Using GWAS to identify novel therapeutic targets for osteoporosis

Abstract

Osteoporosis is a common, increasingly prevalent, global health burden characterized by low bone mineral density (BMD) and increased risk of fracture. Despite its significant impact on human health, there is currently a lack of highly effective treatments free of side effects for osteoporosis. Therefore, a major goal in the field is to identify new drug targets. Genetic discovery has been shown to be effective in the unbiased identification of novel drug targets and genome-wide association studies (GWASs) have begun to provide insight into genetic basis of osteoporosis. Over the last decade, GWASs have led to the identification of ~100 loci associated with BMD and other bone traits related to risk of fracture. However, there have been limited efforts to identify the causal genes underlying the GWAS loci or the mechanisms by which GWAS loci alter bone physiology. In this review, we summarize the current state of the field and discuss strategies for causal gene discovery and the evidence that the novel genes underlying GWAS loci are likely to be a new source of drug targets.

Identification of a core module for bone mineral density through the integration of a co-expression network and GWAS data

“…Although osteoporosis is a multifactorial disease influenced by both environmental and genetic variation, fracture-related traits, such as BMD, are influenced, in large part, by genetics (h 2 >0.5) 3–5 . Over the last decade large-scale genome wide association studies (GWASs) have begun to dissect the genetics basis of bone traits with a primary focus on BMD 6, 7 . These studies have been tremendously successful, identifying over 1100 independent BMD associations 8–10 .…”

“…These studies have been tremendously successful, identifying over 1100 independent BMD associations 8–10 . However, despite the wealth of genetic signals, the genes and mechanisms through which these associations impact bone remain largely unknown 6, 7 .…”

Integration of summary data from GWAS and eQTL studies identified novel causal BMD genes with functional predictions

“…In China, the prevalence rate of osteoporosis in older adults was estimated to be 15.7%, and it will increase rapidly with the increasing age of the total population [6]. Despite the significant impact on human health, there is still a lack of highly effective osteoporosis treatments that are free of negative side effects [7]. Hence, identification of additional therapeutic molecular targets for effective and efficient prevention and treatment of osteoporosis are needed.…”

“…Co-expression networks are modular, and each module represents a group of co-expressed genes. These modules tend to contain genes involved in similar biological processes [7]. Hence, under WGCNA, we explored the functional relevance of the identified novel genes to other known putative osteoporosis genes in order to explore the potential functional mechanisms of the identified novel genes.…”

Assessing the Associations of Blood Metabolites With Osteoporosis: A Mendelian Randomization Study

“…BMD has a strong heritable component, with an estimated heritability of 50% to 85% (5)(6)(7)(8). In recent years, genome-wide association studies identified .100 genetic loci associated with BMD (9,10). For instance, Estrada et al (11) identified 56 BMD-associated loci through a large scale genome-wide meta-analysis.…”