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

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.

Keywords: Admixture; Alzheimer’s disease; Bottleneck; Demography; Founder effect; Frontotemporal dementia; Genetic drift; Motor neuron disease; Neurodegeneration; Selection.

Fig. 1

Population structure and admixture analyses of the TANGL cohort. A PC1 vs PC2 of the PCA of the TANGL cohort (purple) with the European (blue) and African (orange) individuals from the 1000GP and 43 Native American genomes (green). B Ternary plot representing the global ancestry of each of the individuals in the TANGL cohort values according to sum of local ancestries calculated by RFMix. C Q plot of ADMIXTURE results assuming 3 and 6 ancestral populations (K). ESN: Esan in Nigeria. GWD: Gambian in Western Divisions in the Gambia. LWK: Luhya in Webuye, Kenya. MSL: Mende in Sierra Leone. YRI: Yoruba in Ibadan, Nigeria. CEU: Utah Residents (CEPH) with Northern and Western European Ancestry. FIN: Finnish in Finland. GBR: British in England and Scotland. IBS: Iberian Population in Spain. TSI: Toscani in Italia. AYM: Aymara. MAY: Mayan, NAH: Nahuatl. QUE: Quechua. NAT: Native American