Twenty years ago, after the human genome was first sequenced, geneticists began large-scale, genome-wide association studies to identify genomic regions associated with human disease. In addition to DNA sequence, another stable level of molecular information—epigenetic modifications established during development—can influence disease risk. For over a decade, scientists have studied these epigenetic modifications to test their relevance to disease. Today, more than 1,000 epigenome-wide association studies have been published.
Now, in a study published in the journal genome biologya team led by researchers at Baylor College of Medicine has revealed that the commercial tools that have been the mainstay of these studies are not really suitable for population epigenetics.
“Most people know that each person has a unique DNA sequence or genome. It’s about having a personality,” said the co-lead author. Dr. Robert A. Waterland,Professor Pediatrics – Nutrition at Baylors USDA/ARS Pediatric Nutrition Research Center.
The epigenome – meaning “above” the genome – is a system of molecular markings on DNA that tell different cells in the body which genes to turn on or off in that cell type. “Epigenetic differences between people can affect disease risk,” said Waterland, a member of the Dun L Duncan Comprehensive Cancer Center in Baylor.
To look for such differences, epigeneticists study DNA methylation that occurs at specific locations called CpG sites. A standard tool for population studies of DNA methylation is a commercially available array that assays hundreds of thousands of her CpG sites distributed throughout the genome.
for the past 15 years, waterland lab Focuses on a different set of CpG sites: DNA methylation varies significantly from person to person, but is consistent across different tissues in each person. They thought these sites would be most useful for population studies because DNA from blood samples could be used to investigate the epigenetic causes of disease in internal organs such as the brain and heart.
“Three years ago, we reported nearly 10,000 such regions in the human genome (named CoRSIV for their correlated regions of systemic inter-individual variability), suggesting that studying them could be the epigenetic cause of disease. I suggested that it could be a new way to reveal ,” said Waterland.
As a step towards this, the current study investigated how DNA methylation in CoRSIV is influenced by genetics. Correlations between genetic variants and methylation at specific CpG sites are termed methylation quantitative trait loci (mQTL). Over 200 of his studies of human mQTLs have been reported, almost all using commercially available methylation arrays.
The team developed a CoRSIV-targeted approach to study methylation in DNA samples from multiple tissues in about 200 individuals. When they compared their results to those of the largest previous study, “what we found was somewhat shocking,” says lead author Chathura J. Gunasekara, a data analyst at the Waterland Institute. says Dr. Our much smaller study focusing on CoRSIV, involving 33,000 people, found 72-fold higher mQTL. “
In an attempt to explain this surprising finding, the research team found that approximately 95% of the CpG sites on commercial methylation arrays showed no apparent differences in methylation between humans. Interpersonal variability, which scientists call variance, is the basis of statistical relevance. Without population variance, there is no chance of detecting an mQTL.
This finding should also have an impact on the field of epigenetic epidemiology. “Population variance is essential not only for mQTL detection, but also for detecting associations between DNA methylation and disease risk,” said the co-corresponding authors. Dr. Christian Koafa,Associate Professor molecular cell biology Dan L. Duncan Comprehensive Cancer Center and Precision Environmental Sanitation Center at Baylor. “We anticipate that focusing on CoRSIV will make epigenome-wide association studies about 70 times more powerful compared to what the field has done.”
In fact, CoRSIV has already been linked to a variety of health outcomes, including thyroid function, cognition, cleft palate, schizophrenia, childhood obesity, and autism spectrum disorders.
“There seems to have been this big, very expensive fishing expedition in the last decade, and everyone was fishing in the wrong places,” Waterland said. “We hope that the new tools we have developed will accelerate progress in understanding the epigenetic causality of disease.”
Other contributors to this work include Harry MacKay, C. Anthony Scott, Shaobo Li, Eleonora Laritsky, Maria S. Baker, Sandra L. Grimm, Goo Jun, Yumei Li, Rui Chen, and Joseph L. Wiemels. will be The authors are affiliated with Baylor College of Medicine, the University of Southern California or the University of Texas Health Science Center at Houston.
Funding for this project was provided by NIH/NIDDK (1R01DK111522), Texas Institute of Cancer Prevention (RP170295), USDA/ARS (CRIS 3092-5-001-059), NIH Shared Equipment Grant S10OD023469, Common Fund. I was. By the Office of the Director of the National Institutes of Health, and NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.