Understanding how genetic variation (genotype) contributes to diverse traits (phenotype) is a grand challenge in biology and the overarching theme of this dissertation. Neurological disorders include over 600 diseases and affect the central and peripheral nervous systems. Communication, intelligence, memory, and consciousness -- fundamental abilities that have elevated humankind above the rest of the animal kingdom, are all susceptible to attack from neurological disorders. The contribution of genetic variation to human traits and diseases has been studied for over a century, revealing a strong genetic component to almost every phenotype examined. Establishing genetic associations and delineating their molecular mechanisms in neurological disorders can reveal insight into the establishment, restoration, and enhancement of key human traits.

The commencement of my doctoral studies coincided with the emergence of two groundbreaking scientific achievements: whole-genome sequencing and induced pluripotent stem cells. Here, I used these seminal technological advancements in biology as novel approaches to establish phenotype-genotype connections in neurological disorders. Functional genomics aims to integrate high throughput genomic and transcriptomic data to understand the biological function of genetic variation. This dissertation is split into two parts presenting divergent functional genomics approaches to understand two neurological disorders: whole-genome sequencing in Alzheimer's disease and induced pluripotent stem cell modeling of Williams syndrome.

In the first part of this thesis, I used whole-genome sequencing data to identify genetic variants modifying age at onset of Alzheimer's disease in the world's largest family affected with this disease. This family, living in Antioquia, the mountainous region surrounding the major Colombian city Medellin, suffers from a rare form of Alzheimer's caused by a single mutation. This mutation, originating spontaneously in a single Spanish Conquistador, crossed the Atlantic and permeated throughout the pueblos indigenas living in Colombia. Over generations of geographic and genetic isolation coupled with exponential population growth, this single mutation spread to thousands of individuals, all who will develop a form of Alzheimer's at an average age of just 49 years. By sequencing the entire genomes of individuals affected with this disease at a range of different ages, we sought to identify genetic variants controlling the onset of this disease. First, we established a pipeline to sift through the wealth of information in a single genome. Next, we examined the genomic locus spanning the causal mutation to show definitively that the mutation originated in a Spanish settler in the early 16th century. Finally, we found a set of genetic variants in a cluster of chemokines that modifies the onset of Alzheimer's in this family and possibly in the general Alzheimer's population as well.

In the second part of this thesis, I used induced pluripotent stem cells from individuals with Williams syndrome (WS) to identify disease-relevant pathways, a first step in connecting gene deletions to complex neurological traits. Arising from a hemizygous microdeletion of ~30 genes on chromosome 7, WS offers one of the best platforms to dissect the contributions of specific genes to neurocognitive phenotypes. Among various symptoms of the syndrome including specific craniofacial abnormalities and a characteristic heart valve defect, hyper-social behavior and enhanced language despite intellectual impairment are unique to WS. Converting induced pluripotent stem cells to neurons effectively allows us to study the brains of these individuals and identify which of the deleted genes may contribute to the neurological hallmarks. Integrating high-throughput transcriptional profiling with chromatin-immunoprecipitation of a gene deleted in WS, we identify a critical developmental node dysregulated in WS and the WS-deleted gene contributing to this defect.