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The environment on complex diseases: schizophrenia

An introductory and comprehensive review of complex diseases and their environmental influences. Using Schizophrenia as an example, we are interested in exploring one of the biggest questions that underlie complex diseases.

Introduction: Not Exactly a Yes or No Question

 

Many things in science revolve around questions. It is remarkable to find the number of questions left for scientists to answer or those that will remain unanswered. Indeed, one of the most daunting tasks for any scientist would be to see through every detail of a piece of information, even if everyone has seen it, but with different sets of lenses and asking different sets of questions. After all, “why did the apple fall from its tree?”. However, asking questions is one thing. Finding answers and, more importantly, the evidence or proof that supports them does not always yield conclusive results. Nevertheless, perhaps some findings may shine a new light on a previously unanswered question.

 

We can categorise the study of genetics into two questions: “What happens if everything goes well?” and “What happens if it goes wrong?”. Whilst there are virtually limitless potential causes of any genetic disease, most genetic diseases are known to be heritable. A mutation in one gene that causes a disease can be inherited from the parents to their offspring. Often, genetic diseases are associated with a fault in one gene, known as a single-gene disorder, with notorious names including Huntington’s disease, cystic fibrosis, sickle cell anaemia, and familial hypercholesterolaemia. These diseases have different mechanisms, and the causes are also diverse. But all these diseases have one thing in common: they are all caused by a mutation or fault in one gene, and inheriting any specific genes may lead to disease development. In other words, “either you have it, or you do not”.

The role of DNA and mutations in complex diseases. Image/ craiyon.com

 

Multifactorial or complex diseases are a classification geneticists give to diseases caused by factors, faults or mutations in more than one gene. In other words, a polygenic disease. As a result, the research, diagnosis, and identification of complex diseases may not always produce a clear “black-and-white” conclusion. Furthermore, complex diseases make up most non-infectious diseases known. The diseases associated with leading causes of mortality are, in their respective ways, complex. Household names include heart diseases, Alzheimer’s and dementia, cancer, diabetes, and stroke. All of these diseases may employ many mechanisms of action, involving multiple risk factors instead of direct cause and effect, using environmental and genetic interactions or factors to their advantage, and in contrast to single-gene disorders, do not always follow clear or specific patterns of inheritance and always involve more than one problematic genes before the complete symptoms manifest. For these reasons, complex diseases are infamously more common and even more challenging to study and treat than many other non-infectious diseases. No longer the easy “yes or no” question.

The Complex Disease Conundrum: Schizophrenia

 

Here we look at the case of a particularly infamous and, arguably, notorious complex disease, schizophrenia (SCZ). SCZ is a severely debilitating and chronic neurodevelopmental disorder that affects around 1% of the world’s population. Like many other complex diseases, SCZ is highly polygenic. The NHS characterise SCZ as a “disease that tends to run in families, but no single gene is known to be directly responsible…having these genes does not necessarily mean one will develop SCZ”. As previously mentioned, many intricate factors are at play behind complex diseases. In contrast, there is neither a single known cause for SCZ nor a cure. Additionally, despite its discovery a century ago, SCZ is arguably not well understood, giving a clue to the sophisticated mechanisms that underlie SCZ. To further illustrate how such complexities may pose a challenge to future medical treatments, we shall consider a conundrum that diseases like SCZ may impose.

 

The highly elaborate nature of complex diseases means that it is impossible to predict disease outcomes or inheritance with absolute certainty nor rule out potential specific causes of diseases. One of the most crucial aspects of research on complex diseases is their genetic architecture, just as a house is arguably only as good as its blueprint. Therefore, a fundamental understanding of the genes behind diseases can lead to a better knowledge of diseases’ pathogenesis, epidemiology, and potential drug target, and hopefully, one day bridge our current healthcare with predictive and personalised medicine. 

 

However, as mentioned by the NHS, one of the intricacies behind SCZ is that possessing variants of diseased genes does not translate to certainty in disease development or symptom manifestation. Our conundrum, and perhaps the biggest question on complex diseases like SCZ is: “Why, even when an individual possesses characteristic genes of a complex disease, they may not necessarily exhibit symptoms or have the disease?”. The enigma surrounding complex diseases lies in the elegant interactions between our genes, the blueprint of life, and “everything else”. Understanding the interplay of factors behind complex diseases may finally explain many of the intricacies behind diseases like SCZ.

Genes and Environment: An Obvious Interaction?

 

The gene-environment important implications on complex disease development were demonstrated using twin studies. A twin study, as its name suggests, is the study of twins by their similarities, differences, and many other traits that twins may exhibit to provide clues to the influences of genetic and external factors. Monozygotic (MZ) twins each share the same genome and, therefore, are genetically identical. Therefore, if one twin shows a phenotype, the other twin would theoretically also have said genes and should exhibit the corresponding trait. Experimentally, we calculate the concordance rate, which means the probability of both twins expressing a phenotype or characteristic, given that one twin has said characteristic. Furthermore, the heritability score may be mathematically approximated using MZ concordance and the concordance between dizygotic twins (twins that share around half a genome). These studies are and have been particularly useful in demonstrating the exact implications genetic factors have on phenotypes and how the expression of traits may have been influenced by confounding factors. 

 

In the case of SCZ, scientists have seen, over decades, a relatively low concordance rate but high heritability score. A recent study (published in 2018) through the Danish SCZ research cohort involved the analysis of around 31,500 twins born between the years 1951 and 2000, where researchers reported a concordance rate of 33% and estimated heritability score of 79%, with other older studies reporting a concordance rate up to and around 50%. The percentages suggest that SCZ is likely to be passed down. In other words, a genetically identical twin only has approximately 1 in 2 risks of also developing symptoms of SCZ if its opposite twin also displays SCZ. The scientists concluded that although genetic predisposition significantly affects one’s susceptibility or vulnerability against SCZ, it is not the single cause of SCZ. 

 

Demographically, there have been studies that directly link environmental risks to SCZ. Some risk factors, such as famines and malnutrition, are more evident than others. However, some studies also associate higher SCZ risk among highly industrialised countries and first or second-generation migrants. For instance, few studies point out an increased risk of SCZ within ethnic minorities and Afro-Caribbean immigrants in the United Kingdom. Hypotheses that may explain such data include stress during migration, potential maternal malnutrition, and even exposure to diseases. With this example, hopefully, we all may appreciate how the aetiology of SCZ and other complex diseases are confounded by environmental factors. In addition, how such factors may profoundly influence an individual’s genome.

 

SCZ is a clear example of how genetic predisposition, the presence of essential gene variants characteristic of a disease, may act as a blueprint to a terrible disease waiting to be “built” by certain factors as if they promote such development. It is remarkable how genetic elements and their interactions with many other factors may contribute almost collectively to disease pathogenesis. We can reflect this to a famous quote amongst clinical geneticists: “genetics loads the gun, and environment pulls the trigger.” Carrying high-risk genes may increase the susceptibility to a complex disease, and an environment that promotes such disease may tip the balance in favour of the disease. However, finding and understanding the “blueprints” of SCZ, what executes this “blueprint”, and how it works is still an area of ongoing research. Furthermore, how the interplay between genetics and external factors can lead to profound effects like disease outcomes is still a relatively new subject.


 

The Epigenome: The Environment’s Playground

 

To review, it is clear that genes are crucial in complex disease aetiology. In the case of SCZ, high-risk genes and variances are highly attributed to disease onset and pathogenesis. However, we also see with twin studies that genetics alone cannot explain the high degree of differences between twins, particularly when referring to SCZ concordance between identical twins. In other words, external factors are at play, influencing one’s susceptibility and predisposition to SCZ. These differences can be explained by the effects epigenetics have on our genome.

 

Epigenetic mechanisms regulate gene expression by modifying the genome. In short, on top of the DNA double strands, the genome consists of additional proteins, factors, and even chemical compounds that all aid the genetic functions our body heavily relies on. The key to epigenetics lies in these external factors’ ability to regulate gene expression, where some factors may promote gene expression whilst others may prevent it. Epigenetic changes alter gene functions as they can turn gene expression “on” and “off”. Furthermore, many researchers have also shown how epigenetic changes may accumulate and be inherited somatically with cell division and even passed down through generations. Therefore, epigenetic changes may occur without the need to change any of the DNA codes, yet, they may cause a profound effect by controlling gene expression throughout many levels of the living system. 

 

These underlying mechanisms are crucial for the environment’s effect on complex diseases. Some external factors may directly cause variances or even damage to the genome (e.g. UV, ionising radiation), and other sources may indirectly change gene expression by manipulating epigenetic changes. The exact molecular genetics behind epigenetic mechanisms are elaborate. However, we can generally find three common epigenetic mechanisms: DNA Methylation, Histone Modification, and Non-coding RNA. Although each method works differently, they achieve a common goal of promoting or silencing gene expression. All of these are done by the many molecular components of epigenetics, altering the genome without editing the gene sequence. We refer to the epigenome, which translates to “above the genome”, the genome itself and all the epigenetic modifiers that regulates gene expression on many levels. 

 

Environmental factors and exposure may influence epigenetic mechanisms, affecting gene expression in the cell or throughout the body, sometimes permanently. Therefore, it is clear how the epigenome may change throughout life as different individuals are exposed to numerous environmental factors. Furthermore, each individual may also have a unique epigenome. Depending on which tissues or cells are affected by these mechanisms, tissues or cells may even have a distinct epigenome, unlike the genome, which is theoretically identical in all cells.

 

One example of this is the potential effects of DNA methylation on schizophrenia epidemiology. DNA methylation can silence genes via the enzymes DNA methyltransferases (DNMT),  a family of enzymes capable of catalysing the addition of methyl groups directly into the DNA. The DNMT enzymes may methylate specific nucleotides on the gene, which usually would silence said gene. Many researchers have found that the dysregulation of DNA methylation may increase the risk towards the aetiology of numerous early onset neuro-developmental disorders. However, SCZ later-onset development also points towards the influence of environmental risk factors that target DNA methylation mechanisms. Studies show links between famines and SCZ increased prevalence, as the DNMT enzymes heavily rely on nutrients to supply essential amino acids. Malnutrition is thought to play a considerable role in DNA methylation changes and, therefore, the risk of SCZ.

Small Piece of a Changing Puzzle

 

Hopefully, we can see a bigger picture of the highly intricate foundation beneath complex diseases. Bear in mind that SCZ is only one of many complex diseases known. SCZ is ultimately not a pristine and impartial model to study complex disorders. For instance, concordance rates of complex diseases change depending on their genetic background. In addition, they may involve different mutations, variance, or dysregulation of differing pathways and epigenetic mechanisms. After all, complex diseases are complex. 

 

Finally, this article aimed to give a rundown of the epigenetics behind complex diseases like SCZ. However, it is only a snapshot compared to the larger world of the epigenome. Furthermore, some questions remain unanswered: the genetic background and architecture of complex diseases, and ways to study, diagnose, and treat complex diseases. This Scientia article is one of the articles in Scientia on the theme of complex disease science and genetics. Hopefully, this introductory article is an insight and can be used to reflect upon, especially when tackling more complicated subjects of complex diseases and precision medicine.

Written by Stephanus Steven 

Related articles: Schizophrenia, Inflammation, and Accelerated Ageing / An Introduction to Epigenetics / How Epigenetic Modifications Gave the Queen Bee Her Crown

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