Genes Identified that are Associated with Risk of Fracture

In the study outlined below, genes were identified that are associated with increased risk of fracture.  Importantly, six genes NOT known to have a role in bone biology were found to correlate with bone mineral density.  This speaks to the importance of looking for diseases related genes within AND outside of known pathways.  See abstract below.

AM

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

• Karol Estrada,
• Unnur Styrkarsdottir,
• Evangelos Evangelou,
• Yi-Hsiang Hsu,
• Emma L Duncan,
• Evangelia E Ntzani,
• Ling Oei,
• Omar M E Albagha,
• Najaf Amin,
• John P Kemp,
• Daniel L Koller,
• Guo Li,
• Ching-Ti Liu,
• Ryan L Minster,
• Alireza Moayyeri,
• Liesbeth Vandenput,
• Dana Willner,
• Su-Mei Xiao,
• Laura M Yerges-Armstrong,
• Hou-Feng Zheng,
• Nerea Alonso,
• Joel Eriksson,
• Candace M Kammerer,
• Stephen K Kaptoge,
• Paul J Leo
• et al.

Nature Genetics

 

44,

 

491–501

 

(2012)

Received

 

07 October 2011 

Accepted

 

16 March 2012 

Published online

 

15 April 2012

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10⁻⁸). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10⁻⁴, Bonferroni corrected), of which six reached P < 5 × 10⁻⁸, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.