Genetics vs. Lifestyle: The Complex Relationship in Chronic Diseases
Sitting in my doctor’s examination room, I was surprised when she told me, "Genetics don’t really matter for chronic disease." Rather, she continued, "A person’s lifestyle, what they eat, and how much they exercise, determine whether they get heart disease."
As a researcher who studies the genetics of disease, I don’t fully disagree – lifestyle factors play a large role in determining who gets a disease and who doesn’t. But they are far from the entire story. Since scientists mapped out the human genome in 2003, researchers have learned that genetics also play a large role in a person’s disease risk.
Studies that focus on estimating disease heritability – that is, how much genetic differences explain differences in disease risk – usually attribute a substantial fraction of disease variation to genetics.
Mutations across the entire genome seem to play a role in diseases such as type 2 diabetes and schizophrenia. In contrast to diseases such as Tay-Sachs or cystic fibrosis, where mutations in a single gene cause a disease, chronic diseases tend to be polygenic, meaning they’re influenced by multiple mutations at many genes across the whole genome.
Every complex disease has both genetic and environmental risk factors. Most researchers study these factors separately because of technical challenges and a lack of large, uniform datasets. Although some have devised techniques to overcome these challenges, they haven’t yet been applied to a comprehensive set of diseases and environmental exposures.
In our recently published research, my colleague Alkes Price and I developed tools to leverage newly available datasets to quantify the joint effects that genetic and environmental risk factors have on the biology underlying disease.
Aspirin, genetics, and colon cancer
To illustrate the effect gene-environment interactions have on disease, let’s consider the example of aspirin use and colon cancer.
In 2001, researchers at the Fred Hutchinson Cancer Research Center were studying how regularly taking aspirin decreased the risk of colon cancer. They wondered whether genetic mutations that slowed down how quickly the body broke down aspirin – meaning aspirin levels in the body would stay high longer – might increase the drug’s protective effect against colon cancer.
They were right: Only patients with slow aspirin metabolism had a decreased risk of colon cancer, indicating that the effectiveness of a drug can depend on a person’s genetics.
This raises the question of how genetics and different combinations of environmental exposures, such as the medications a patient is taking, can affect a person’s disease risk and how effective a treatment will be for them. How many cases of genetic variations directly influencing a drug’s effectiveness are there?
The gene-environment interaction of colon cancer and aspirin is unusual. It involves a mutation at a single location in the genome that has a big effect on colon cancer risk. The past 25 years of human genetics have shown researchers that these sorts of large-effect mutations are rare.
For example, an analysis found that the median effect of a genetic variant on height is only 0.14 millimeters. Instead, there are usually hundreds of variations that each have small but cumulative effects on a person’s disease risk, making them hard to find.
How could researchers detect these small gene-environment interactions across hundreds of spots in the genome?
Polygenic gene-environment interactions
We started by looking for cases where genetic variants across the genome showed different effects on a person’s biology in different environments. Rather than trying to detect the small effects of each genetic variant one at a time, we aggregated data across the entire genome to turn these small individual effects into a large, genome-wide effect.
Using data from the UK Biobank – a large database containing genetic and health data from about 500,000 people – we estimated the influence of millions of genetic variants on 33 complex traits and diseases, such as height and asthma.
We grouped people based on environmental exposures such as air pollution, cigarette smoking, and dietary patterns. Finally, we developed statistical tests to study how the effects of genetics on disease risk and biomarker levels varied with these exposures.
We found three types of gene-environment interactions.
First, we found 19 pairs of complex traits and environmental exposures that are influenced by genetic variants across the genome. For example, the effect of genetics on white blood cell levels in the body differed between smokers and nonsmokers.
When we compared the effects of genetic mutations between the two groups, the strength of gene-environment interaction suggested that smoking changes the way genetics influence white blood cell counts.
Second, we looked for cases where the heritability of a trait varies depending on the environment. In other words, rather than some genetic variants having different effects in different environments, all of them are made stronger in some environments.
For example, we found that the heritability of body mass index – the ratio of weight to height – increased by 5% for the most active people. This means genetics plays a larger role in BMI the more active you are.
In conclusion, the relationship between genetics and lifestyle in chronic diseases is complex and multifaceted. While lifestyle factors play a significant role in disease risk, genetics also contribute substantially to an individual’s susceptibility to certain diseases. Understanding the interplay between genetics and environmental factors is crucial for developing personalized and effective treatments for complex diseases. New research has identified 28 trait-environment pairs that shed light on the intricate interplay between genetic factors and environmental influences on various health outcomes. These pairs include associations like HDL cholesterol levels and alcohol consumption, as well as neuroticism and self-reported sleeplessness.
Furthermore, the study delved into a type of gene-environment interaction known as proportional or joint amplification. This type of interaction involves genetic effects that escalate with increased environmental exposures, and vice versa. As an example, the study found that as self-reported time spent watching television increased, both genetic and environmental variance also increased for a person’s waist-to-hip ratio. This suggests a link between sedentary behavior and physical health outcomes.
In addition to this, the research uncovered 15 trait-environment pairs, such as lung capacity and smoking, and glucose levels and alcohol consumption. These findings highlight the complex relationships between genetic predispositions and environmental factors in shaping health outcomes.
Moreover, the study explored the influence of biological sex on gene-environment interactions, revealing that genetic effects can vary across sexes. This underscores the importance of considering sex-specific factors when studying the interplay between genetics and the environment.
The research also found instances where multiple types of gene-environment interactions can impact the same trait. For instance, genetic effects on systolic blood pressure were found to vary by sex, indicating sex-specific differences in how genetic variants influence health outcomes.
The study’s findings provide valuable insights into how different types of gene-environment interactions can elucidate the underlying biological mechanisms that contribute to disease risk. By understanding how genetic variation and environmental exposures intersect to influence health outcomes, researchers can develop more personalized treatments based on an individual’s genetic profile.
In the future, these findings could pave the way for tailored interventions that take into account an individual’s genetic makeup and environmental exposures. This personalized approach to healthcare could revolutionize disease prevention and treatment strategies, ultimately improving health outcomes for individuals.
Overall, the study highlights the importance of studying gene-environment interactions to gain a deeper understanding of disease risk factors and how they manifest in the body. By unraveling the complexities of genetic and environmental influences on health, researchers can pave the way for more targeted and effective healthcare interventions.
Arun Durvasula, Assistant Professor of Population and Public Health Sciences, University of Southern California
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