The influence of demographic history on the genetics of neurodegenerative illnesses in Colombia

High throughput genomic technologies have radically changed the way we understand the genetic landscape of disease. As the field of genomic medicine is growing exponentially, challenges like “lack of transferability" of genetic studies (such as polygenic risk scores) between populations arise. One of the main reasons for this issue, is that recent evolutionary history has created differences in the genetic architecture for disease between human populations. As an example, rare variants show higher geographic clustering and tend to be population-specific. Linkage disequilibrium structure and haplotype blocks around common variants are affected by demographic history as well. One way to circumvent this obstacle is to incorporate diverse populations into genetics studies. Admixed cohorts have proven to be particularly valuable to identify genetic risk for illnesses that are stratified between ancestral origins. This dissertation presents a series of genomic analyses on Colombian individuals with neurodegenerative diseases. We demonstrate that the demographic history of this population affected the genetic burden for neurological disorders, and that by studying individuals with genetic forms of these diseases, we can expand our understanding of the genetic basis of neurodegeneration.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 ancestors. We performed whole genome sequencing in a large cohort of Colombian individuals with Alzheimer’s disease (AD), frontotemporal lobar degeneration-motoneuron disease continuum, early onset dementia and healthy participants. We analyzed their global and local ancestry proportions and screened this cohort for deleterious ...