Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

New Genetic Regions Linked to Bone-Weakening Disease and Fractures, Researcher Says

Published: Friday, April 20, 2012
Last Updated: Friday, April 20, 2012
Bookmark and Share
Thirty-two previously unidentified genetic regions associated with osteoporosis and fracture have been identified by a large, worldwide consortium of researchers, including Stanford Prevention Research Center chief John Ioannidis, MD, DSc.

Variations in the DNA sequences in these regions confer either risk or protection from the bone-weakening disease. Many, but not all, of the regions encode proteins involved in pathways known to involve bone health.

The research shows that osteoporosis results from the combined contributions of dozens, if not hundreds, of genes. It also suggests many new avenues for anti-osteoporosis drug development.

“We’re learning that the genetic architecture of disease is very complex,” said Ioannidis, who is one of seven senior authors of the study and the methodological leader of the consortium. The research was published online April 15 in Nature Genetics.

The unprecedented prospective meta-analysis — which involved 17 genome-wide association studies, 180 researchers and more than 100,000 participants — also identified six regions strongly correlated with the risk of fractures of the femur or lower back. However, the predictive power of the study for individuals is relatively low: Those with multiple risk-increasing variants are only about three to four times more likely than those with the fewest variants to have lower bone mineral density and experience fractures.

“As a result,” said Ioannidis, “the next step of incorporating this information into basic patient care is not clear. Each variant conveys a small quantum of risk or benefit. We can’t predict exactly who will or won’t get a fracture.”

Although factors such as body weight, build and gender are currently much more predictive of osteoporosis than any of the genetic variants identified in the study, the research identified many pathways involved in bone health. The biological relevance of the findings was confirmed by the fact that some of the pathways are already targeted by current anti-osteoporosis drugs. Other, previously unsuspected pathways will help researchers understand more about the disease and how to develop drugs to fight it.

The research belies recent frustration with the ability of genome-wide association studies, or GWAS, to live up to their early hype. When first introduced in 2005, many researchers predicted that GWAS — a way of quickly scanning whole genomes for minute differences associated with disease occurrence — would quickly identify critical mutations for many conditions. This optimistic assessment proved to be largely unfounded for complex conditions such as osteoporosis, type-2 diabetes and obesity, which likely involve the combined effects of many genes and environmental components.

This study suggests that the number of participants in most GWAS may need to be vastly expanded to render useful data.

“The real power of our study lies in the ability to generate prospectively a huge combined data set and analyze it as a single study,” said Ioannidis, who is the the C.F. Rehnborg Professor in Disease Prevention at Stanford. “It’s likely that our expectations have been too high in terms of what single studies can accomplish. Each one of the many teams identified at most only one or two markers; many found none.”

Instead, increasingly larger studies will be needed to identify genes important in disease. “In reality, there may be 500 or more gene variants regulating osteoporosis,” said Ioannidis. “To find all of them, we’ll need to study millions of patients. Is this unrealistic? I don’t think so. Sooner or later this will be feasible.”

With a few exceptions, people have all the same genes in their DNA as everyone else; it’s one of the things that makes us human. But the way those genes are spelled in each person’s DNA can vary — much like how some words are spelled differently in the United States and Britain (think “organization” and “organization”). Our genomes are riddled with such differences, which sometimes affect the gene’s function. Studies like this one correlate certain genetic spellings, or variants, with specific outcomes, such as low bone mineral density and fractures. Any one person can have several or none of the variants identified by the study.

The current study grew gradually out of a decade of research conducted by Ioannidis and a few colleagues. At the time, a few teams across the world were attempting to correlate variations in individual genes with the development of osteoporosis. “We were doing small studies here and there on popular genes,” said Ioannidis, “and then we thought we should collaborate with other researchers to do a meta-analysis. That marked the beginning of the first consortium.”

However, despite the researchers’ enthusiasm, they were hampered by the lack of whole-genome information and had instead to focus on specific genetic clusters they suspected might be involved in osteoporosis. That changed with the advent of the first GWAS. “The technology kept getting better, and we began to recruit more people,” said Ioannidis.

For the current study, teams around the world combined data from 17 genome-wide association studies focused on bone mineral density on nearly 33,000 participants in North America, Europe, east Asia and Australia. Combining the study results allowed the researchers to identify even weak associations that would have been missed in any one study.

 Together, the teams identified 87 regions of the genome for further study. They then analyzed these regions in an additional 34 studies of bone mineral density with a total of nearly 51,000 participants. This validation step narrowed the field to 56 associated regions — 32 of which had not been previously associated.

Finally, the teams checked to see if there was an association between those variants that affect bone mineral density and the actual prevalence of fractures. To do so, they compared the sequences, or spelling, of those regions among 31,000 people who had experienced fractures of the spine or femur, with that of more than 100,000 people who had not had a fracture. They found six variants that were significantly associated with fracture risk.

People with the highest number of variants associated with decreased bone mineral density were about 1.56 times more likely than people with an average number of variants to have osteoporosis, and those with the most of those variants associated with fracture risk were about 1.60 times more likely to have experienced fractures. Compared with those who had the fewest associated variants, they were about four times more likely to have either osteoporosis or a fracture.

When the researchers looked more closely at the regions identified by their analyses, they found many genes that had been previously implicated in bone formation and bone health: members of the Wnt signaling pathway that is important in many types of development, several involved in a pathway important to the differentiation of mesenchymal cells that become bone, and others involved in endochondrial ossification during the formation of the mammalian skeleton.

“We saw many of these regions and genes clustering within specific types of pathways, which suggests certain disease mechanisms,” said Ioannidis. “It certainly wouldn’t be unexpected to eventually identify many more genetic regions involved in the regulation of osteoporosis and fracture risk.”

A full list of the funding institutions and co-authors of the work is available in the Nature Genetics paper.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Thursday, November 26, 2015
Ancient Viral Molecules Essential for Human Development
Genetic material from ancient viral infections is critical to human development, according to researchers at the Stanford University School of Medicine.
Wednesday, November 25, 2015
Combination Drug Therapy Shrinks Pancreatic Tumors In Mice
Two drugs that affect the structure and function of DNA have been found to block the growth of pancreatic tumor cells in mice, researchers hope the drugs can soon be tested in humans with the disease.
Thursday, September 24, 2015
Key Mechanism in Gene Expression Discovered
RNA polymerase II makes life possible by expressing genes. Now, a team of Stanford biologists, chemists and applied physicists has observed it at work in real time.
Thursday, September 17, 2015
Scientists Home In On Origin Of Human, Chimpanzee Facial Differences
A study of species-specific regulation of gene expression in chimps and humans has identified regions important in human facial development and variation.
Monday, September 14, 2015
Identifying Defective Heart Genes
A new technique could eventually enable doctors to diagnose genetic heart diseases by rapidly scanning more than 85 genes known to cause cardiac anomalies.
Thursday, August 13, 2015
DNA Damage Seen in Patients Undergoing CT Scanning
Along with the burgeoning use of advanced medical imaging tests over the past decade have come rising public health concerns about possible links between low-dose radiation and cancer.
Monday, July 27, 2015
Genetic Signature Enables Early, Accurate Sepsis Diagnosis
Systemic inflammation after injuries or surgery can dramatically alter the activity of thousands of genes, but a new study shows that changes in just 11 of them are enough to detect the presence or absence of accompanying infection.
Monday, May 18, 2015
Existing Drug May Treat Deadliest Childhood Brain Tumor
For the first time, scientists have identified an existing drug that slows the growth of the deadliest childhood brain tumor.
Friday, May 08, 2015
Foreign Antibodies Mobilize Immune System to Fight Cancer
A mouse’s T cells can be primed to attack and eliminate a malignant tumor by injecting antibodies from another mouse with resistance to the tumor, as well as by activating certain signaling cells, a study has found.
Thursday, May 07, 2015
Tiny Fish Makes Big Splash In Aging Research At Stanford
Researchers disabled aging-associated genes in the short-lived African killifish, including one for an enzyme called telomerase, whose absence caused humanlike disease in the animal.
Friday, February 13, 2015
Tumor Suppressor Also Inhibits Key Property Of Stem Cells
The retinoblastoma protein inhibits cancer by controlling cell division. Now, researchers have shown that it also binds to and inhibits genes necessary for pluripotency.
Friday, November 14, 2014
Scientists Discern Signatures of Old Versus Young Stem Cells
A chemical code scrawled on histones determines which genes in that cell are turned on and which are turned off.
Wednesday, July 03, 2013
Protein Complex May Play Role in Preventing Many Forms of Cancer, Study Shows
Researchers at the Stanford University School of Medicine have identified a group of proteins that are mutated in about one-fifth of all human cancers.
Tuesday, May 07, 2013
Antibody Hinders Growth of Gleevec-Resistant Gastrointestinal Tumors in Lab Test
An antibody that binds to a molecule on the surface of a rare but deadly tumor of the gastrointestinal tract inhibits the growth of the cancer cells in mice.
Thursday, February 07, 2013
Scientific News
New Tech Vastly Improves CRISPR/Cas9 Accuracy
A new CRISPR/Cas9 technology developed by scientists at UMass Medical School is precise enough to surgically edit DNA at nearly any genomic location, while avoiding potentially harmful off-target changes typically seen in standard CRISPR gene editing techniques.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Biologists Induce Flatworms to Grow Heads and Brains of Other Species
Findings shed light on role of a new kind of epigenetic signaling in evolution, could yield clues for understanding birth defects and regeneration.
Turning up the Tap on Microbes Leads to Better Protein Patenting
Mining millions of proteins could become faster and easier with a new technique that may also transform the enzyme-catalyst industry, according to University of California, Davis, researchers.
Mathematical Model Forecasts the Path of Breast Cancer
Chances of survival depend on which organs breast cancer tumors colonize first.
Exploring the Causes of Cancer
Queen's research to understand the regulation of a cell surface protein involved in cancer.
Ancient Viral Molecules Essential for Human Development
Genetic material from ancient viral infections is critical to human development, according to researchers at the Stanford University School of Medicine.
Tardigrade's Are DNA Master Thieves
Tardigrades, nearly microscopic animals that can survive the harshest of environments, including outer space, hold the record for the animal that has the most foreign DNA.
The Secret Behind the Power of Bacterial Sex
Migration between different communities of bacteria is the key to the type of gene transfer that can lead to the spread of traits such as antibiotic resistance, according to researchers at Oxford University.
Farming’s in Their DNA
Ancient genomes reveal natural selection in action.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos