In the Davis Lab, we are interested in understanding the genomics of a wide range of phenotypes.  Many of these phenotypes are represented in the Vanderbilt University Biobank (BioVU) which consists of DNA and de-identified electronic medical record (EMR) data on over 215,000 individuals (and growing). Several of our projects take advantage of this resource for discovery.

In addition to our research in collaboration with the many talented trainees and faculty here at Vanderbilt, we work with investigators across the globe to tackle research questions. For most complex traits, genetic risk is distributed throughout the genome and therefore each individual single nucleotide polymorphism (SNP) explains a very small proportion of the heritability estimated from twin and family studies. In recent years it has become increasingly obvious that understanding the genetics of polygenic phenotypes requires very large sample sizes, far greater than any one investigator could amass in her lifetime. Therefore, investigators from all over the world are connecting and working together to form consortia with the goal increasing sample size and facilitating discovery. Dr. Davis and lab members are honored to play integral roles in many such consortia including:

Psychiatric Genomics Consortium (PGC)
International OCD Foundation Genomics Consortium (IOCDFGC)
Tourette Syndrome Association International Consortium for Genetics (TSAICG)
Polycystic Ovarian Syndrome Consortium (PCOS Consortium)
International Gender Diversity Genomics Consortium (IGDGC)

Here are a few of the projects we are currently working on!

Sex-specific analysis of Obsessive Compulsive Disorder: In humans, many traits exhibit differences in onset, prevalence, prognosis, and clinical features between sexes, including neuropsychiatric disorders such as bipolar disorder, schizophrenia, Tourette syndrome, autism spectrum disorders, and OCD. We are interested in determining the sex-specific genetic architecture of these phenotypes to understand how we can best explain the differences in presentation between males and females. Postdoc Katya Khramtsova is leading these analyses beginning with OCD.

Polycystic Ovarian Syndrome is the most common endocrine disorder in women of reproductive age. It encompasses a broad spectrum of signs and symptoms including menstrual cycle disturbances, decreased fertility, hyperandrogenism, and polycystic morphology of the ovaries (PCOM). Moreover, it is associated with insulin resistance, obesity, and dyslipidemia. Familial clustering of PCOS and its associated symptoms is well established, and its heritability is estimated to be about 65%, but little is known about the genetic architecture — the underlying genetic basis — of PCOS. The PCOS consortium is collecting large samples of cases and controls for the purpose of conducting meta-analysis to identify contributory genetic variation. The Davis lab, in collaboration with Dr. Melissa Wellons in the Division of Diabetes, Endocrinology, and Metabolism and Dr. Digna Velez-Edwards in the Division of Obstetrics and Gynecology, is working with the PCOS consortium to gain insight into the complex etiology of PCOS.

Investigating the heritability of pharmacogene expression: In this project, we aim to utilize expression data from the Genotype-Tissue Expression (GTEx) Consortium to understand how genes that play a role in response to pharmacological treatment are regulated across tissues. Postdoc Sabrina Mitchell is working on this project in collaboration with the Davis Lab and the Altman Lab in Stanford University. 

Inverse axis of risk for polygenic and rare variant burdens: Research has shown that both polygenic risk and risk from rare but highly penetrant variants contribute to many complex traits. If an individual may develop a particular phenotype by crossing either a polygenic risk liability threshold or a rare variant liability threshold, we would expect to detect an inverse correlation between these two orthogonal sources of genetic risk among cases. Our studies involving simulated and real data from multiple complex phenotypes, including Tourette Syndrome (TS), obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), and type 1 diabetes (T1D) have shown that, indeed, both sources of genomic risk are critically important, may be inversely related, and should be considered jointly.

Genomics of gender diversity: Gender Dysphoria (GD) is a diagnostic term describing a persistent marked difference between expressed/experienced gender identity and sex identified at birth, causing clinically significant distress or impairment. It is widely believed that the interaction of complex biological and environmental factors contributes to the gender dissonance at the core of the GD diagnosis. Evidence from twin and family studies, presentation in early childhood, presence of documented GD in human populations from diverse cultures across the world, and the presence of highly comorbid phenotypes, such as polycystic ovarian syndrome (PCOS) and autism spectrum disorders (ASD), all strongly support a biological contribution to GD. Despite these observations, very little research has focused on the biological contribution to GD. This knowledge gap results in significant stigmatization for people with GD and their families, leading to great logistic, legal, and social obstacles to obtaining desired gender affirming medical treatment. The International Gender Dysphoria Genomics Consortium (IGDGC) was established to respond to this need. The IGDGC brings world-renowned experts in the endocrinology, psychology, and epidemiology of GD from Europe and the United States together with leaders in the field of complex trait genomics to conduct the first systematic, robust, and comprehensive assessment of the genetic contribution to GD. Understanding the genetic contribution to GD will be paradigm shifting and stands to significantly reduce the often unattainable burden of “authentication” that individuals with GD currently face before being able to receive gender affirming, and in many cases, lifesaving treatment.

Identifying and characterizing genetic factors of high-risk phenotypes associated with ancestry: This project examines the risk factors contributing to health disparities in disease and outcomes by systematically identifying phenotypes with marked differences in lifetime risk across ancestral backgrounds. We are using BioVU to identify phenotypes for which prevalence, outcomes, and response to treatments vary by ancestry after controlling for environmental risk factors. The goal of this analysis is to discover health risks that may disproportionately affect minority populations so we can improved personalized medicine in all populations.

Systematic assessment of signatures of selection across brain-related phenotypes: Inter-individual variation in neuropsychiatric traits is present across diverse human populations, has persisted through recorded history, and has been shown to have a genetic basis primarily accounted for by common (minor allele frequency > 5%) SNPs. Many of the characteristics of psychiatric disorders, including their early age of onset, moderate to high prevalence (1% for schizophrenia – 20% for major depression), reduced fecundity (Power et al., 2013), and high heritability (Polderman et al., 2015) have led researchers to question how risk alleles have persisted throughout evolutionary history (Huxley et al., 1964; Jablensky et al., 1992; Bigdeli et al., 2013). While several potential mechanisms for maintaining high allele frequency of risk variants have been hypothesized (e.g., weak positive selection, balancing selection), few have been empirically tested (Pearlson and Folley, 2008; Keller and Miller, 2006). Together with the Capra Lab we are investigating the influence of numerous selective pressures across different epochs in shaping the landscape of brain-related genetic variation.

Psychiatric genetics in the context of the medical phenome: The large-scale collection of DNA combined with expansive phenotype information from electronic medical records provides a broader context (i.e., “the phenome”) in which to study the genetics of neuropsychiatric phenotypes.  The Davis lab is working with faculty and trainees at Vanderbilt and across the country to develop gold standard phenotyping algorithms for a number of neuropsychiatric and developmental diagnoses including OCD, Tourette Syndrome, anorexia nervosa and autism spectrum disorders. Additionally, we are implementing polygenic approaches to identify potential novel biomarkers from our collection of > 500 routinely-collected clinically-validated lab tests. Identifying correlated phenotypes and laboratory measurements, and assessing the broader role of implicated variants/genes are only a few of the many ways in which these studies could provide a unique lens through which to interpret genetic findings.