TY - JOUR
T1 - A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects
AU - Acosta-Uribe, Juliana
AU - Aguillón, David
AU - Cochran, J. Nicholas
AU - Giraldo, Margarita
AU - Madrigal, Lucía
AU - Killingsworth, Bradley W.
AU - Singhal, Rijul
AU - Labib, Sarah
AU - Alzate, Diana
AU - Velilla, Lina
AU - Moreno, Sonia
AU - García, Gloria P.
AU - Saldarriaga, Amanda
AU - Piedrahita, Francisco
AU - Hincapié, Liliana
AU - López, Hugo E.
AU - Perumal, Nithesh
AU - Morelo, Leonilde
AU - Vallejo, Dionis
AU - Solano, Juan Marcos
AU - Reiman, Eric M.
AU - Surace, Ezequiel I.
AU - Itzcovich, Tatiana
AU - Allegri, Ricardo
AU - Sánchez-Valle, Raquel
AU - Villegas-Lanau, Andrés
AU - White, Charles L.
AU - Matallana, Diana
AU - Myers, Richard M.
AU - Browning, Sharon R.
AU - Lopera, Francisco
AU - Kosik, Kenneth S.
N1 - Funding Information:
FL and EMR are the principal investigator of Alzheimer’s prevention trials supported by NIH, philanthropy, and Genentech/Roche. EMR is also the principal investigator of Alzheimer’s prevention trials supported by Eli Lilly, scientific advisor to Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics & Vaxxinity, a co-founder and share-holder of ALZPath, and co-inventor of a pending patent and inventor of existing patents related to Alzheimer’s drug treatment discovery and the accelerated evaluation of Alzheimer’s prevention therapies. The remaining authors declare that they have no competing interests.
Funding Information:
Genome sequencing was supported by funding from the HudsonAlpha Foundation Memory and Mobility program. This project was funded by the Tau Consortium (F.L., K.S.K.), Larry L. Hillblom Foundation grant 2018-A-0004-NET (K.S.K.), Banner Alzheimer’s Foundation (F.L., E.M.R.), NOMIS Foundation (E.M.R), and the National Institutes of Health grants GG013379 (K.S.K), RF1 AG062479 (K.S.K.), R01 AG055444 (E.M.R, F.L.), and P30 AG019610 (E.M.R).
Funding Information:
We thank the individuals and the families who participated in this study. We also thank the Grupo de Neurociencias de Antioquia (GNA) staff who helped with the participant recruitment, evaluation and sample processing. In addition, we acknowledge the collaboration of Juan Fernando Calle, Mauricio De la Espriella, Dora Lilia Hern?ndez, Laura Ram?rez-Aguilar, Nora Tob?n, Ligia Eugenia Uribe, and the Instituto Neurol?gico de Colombia who helped with patient referral for the present study. We also acknowledge Juan P. Mej?a at the GNA for the brain tissue processing and imaging. Elkin Garc?a Cifuentes, Juan E. V?lez, Manuela G?mez Vega, and Alberto Jaramillo-Jim?nez for the thorough review of the participants medical records; Gregory Cooper at HudsonAlpha for helpful discussions about CNV calling; Kevin Wojta and Giovanni Coppola at the University of California Los Angeles for C9ORF72 sequencing; Jae-Hoon Sul and Sarah Spendlove for their time and thoughtful discussions about quality control and haplotype phasing; Ada A. Madejska and Sarah Eger at the University of California Santa Barbara for helping with local ancestry plotting; and Maria del Pilar Ramirez at the History department of the University of California Santa Barbara for helping with the historical background.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Admixture
KW - Alzheimer’s disease
KW - Bottleneck
KW - Demography
KW - Founder effect
KW - Frontotemporal dementia
KW - Genetic drift
KW - Motor neuron disease
KW - Neurodegeneration
KW - Selection
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U2 - 10.1186/s13073-022-01035-9
DO - 10.1186/s13073-022-01035-9
M3 - Article
C2 - 35260199
AN - SCOPUS:85126080919
VL - 14
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 27
ER -