Genes vs. Environment: What Makes Us Sick?

Our genes make us more susceptible to environmental factors such as smoking or infectious pathogens, increasing the risk of developing a wide variety of conditions, says Dr. Artūras Petronis, a pioneer of epigenetic studies of psychiatric diseases.

Petronis is the head of the Krembil Family Epigenetics Laboratory at Canada's Centre for Addiction and Mental Health (CAMH). He is also a professor in the psychiatry and pharmacology departments at the University of Toronto. Petronis was the first in the world to launch a comprehensive program of psychiatric epigenetics in 2000.

Epigenetics is the science of how our behaviors and environment can cause changes that affect our gene expression. The term 'epigenetics' is increasingly used when talking about longevity — researchers are now investigating whether reversing our epigenetic age can result in longer and disease-free lives.

However, Petronis says there is still a lot of unknown about manipulating the epigenetic clock, and changes caused by reversing it could be similar to those inflicted by accelerated aging.

Explaining diseases with epigenetics

Petronis says a human cell contains about three billion nucleotides, which must be regulated. Regulators of these genes or DNA sequences are called epigenetic factors.

A mutation in a functionally important part of the genome and DNA sequences causes a disease. There are hundreds of thousands of monogenic conditions where a mutation in one gene unambiguously causes the disease.

Dr. Artūras Petronis

"The situation is more difficult in complex diseases, which are dominating and probably account for about 97% of human pathology. In these cases, genes do not decide if we get sick; they increase or change the predisposition to develop a disease. These regulatory mechanisms are probably even more important than changes in DNA sequences," he told Healthnews.

Epigenetic mechanisms explain many features of complex diseases. One classic example is discordance, when identical twins have the same predisposition to a disease, but only one develops it.

Petronis says, "Their genomes are identical, and they spend most of their lives in similar environments; therefore, it is really hard to identify environmental factors that can cause the disease in one of the twins. Meanwhile, epigenetic factors can react to the environment, but different processes occur. And these epigenetic differences may be the reason for discordance."

The environment is not always to blame

Petronis says that unambiguously proving that environmental factors cause a certain disease is possible but not easy, and there are very few such conditions.

The relationship between smoking and lung cancer is well established, but smoking may not be an isolated environmental factor. Many people try smoking, but only some develop an addiction to it. And that depends on our biology, such as susceptibility to addiction or how nicotine affects us.

"This is where environmental factors and endogenously determined processes deciding to which environmental factors we react to start to intertwine," he says.

Stressful life events are considered to be another environmental factor. However, several twin studies showed that people have a specific genetic predisposition to end up in these stressful situations.

High-conflict personalities with certain innate personality traits find themselves in these situations not because there is a lot of stress around them but because they create such microclimate around themselves. Formally, we could consider it to be stress that comes from the environment, but it is rooted in their personality.

- Dr. Artūras Petronis

There are well-established environmental factors that increase the risk for several conditions, such as physical inactivity. However, the role of the environment in diseases such as schizophrenia, Parkinson’s, or type 1 diabetes is less clear.

"Studies showed that almost all diseases, even infectious, have the heritability element because we react to pathogens and viruses slightly differently. Some are not susceptible at all, while others are very sensitive. Our genes determine it," Petronis told Healthnews.

As schizophrenia's heritability is about 70%, what could one with a family history of the disease do to reduce the risk of developing the condition? Nothing much, Petronis says.

"According to some theories, the use of marijuana can increase the risk or provoke psychosis. Therefore, it should be avoided. But its effect is not very significant — it's just one of the factors we better understand," he adds.

Important questions unanswered

Petronis and his team are looking for an answer to why most diseases develop later in life. If there is some genetic predisposition that increases the risk of the disease, what's been happening in the cells for decades that they managed not to get sick?

"During this time, genomes haven't changed — we still have what we've inherited from our parents. But epigenetic regulators are changing, so maybe they are a primary reason why the disease occurs long decades after we are born." Petronis says.

Schizophrenia usually starts around the age of 20 and may lead to three decades of severe episodes and multiple hospitalizations. The disease severity decreases when the patients are in their 50s or 60s. At this age, one in four people with Schizophrenia is considered recovered.

"At a certain age, cells can no longer cope with the disease. But if they were 15 or 50 years old, they would probably manage to do it. So, maybe we can rejuvenate or age them." he says.

Manipulating epigenetic clocks

Petronis says that aging, in large part, is an epigenetic process, as epigenomes of old cells significantly differ from young ones. In some diseases, epigenetic aging is accelerated and is a few years older than the chronological age.

"If aging is accelerated in a disease, we can chronologically explain that it is a process of the disease, that it is exhausting cells and genomes react to it," he says.

However, slowed-down epigenetic aging may also be a sign of a disease and mean that changes are similarly bad as caused by accelerated aging.

Should we aim to reverse the epigenetic clock? Petronis says it could be a good idea if we knew exactly what needs to be reversed and would be able to control all the processes.

He adds, "There is always a risk that we would put it too much forward, that we would reverse only a part of the cell’s epigenome, and the result would be an intermediate variant."


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