Identification and Interpretation of Causal Genetic Variants Underlying Human Phenotypes

Abstract

Human genetics provides a powerful approach for the identification of genetic loci involved in the pathogenesis of human disease. Whole exome (WES), and increasingly whole genome, sequencing have allowed for the identification of rare, highly penetrant variants that result in severe disease. Scalable genotypic array approaches have similarly empowered the robust association of thousands of common genetic variants with modest effects on complex human traits. In both cases, it remains difficult to distinguish between pathogenic or benign and causal or passenger variants. In the following works, I develop and apply methodologies to better identify and understand the effects of a wide spectrum of variants in the human genome.

In Chapter 1, I analyze WES of 472 individuals with Diamond-Blackfan anemia (DBA), a classic Mendelian disease characterized by a pure red cell aplasia. By combining population genetic databases, RNA sequencing, and copy number variant analyses, I identify a pathogenic variant for 78% of DBA individuals, including a number of prominent phenocopies.

In Chapter 2, I identify associations for common variants in 115,000 individuals with heritable blood cell measurements. By applying fine-mapping, an approach to disentangle correlations between neighboring inherited variants, I pinpoint hundreds of likely causal variants contributing to differences in blood cell production.

In Chapter 3, I expand my fine-mapping studies to 360,000 individuals across 96 human phenotypes. After carefully benchmarking and evaluating these approaches, I apply them to identify 2,519 likely causal common genetic variants that influence physiological human traits. In

both this and the previous chapter, I use experimental and statistical approaches to dissect the molecular mechanisms of variants that regulate gene expression.

Finally, in several collaborative studies, I apply these methods to traits related to genome instability, show how different Bayesian priors can be used to improve causal variant resolution, extend these methods across genetic ancestry and genetic variant type, validate fine-mapped variants using high-throughput assays, develop a benchmark for commonly used target gene discovery methods, and finally demonstrate the usefulness of mitochondrial genome variants for lineage tracing applications. Together, these studies advance our understanding of how genetic variants alter human physiology.