Novel genetic regulators of body fat distribution in humans, HCK, ITPRIPL2, and ZMIZ2 uncovered using network modeling approaches Reed, JN, Civelek, M University of Virginia, Center for Public Health Genomics Body fat distribution (BFD) is a complex trait that describes the non-uniform storage of fat in various adipose tissue depots. Excess fat storage in the abdominal region is a well-established risk factor for Type II Diabetes (T2D) and contributes to higher rates of hospitalization and death. The comparative storage between abdominal and gluteofemoral depots is approximated in large studies by the waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a metric that is independent of overall adiposity and is a more significant disease risk indicator than BMI. While genome-wide association studies (GWAS) have uncovered novel loci and genes associated with WHRadjBMI, a majority of these genes are understudied, and the link between gene expression and fat storage remains largely unknown. Our objective was to identify novel genes that regulate BFD using systems biology approaches. We modeled gene-gene interactions on a large scale by creating directed networks from a curated gene set of ~7,000 putative BFD-related genes. We used adipose tissue gene expression data from 3 independent cohorts ranging from n = 434 to n = 663 males and females to create 3 independent networks. Because of the unique structure of these networks, we could mathematically calculate genes whose expression regulates the expression of many others in the network. We then chose genes whose expression was highly correlated with WHRadjBMI and whose expression regulated BFD genes identified in GWAS in the network. We determined HCK, ITPRIPL2, and ZMIZ2 regulate genes identified in BFD GWAS in 2 out of 3 independent network models. HCK, ITPRIPL2, and ZMIZ2 may play an important role in the differential fat storage in adipose tissue that contributes to overall BFD. In future studies, we will manipulate the expression of these genes in adipocytes using a modified CRISPR system to study their role in adipocyte function and fat storage.