Genes for fracture susceptibility and osteoporosis risk discovered

Osteoporosis is a common, silent and devastating age-related disease. 25% of Australian women with osteoporosis who sustain a hip fracture die within 12 months, with a greater mortality risk of women older than 65 than from breast cancer. In comparison to women, the mortality rate amongst men with hip fractures is even higher. Even though scientists are aware of the consequences of osteoporosis, their knowledge about the causes of the disease is still elusive. Scientists have known for years that osteoporosis has a strong genetic link. However, the genes responsible for the disease have still remained largely unknown until now. The leading genetic journal Nature Genetics reports that researchers from the Diamantina Institute at The University of Queensland have now discovered over double the number of genes involved in osteoporosis compared with those that were already known. This is the first time that such a large number of genetic variants (56) has been discovered to influence Bone Mineral Density (BMD) in individuals linked to the risk of fracture. The UQDI researchers and their team also discovered that fourteen of these variants increased the risk of fracture. BMD is measured by Dual Energy X-Ray absorptiometry (DXA), the most frequently used measure for diagnosing osteoporosis and to evaluate the risk of fracture. In general, a high BMD translates to a lower risk of fracture. In the largest genetic study of osteoporosis to date to assess BMD, UQDI researchers Associate Professor Emma Duncan and Professor Matt Brown led a consortium of researchers from Australia, Europe, North America and East Asia, evaluating more than 50 independent studies that involved over 80,000 individuals with DXA scans. They examined over 30,000 incidents with fracture and 100,000 controls without fracture. Professor Duncan states: "The Australian Osteoporosis Genetics Consortium played a key role in this recent paper. Our own study, involving bone researchers from Australia, New Zealand and the United Kingdom, and supported by the National Health and Medical Research Council of Australia, was particularly important because of our unique approach of recruiting individuals with more extreme bone density. This meant that although we contributed a modest number of individuals to this current study, their impact was disproportionately powerful; and as a consequence the Australian contribution was the most powerful individual component of the entire project overall." Dr. Dana Willner was responsible for identifying critical molecular pathways that are now candidates for therapeutic applications. Leading senior study author, Dr Fernando Rivadeneira, an Assistant Professor at the Erasmus Medical Centre in Rotterdam, declared: "Such potential is highlighted by the identification (among others) of genes encoding proteins that are currently subject to novel bone medications. Yet, even more interesting is the identification of several factors that can constitute targets for true bone-building drugs." This study paves the way to better understand the biology of skeletal health and fracture susceptibility. First author Karol Estrada, a scientific researcher at Erasmus MC declared: "In addition to the known proteins and pathways we have identified we are also confronted with completely new biology. There is, for example, very little known about the genomic region on chromosome 18 where we discovered the strongest genetic factor associated with fracture risk. Just less than a month ago the factor underlying the genetic signal was recognized as a gene, now known as FAM210A." Dr Douglas Kiel, a Professor of Medicine at Harvard Medical School and the Institute for Aging Research at Hebrew SeniorLife in Boston, MA in the USA and a senior author who co-lead the study, added: "We also established that, as compared to women carrying the normal range of genetic factors, women with an excess of BMD-decreasing genetic variants had up to 56 per cent higher risk of having osteoporosis and 60 per cent increased risk for all-types of fractures. Even more interesting is our discovery of groups of individuals with a smaller number of variants which protected them against developing osteoporosis or sustaining fractures." According to André Uitterlinden, Professor of Complex Genetics at Erasmus MC, the new approach in terms of associated genomes means that researchers can continue to discover hundreds of common variants, which cause the risk of osteoporosis and fracture. Uitterlinden says: "Nevertheless, we will need new technologies and approaches to understand more." Professor Matthew Brown, who supports Uitterlinden's view, states: "Researchers at UQDI have been doing exactly this, by performing a sequencing project in 1,000 individuals from our Australian Osteoporosis Genetics Consortium." He concludes, saying: "This further study, also supported by the NHMRC, will help us to understand the genetic underpinnings of this complex disease that is osteoporosis."