September 28, 2015

Bone Risks Linked to Genetic Variants

At a Glance

  • A large-scale genomic study uncovered novel genetic variants and led researchers to an unexpected gene that affects bone density and fracture risk.
  • The results provide insights into the genetics underlying osteoporosis and may lead to new ways to prevent bone loss and fractures.
X-ray style illustration of a skeleton. The researchers examined data from more than half a million people to uncover genetic variants associated with bone fractures. Eraxion/iStock/Thinkstock

Over 10 million people nationwide have osteoporosis, in which bones become susceptible to fracture. Osteoporosis tends to run in families, and genetics is known to play an important role in bone mineral density, a major risk factor for fractures. Scientists have already identified many genetic factors associated with bone mineral density. But these factors likely represent just a small fraction of the underlying genetic variance.

Past efforts to link genetic variants with traits and diseases have largely uncovered common variants with relatively small effects. Recent studies have found less common non-coding variants with larger effects.

An international team of researchers led by Dr. Brent Richards at McGill University set out to examine the role of rare genetic variants in bone mineral density and fracture risk. The scientists used data from the UK10K Project—a massive, whole‐genome sequence‐based resource of the general European population; the NIH-funded 1000 Genomes Project, one of the world’s earliest efforts to sequence the genomes of a large number of people; and data from several other studies.

The team first performed whole‐genome sequencing of more than 2,800 people from the UK10K Project. They also sequenced the exomes (protein-coding regions) of more than 3,500 people. In a sophisticated analysis, the scientists compared these data with those from previous studies involving tens of thousands of other people. They then analyzed associations between the genetic variants and bone mineral density measurements taken in more than 53,000 people. Finally, they looked at data from more than 508,000 people to determine the relationship of the variants to actual bone fractures. Results appeared online on September 14, 2015, in Nature.

The team identified variants in a region near the engrailed homeobox‐1 gene (EN1) that were associated with bone mineral density in the lumbar area of the spine. One variant was also associated with bone mineral density in the thigh bone at the hip (the “neck” of the femur). Both are common sites of osteoporotic fractures. The effect of these variations, the researchers found, is greater than that of any previously reported genetic variants related to bone density.

Using a mouse model, the team genetically altered En1 levels and confirmed that it plays an important role in bone physiology. Loss of En1 results in low bone mass, probably due to high bone turnover.

EN1 has never before been linked to osteoporosis in humans, so this opens up a brand new pathway to pursue in developing drugs to block the disease,” Richards says.

The researchers also found several other variants associated with bone mineral density in specific areas, including 3 for forearm, 14 for femoral neck, and 19 for lumbar spine. These discoveries indicate that more comprehensive sequencing of diverse populations can lead to the discovery of rare variants influencing common diseases.

“Our findings enhance understanding of the genetics underlying the development of osteoporosis. A variant in a region of the genome that is not coding for a protein can have a relatively large effect on a gene regulating bone health,” says Dr. Douglas Kiel, whose NIH-funded team at Hebrew SeniorLife and Harvard Medical School played a key role in the effort. “Ideally, genomic research will one day lead to more personalized interventions (precision medicine) that, in this case, will reduce bone loss and prevent fractures in older adults.”

—by Harrison Wein, Ph.D.

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Reference:  Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, Kleinman A, Styrkarsdottir U, Liu CT, Uggla C, Evans DS, Nielson CM, Walter K, Pettersson-Kymmer U, McCarthy S, Eriksson J, Kwan T, Jhamai M, Trajanoska K, Memari Y, Min J, Huang J, Danecek P, Wilmot B, Li R, Chou WC, Mokry LE, Moayyeri A, Claussnitzer M, Cheng CH, Cheung W, Medina-Gómez C, Ge B, Chen SH, Choi K, Oei L, Fraser J, Kraaij R, Hibbs MA, Gregson CL, Paquette D, Hofman A, Wibom C, Tranah GJ, Marshall M, Gardiner BB, Cremin K, Auer P, Hsu L, Ring S, Tung JY, Thorleifsson G, Enneman AW, van Schoor NM, de Groot LC, van der Velde N, Melin B, Kemp JP, Christiansen C, Sayers A, Zhou Y, Calderari S, van Rooij J, Carlson C, Peters U, Berlivet S, Dostie J, Uitterlinden AG, Williams SR, Farber C, Grinberg D, LaCroix AZ, Haessler J, Chasman DI, Giulianini F, Rose LM, Ridker PM, Eisman JA, Nguyen TV, Center JR, Nogues X, Garcia-Giralt N, Launer LL, Gudnason V, Mellström D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren Ö, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussière J, Arp PP, Koromani F, Prince RL, Lewis JR, Langdahl BL, Pernille Hermann A, Jensen JB, Kaptoge S, Khaw KT, Reeve J, Formosa MM, Xuereb-Anastasi A, Åkesson K, McGuigan FE, Garg G, Olmos JM, Zarrabeitia MT, Riancho JA, Ralston SH, Alonso N, Jiang X, Goltzman D, Pastinen T, Grundberg E, Gauguier D, Orwoll ES, Karasik D, Davey-Smith G; AOGC Consortium, Smith AV, Siggeirsdottir K, Harris TB, Carola Zillikens M, van Meurs JB, Thorsteinsdottir U, Maurano MT, Timpson NJ, Soranzo N, Durbin R, Wilson SG, Ntzani EE, Brown MA, Stefansson K, Hinds DA, Spector T, Adrienne Cupples L, Ohlsson C, Greenwood CM; UK10K Consortium, Jackson RD, Rowe DW, Loomis CA, Evans DM, Ackert-Bicknell CL, Joyner AL, Duncan EL, Kiel DP, Rivadeneira F, Richards JB. Nature. 2015 Sep 14. doi: 10.1038/nature14878. [Epub ahead of print]. PMID: 26367794.

Funding: NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Aging (NIA), National Center for Advancing Translational Sciences (NCATS), National Cancer Institute (NCI), and National Human Genome Research Institute (NHGRI); and many other funding entities (see reference paper for the full list).