I am a molecular and statistical geneticist specializing in rare variant/common disease associations and the high-throughput functional characterization of rare variants in associated (or interesting) genes.

I began my work in human genetics as an undergraduate in the laboratory of Carole Ober, Phd at the University of Chicago. Training with Emma Thompson, PhD, then a postdoc in the lab, I sequenced a group of olfactory receptor (OR) genes linked to the MHC (HLA) region shown by the Ober lab to be associated with mate preference among Hutterite individuals, the hypothesis being that HLA region variability is a good proxy for relatedness and sexual selection might act on smell preference to reduce the likelihood of related individuals producing offspring. We sequenced the linked OR genes as we hypothesized that linked variation in the OR genes might be the mechanism by which HLA haplotypes were associated with smell preference. We found no evidence of OR haplotypes were associated with smell preference, however, leaving the mechanism of HLA smell preference an open question.

During the summer of 2005, I worked in the laboratory of Dale Dorsett, PhD. Using multiple lines of Nipped-B mutant Drosophila Melanogaster, I bred and isolated mutant larvae, sequenced their Nipped-B gene and correlated apparent phenotype with sequenced genotype.

Returning to the Ober lab for the remained of my time as an undergraduate at the University of Chicago, I undertook the sequencing of the Interleukin-4 (IL4) gene in a cohort of African Americans with asthma. We observed a striking increase in the frequency of private and rare variants within the non-coding region in and around the IL4 locus. This was my first experience with rare variant associations. In the article, we used Tajima’s D, traditionally used to detect areas of the genome with strong negative selection or balancing selection, to measure the relative amount of rare variation in the locus and used a permutation test to compare values in asthmatic cases and controls.

I next moved to Washington University in St. louis for graduate school. In 2009, I joined the laboratory of Alison Goate, DPhil, now at Mount Sinai Hospital in New York City. My work included next-generation pooled sequencing of neuronally expressed nicotinic acetylcholine receptor genes (CHRNs) in a large cohort of nicotine dependent cases and controls and a large cohort of alcohol dependence cases and controls. In each case, we observed specific CHRN genes (CHRNB4 for nicotine dependance and CHRNA6/CHRNB3 for alcohol dependence/cocaine dependence), rare variants in which predicted dependence on the specific substance. Further, in collaboration with Joe Henry Steinbach at Washington University, I measured the functional effects of all rare non-synonymous variants observed in our nicotine dependence cohort and correlated the results with risk. We were able to show that variants that increased response to low levels of nicotine decreased risk of nicotine dependence, suggesting a possible mechanism by which the observed rare variants in CHRNB4 were leading to decreased nicotine dependence risk.

Moving to the laboratory of Christina Gurnett, MD, PhD and Matthew Dobbs, MD in the Department of Orthopaedic Surgery at Washington University in St. Louis, I began investigating the role of rare variant on risk for adolescent idiopathic scoliosis (AIS). Using whole-exome sequencing we have identified a class of extracellular matrix genes that appear to greatly influence AIS risk. The genes include FBN1 and FBN2 and a group of collagen genes, highly damaging mutations in which cause a spectrum of dominant Mendelian musculoskeletal diseases (Ehlers-Danlos syndrome, Osteogenesis Imperfecta, Stickler syndrome, etc). We have been able to show that novel, never before seen variation within this subset of collagen genes confer >2-fold increase risk of AIS and that variants in COL11A2 in particular, a rare cause of Stickler syndrome, confer >3-fold increase risk of AIS. These findings underscore the impact of less damaging variants in Mendelian disease genes on subclinical phentoypes.

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