A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

Genome Medicine

Raquel Sánchez-Valle¹  Eric M. Reiman²  Ricardo Allegri³  Sharon R. Browning⁴  Leonilde Morelo⁵  Dionis Vallejo⁶  Juan Marcos Solano⁶  Liliana Hincapié⁷  Francisco Piedrahita⁷  Lucía Madrigal⁷  Francisco Lopera⁷  David Aguillón⁷  Gloria P. García⁷  Amanda Saldarriaga⁷  Margarita Giraldo⁷  Sonia Moreno⁷  Diana Alzate⁷  Lina Velilla⁷  Andrés Villegas-Lanau⁷  Hugo E. López⁷  Richard M. Myers⁸  J. Nicholas Cochran⁸  Diana Matallana⁹  Ezequiel I. Surace^1,10  Tatiana Itzcovich^1,10  Charles L. White^1,11  Juliana Acosta-Uribe^1,12  Bradley W. Killingsworth^1,12  Nithesh Perumal^1,12  Rijul Singhal^1,12  Sarah Labib^1,12  Kenneth S. Kosik^1,12 

[1] Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, IDIBAPS and University of Barcelona;Banner Alzheimer’s Institute;Centro de Memoria y Envejecimiento (Fleni-CONICET);Department of Biostatistics, University of Washington;Department of Internal Medicine, School of Medicine, Universidad del Sinú;Department of Neurology, School of Medicine, Universidad de Antioquia;Grupo de Neurociencias de Antioquia, School of Medicine, Universidad de Antioquia;HudsonAlpha Institute for Biotechnology;Instituto de Envejecimiento, Department of Psychiatry, School of Medicine, Pontifical Xaverian University;Laboratorio de Enfermedades Neurodegenerativas (Fleni-CONICET);Neuropathology Section, Department of Pathology, University of Texas Southwestern Medical Center;Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California;

关键词: Founder effect;    Bottleneck;    Admixture;    Genetic drift;    Selection;    Demography;   

DOI  :  10.1186/s13073-022-01035-9

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown