In Nature study, OHSU scientists help uncover effects of rare genetic variants on bone

Sept. 15, 2015

How does a complex disease known to run in families maintain the secrets of its genetic control? 

For years, investigators studying osteoporosis have seen common genetic variations with small effects fail to adequately explain complex trait heritability. Those investigators are now turning to whole-genome sequencing in large population samples to find rare variants with large effects. 

In a study published in Nature on Sept. 14, 2015, OHSU researchers Carrie Nielson, MPH, Ph.D., assistant professor of epidemiology, OHSU-PSU School of Public Health, and Beth Wilmot, Ph.D., staff scientist, Oregon Clinical and Translational Research Institute, and Eric Orwoll, M.D., professor of medicine, OHSU School of Medicine, and colleagues report on a previously unrecognized “bone” gene, EN1, with a big impact on bone density. 

The paper is titled, “Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.”

The discovery was made possible by thousands of individuals’ whole-genome sequences in the UK10K and 1000 Genomes studies.

These data, combined with genome-wide genotyping and well phenotyped cohort studies, came together in an “amazing worldwide collaboration of osteoporosis researchers," said Dr. Orwoll.

Key U.S .studies included the Osteoporotic Fractures in Men (MrOS) and Study of Osteoporotic Fractures (SOF), long-running cohorts that include older men and women from the Portland area and beyond. 

“Now that it is possible to perform whole-genome sequencing on thousands of individuals, we can rapidly advance the discovery of these uncommon variants and explore opportunities for personalized prevention and treatment of osteoporosis,” explained Dr. Nielson.

Dr. Nielson is the recipient of a career-development award (K01) from NIAMS with a focus on genetic epidemiology of osteoporosis. She was a co-investigator of the ARRA grant that supported genome-wide genotyping of the MrOS and SOF cohorts.

Dr. Wilmot is a statistical geneticist at OHSU where she plays a key role in interdisciplinary collaborations within the Oregon Clinical and Translational Research Institute (OCTRI) and the OHSU Knight Cancer Institute. Her primary interest is the study of the etiology of common complex traits including complex disease.

Dr. Orwoll, principal investigator of the MrOS study, is an internationally-recognized expert in the area of bone biology and metabolic bone disease, and has considerable experience in basic, clinical, and epidemiological research. His major areas of research interest include the epidemiology, etiology and therapy of osteoporosis in men, the evaluation of new diagnostics and therapeutics, effects of sex steroids on skeletal biology, and skeletal genetics.