Functional Dissection of the MARK3 GWAS Locus for Bone Mineral Density

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Principal Investigator: Thomas L Clemens
Organization: BALTIMORE VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs

The prevalence of osteoporosis among men is still under-recognized. The patient population of the Veterans
Health Administration (VHA) is predominantly male and many Veterans may be at risk of osteoporosis. Bone
mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Large-scale genome wide
association studies (GWAS) have identified dozens of genetic loci harboring variants (SNPs) robustly associated
with BMD. These loci constitute a treasure trove of untapped information on novel skeletal regulatory genes and
the heritable genomic elements that control their function. However, despite their potential to inform bone biology,
the precise causal variants and target genes have not been definitively identified for even a single locus. Using
a strategy newly developed to map genes implicated by BMD GWAS onto a bone co-expression network, we
predicted causal genes for 30 of 64 GWAS loci. One locus located on chromosome 14q32.32 contained SNPs
highly associated with femoral neck BMD (P=5.0 x 10-16) and we predicted that the Microtubule Affinity-
Regulating Kinase 3 (MARK3), one of five genes in the locus, was causal. MARK3 encodes a conserved
serine/threonine kinase known to regulate diverse processes including asymmetric cell division, and neuronal
differentiation, but its potential role in bone was unknown. Provisional assessment of mice deficient in Mark3
either globally or conditionally (osteoblast) revealed closely similar skeletal phenotypes.
Based on these exciting findings, we developed a comprehensive approach to identify the precise causal
variant(s) linked to MARK3 and determine how the activity of this kinase in osteoblasts controls bone mass. The
studies are divided into two aims: Specific Aim 1: Define the causal genetic mechanism underlying the
Chr14q32.32 BMD GWAS locus. Specific Aim 2: Determine how Mark3 functions in bone. This project was
conceived and will be jointly headed by Thomas Clemens (BLR&D Senior VA Research Career Scientist affiliated
with Johns Hopkins University) and Charles Farber at the University of Virginia under the auspices of a
collaboration arrangement. The synergy of their complimentary research programs has already been established
in previous projects. We strongly believe that the approach will define the biological networks impacted by
mutation will contribute substantially to the understanding of their pathology and provide important targets for
intervention.

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