Human Genetic risk factors for Disseminated Coccidioidomycosis (DCM)

Scientific Project 3: Human Genetic Risk Factors for Disseminated Coccidioidomycosis (DCM)
ABSTRACT
This project will focus on elucidating human host genetic risk variants that predispose individuals to DCM. For
the past 80 years, epidemiological studies have demonstrated that certain specific racial and ethnic groups were
more likely to progress towards severe disseminated Coccidioidomycosis, While many of these observations
have held up over, the underlying mechanistic and genetic pathogenesis underlying these epidemiological
observation have not been fully evaluated. There have been several major barriers to these types of genomic
studies where the relationship between host-genetic background and environment (here infection): 1) small-
sample sizes for most studies; 2) challenge of handling terabytes of genomic data; 3) limited sequencing data for
non-european populations;and 4) identifying relevant functional readouts to confirm the effect of variants in
relevant model systems. In this U19 proposal, project 3 brings together over 600 existing exome and genome
sequencing datasets and proposes to collect and sequence over 500 additional cases and controls. This will be
the largest genetic study of coccidioidomycosis to date. Key to this data analysis is the experts in this proposal
whose expertise enables us to handle Terabytes of data and to analyze it using ancestry-specific approaches.
We will explore two major hypotheses: that common variants that make up ancestry-specific approaches underly
race and ethnicity specific differences in DCM or that rare genetic variants in key immune signaling pathways
increase risk of DCM. Both hypotheses are not necessarily mutually exclusive and may explain some of
the disease associations that have been observed. In addition to identifying the DNA variants, we will perform
ATAC-seq, RNA-sequencing studies to functionally validate non-coding and splicing changes caused by non-
coding genetic variants. A key aspect of this project is its ability to rapidly integrate with projects 1 and 2 and
Core C in order to validate novel genetic variants and their effects on immune pathways. It will allow us to directly
bridge the gap between identified genetic variants and clinical function.

Grant Number: 5U19AI166059-04
NIH Institute/Center: NIH
Principal Investigator: Valerie Arboleda