Research Profile - Shifting the paradigm

Epigenetics is helping explain why one identical twin can develop a heritable disorder while the other doesn't.

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Inflammatory bowel disease (IBD) and schizophrenia are very different conditions that require distinctive therapies. It follows, then, that very different researchers usually study them.

As complex non-Mendelian diseases, IBD and brain disorders have much in common, says Dr. Arturas Petronis, Senior Scientist and Head of the Krembil Family Epigenetics Laboratory at the Centre for Addiction and Mental Health (CAMH).

Discoveries made by studying the gut could lead to a better understanding of the key elements of epigenetic misregulation involved in the origins of other complex diseases, including psychiatric ones, says Dr. Petronis – which explains why a mental health expert is dedicating three years to an epigenomic exploration of Crohn's disease, a major IBD condition.

"I can investigate schizophrenia by looking at post-mortem brain tissues. By using the same strategies and logic, I can investigate IBD by looking at gut biopsies," says Dr. Petronis, who is also Tapscott Chair and a Professor at the University of Toronto. "Of course, I don't expect that the [genes] that are epigenetically misregulated are the same in schizophrenia and IBD. But the principles that govern these complex disorders are similar."

There are two major categories of heritable disease: simple Mendelian disorders (such as cystic fibrosis, Huntington's disease, Duchenne muscular dystrophy, and sickle cell anemia) and complex non-Mendelian disorders (such as cancer, diabetes, asthma, multiple sclerosis, schizophrenia and other psychiatric conditions, and IBD).

The simple Mendelian disorders – named after Gregor Mendel, who founded the field of genetics nearly 150 years ago – all fit within a DNA-based framework: a faulty gene sequence is passed down from parents to children and any offspring with the mutation will get the disorder. For example, if identical twins inherit the DNA variation associated with Huntington's disease both will eventually get it.

In complex non-Mendelian disorders, however, there can be an inherited predisposition – a child may get a disease borne by a parent or a grandparent – but there is more at play than just DNA sequencing. For example, one identical twin may develop IBD while the other, with the identical genome, may not. The phenomenon is called twin discordance.

Another common feature of complex diseases is that they tend to wax and wane. "For example, in IBD there are periods when affected individuals feel quite good and don't have any symptoms. But six months later, they may be very sick again," says Dr. Petronis. "Gut diseases allow for unique experimental designs such as testing affected tissues from the same individual during remission and relapse, which would not be possible in brain studies."

As well, IBD may ravage one part of a bowel and leave another section untouched. From a purely genetics-based perspective, that shouldn't happen, he says. "We have the same DNA in all regions of the gut, exactly the same genome. Yet some patches are affected and others are not. Shifting the focus from DNA sequence variation to epigenetic misregulation may go a long way to explain all these unclear phenomena in complex diseases."

Environmental factors can also be involved, of course. But our understanding of environmental impacts – beyond the knowledge that smoking increases the risk of lung cancer, asbestos exposure can trigger mesothelioma and a rich diet and lack of exercise predispose a person to obesity and type 2 diabetes – is still quite limited. According to Dr. Petronis, environmental factors often leave vestiges on our epigenomes, and therefore by studying epigenetics we can learn more about environmental hazards.

"With epigenetics, we can come up with a cohesive theory for the hereditary predisposition to complex diseases, the discordance of identical twins and why males and females display differences in terms of susceptibility to various diseases – such as why boys are more prone to autism and women are more likely to get lupus."

The work, he cautions, is in the very early stages. "Our goal – and the goal of the entire epigenetic research enterprise – is to focus on the identification on the primary epigenetic causes of disease that will lead to new diagnostics and new treatment strategies. But it's something of a needle in a haystack. We have to identify the epigenetic misregulation in this entire huge universe called the epigenome."

"Genetics and environment can explain some – but not all – aspects of complex disease. Epigenetics comes as an interesting alternative interpretation to traditional genetic and environmental studies.
-- Dr. Petronis