UC Santa Barbara

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 variants in disease-causing and risk-conferring genes. Then, we present a deeper analysis of one of the families with genetic AD due to a novel variant in PSEN1 (Ile416Thr) of African origin. We describe the phenotype of the symptomatic carriers, as well as their brain accumulation of amyloid-beta and Tau prior to disease onset. Lastly, we explore genetic modifiers of the age at onset for dementia in a large family with autosomal dominant AD due to PSEN1 Glu280Ala. We performed a classic whole genome association study and a novel approach for genetic association using a package that performs a likelihood ratio test with a linear mixed model to adjust for relatedness between individuals.

The genomes revealed multiple rare mutations associated with various forms of adult onset familial dementias. Most of these mutations originated from founders and, remarkably, when the entire founder set of mutations was considered together, the genetic consequences of the local demographic histories emerged. In addition, we identified dozens of genome-wide significant loci that modified the age at onset for AD in the Glu280Ala kindred. We also observed a substantial number of individuals with an age of onset well beyond the typical age of onset for this kindred, some of which had high impact coding variants with effect sizes similar to the APOE Christchurch variant (Arg154Ser) recently described in another study.

The results here reveal an unexpected genetic richness in a large Colombian cohort selected for the presence of neurodegenerative conditions affecting cognition. Our results suggests that the demographic history of Colombia is likely to underlie the modern clustering of familial neurodegenerative diseases arising from multi-ancestral rare disease-associated alleles. It additionally reinforces the value of these large families with genetic neurodegenerative diseases as platforms for genetic discovery. This set is to our knowledge the largest published study in the literature of the genetics of dementia in a Hispanic descent population. Furthermore, this dissertation underscores the numerous insights that can emerge from Latin American population and the importance of inclusiveness in future genetic studies.