Most of the efforts in human genetics are directed towards identifying and characterizing genetic variants that impact human traits, achieved by examining relationships between traits and variants. A Genome Wide Association Study (GWAS) quantifies statistical association between genetic variation and phenotypes. These statistical associations can tell us about the biological mechanisms affecting the phenotype and can allow us to predict the phenotype from genetic information in a clinical setting. However, the majority of GWAS datasets have been generated with commodity genotype arrays of single-nucleotide polymorphism (SNP) that fail to explain the majority of heritability for many complex traits even with large sample sizes.

One compelling hypothesis explaining the missing heritability dilemma is that complex variants, such as multi-allelic repeats not in strong linkage with common SNPs, are important drivers of complex traits but are largely invisible to current analyses. Short tandem repeats (STRs), consisting of repeated motifs of 1–6bp in tandem, comprise more than 3% of the human genome. Multiple lines of evidence support a role of STRs in complex traits, particularly in neurological and psychiatric phenotypes. However, existing technologies have not allowed for systematic STR association studies.

To overcome these challenges, we recently generated a reference STR+SNP haplotype panel that enables imputation of STR genotypes into SNP genotypes available for most GWAS cohorts. Our imputation pipeline achieves a high concordance and can be used to impute nearly 500,000 STRs genome-wide. Next, we leveraged our reference haplotype panel to impute STRs into GWAS data for more than 50,000 samples from the Psychiatric Genomics Consortium (PGC) to perform a genome-wide analysis of associations between STR lengths and schizophrenia.

In this dissertation, I demonstrate an end-to-end pipeline for conducting large biobank scale GWAS using STRs that serves as one of the initial studies which researchers can find useful for incorporating complex variants into their analysis.

South American populations have a complex admixture history. The earliest Native Americans are known to have migrated into the Americas as early as 14000 years ago. The region saw large scale migrations from European colonial powers starting early 1500s. In just a couple of centuries the entire Western hemisphere came under the control of these European powers. These colonial powers brought millions of Africans across the Atlantic between the 1500s and 1800s through the slave trade which led to further admixture of African populations into the Americans. Due to multiple migrations events, presence of different colonial powers that followed different slave trade practices, South Americans populations have a highly heterogeneous genetic composition. We investigate the admixture history of one of the South American populations living in Cerro de Pasco, a high altitude mining town in the Andes region of Peru. Studying the admixture history of this population can give us important insights into the origins of several selection forces at play in this population. We found the Andean population to have lesser proportions of European and African ancestry as compared to the other South American populations. The timing of European and African admixture into this population was also found to be significantly different from other populations, which could be a direct result of lower European and African ancestry proportion. These results indicate a higher level of segregation between the Native Americans and the European/African populations in Peru as compared to other regions.

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