humans
;
latin america
;
male
;
middle aged
;
multifactorial inheritance
;
polymorphism, single nucleotide
;
risk factors
;
whole genome sequencing
;
abc transporter
;
abc transporter a1
;
abca7 protein, human
;
apolipoprotein e
;
aged
;
alzheimer disease
;
cohort analysis
;
female
;
frontotemporal dementia
;
genetic predisposition
;
genetics
;
genome-wide association study
;
genotype
;
human
;
male
;
middle aged
;
multifactorial inheritance
;
risk factor
;
single nucleotide polymorphism
;
south and central america
;
whole exome sequencing
;
whole genome sequencing