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Title: A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.
Author: Acosta Uribe, Juliana
Aguillón, David
Cochran, J. Nicholas
Giraldo, Margarita
Madrigal, Lucia
Killingsworth, Bradley W.
Singhal, Rijul
Labib, Sarah
Alzate, Diana
Velilla, Lina
Moreno, Sonia
García, Gloria P.
Saldarriaga, Amanda
Piedrahita, Francisco
Hincapié, Liliana
López, Hugo E.
Perumal, Nithesh
Morelo, Leonilde
Vallejo, Dionis
Solano, Juan Marcos
Reiman, Eric M.
Surace, Ezequiel I.
Itzcovich, Tatiana
Allegri, Ricardo
Sánchez Valle, Raquel
Villegas Lanau, Andrés
White III, Charles L.
Matallana, Diana
Myers, Richard M.
Browning, Sharon R.
Lopera, Francisco
Kosik, Kenneth S.
Keywords: Demència
Neurones motores
Genètica de poblacions
Malaltia d'Alzheimer
Malalties neurodegeneratives
Motor neurons
Population Genetics
Alzheimer's disease
Neurodegenerative Diseases
Issue Date: 8-Mar-2022
Publisher: BioMed Central
Abstract: Background: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.
Note: Reproducció del document publicat a:
It is part of: Genome Medicine, 2022, vol. 14, num.1
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ISSN: 1756-994X
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Medicina)

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