Researchers develop roadmap for gene expression

May 5, 2014

In a new study, researchers from The University of North Carolina at Chapel Hill, North Carolina State University and other national and international institutions have taken the first steps toward developing a roadmap that may help scientists narrow down the genetic cause of numerous diseases. Their work also sheds new light on ways heredity and environment can affect gene expression.

Co-authors from the UNC Gillings School of Global Public Health’s Department of Biostatistics include faculty members Fei Zou, PhD, professor, and Wei Sun, PhD, associate professor; Kai Xia, PhD, postdoctoral researcher in biostatistics at the time of the study and now assistant professor of psychiatry at UNC; Vered Madar, PhD, postdoctoral research associate; Wonil Chung, PhD, and Min Jin Ha, PhD, recent graduates; Guanhua Chen, Ting-Huei Chen and Zhaoyu Yin, doctoral students.

Image by Icahn School of Medicine, Mt. Sinai

Image by Icahn School of Medicine, Mt. Sinai

Patrick Sullivan, MD, Distinguished Professor of Genetics and Psychiatry in UNC’s School of Medicine and director of UNC’s Center for Psychiatric Genomics, and Fred Wright, PhD, formerly professor in the Gillings School’s Department of Biostatistics and now professor of statistics and biological sciences and director of the Bioinformatics Center at N.C. State University, are co-first authors of the study.

Pinpointing the genetic causes of common diseases is not easy, as multiple genes may be involved with a disease. Moreover, disease-causing variants in DNA often do not act directly, but by activating nearby genes. To add to the complexity, genetic activation is not like an electric light’s on/off switch, but rather behaves more like a “dimmer switch.” Some people may have a particular gene turned all the way up, while others have it turned halfway on, completely off, or somewhere in between. Factors such as DNA and the environment also play a role in the dimmer switch’s setting.

“Everyone has the same set of genes,” co-first author Wright noted. “It’s difficult to determine which genes are heritable, or controlled by your DNA, versus those that may be affected by the environment. Teasing out the difference between heredity and environment is key to narrowing the field when you’re looking for a genetic relationship to a particular disease.”

Wright, Sullivan and colleagues analyzed blood sample data from 2,752 adult twins (both identical and fraternal) from the Netherlands Twin Register and an additional 1,895 participants from the Netherlands Study of Depression and Anxiety. For all 20,000 individual genes, they determined whether those genes were heritable – controlled by the DNA “dimmer switch” – or largely affected by environment.

“Identical twins have identical DNA, so if a gene is heritable, its expression will be more similar in identical twins than in fraternal twins,” Wright said. “This process allowed us to create a database of heritable genes, which we could then compare with genes that have been implicated in disease risk. We saw that heritable genes are more likely to be associated with disease – something that can help other researchers determine which genes to focus on in future studies.”

The study was published online April 13 in Nature Genetics.  

“This is by far the largest twin study of gene expression ever published, enabling us to make a roadmap of genes versus environment,” said Sullivan, adding that the study measured relationships with disease more precisely than had been previously possible, and uncovered important connections to recent human evolution and genetic influence in disease.

The Netherlands Twin Register has followed twin pairs for over 25 years and, in collaboration with the longitudinal Netherlands Study of Depression and Anxiety, established a resource for genetic and expression studies.

“In addition to the fundamental insights into genetic regulation and disease, the results provide valuable information on causal pathways,” said Professor Dorret Boomsma, who started the twin register. “The study shows that the twin design remains a key tool for genetic discovery.”

Blood samples from the Netherlands were processed by the NIMH Center for Collaborative Genomics Research on Mental Disorders at Rutgers University. N.C. State research scholar Yi-Hui Zhou and associate professor of statistics Jung-Ying Tzeng contributed to the work. Funding for the study included grants from the National Institute of Mental Health and other NIH Institutes, the Gillings School of Global Public Health’s Gillings Innovation Lab, the Netherlands Organization for Scientific Research, the Center for Medical Systems Biology, Biobanking and Biomolecular Resources Research Infrastructure, and the European Science Foundation and European Research Council.


 
Gillings School of Global Public Health contact: David Pesci, director of communications, (919) 962-2600 or dpesci@unc.edu.