# Functional Dissection of the MARK3 GWAS Locus for Bone Mineral Density

> **NIH NIH R56** · JOHNS HOPKINS UNIVERSITY · 2020 · $549,166

## Abstract

SUMMARY/ABSTRACT
Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture (ref). 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 identified by 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
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 three 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 Specific Aim 3: Test function of the regulatory SNP(s) in vivo. This project
was conceived and will be jointly headed by Thomas Clemens at Johns Hopkins University and Charles Farber
at the University of Virginia under the auspices of a Multi PI 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.

## Key facts

- **NIH application ID:** 10255877
- **Project number:** 1R56AR076707-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Thomas L Clemens
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $549,166
- **Award type:** 1
- **Project period:** 2020-09-22 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10255877

## Citation

> US National Institutes of Health, RePORTER application 10255877, Functional Dissection of the MARK3 GWAS Locus for Bone Mineral Density (1R56AR076707-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10255877. Licensed CC0.

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