In one of our recent posts, we addressed the types of genetic variability that exist in humans and why a greater understanding of these is critical in diagnostics, for predicting our response to new drugs, and in the development of personalized treatments. Here, we will look at how genetic variability can serve as a tool to expand our understanding of disease susceptibility and mechanisms, using schizophrenia as a case study.
Schizophrenia in Brief
According to the US National Institutes of Health (NIH), “Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves”. Among the broad spectrum of symptoms associated with schizophrenia are the so-called positive symptoms, which refer to psychotic behaviors not seen in healthy people (e.g., hallucinations and delusions), negative symptoms, which are disruptions to a person’s normal emotions and behaviors, and cognitive symptoms that may occur on a continuum from subtle to severe.
Schizophrenia usually strikes between the mid-teens and the third decade of life, although it has also been known to debut in children. According to the World Health Organization (WHO), a staggering 21 million people suffer from schizophrenia worldwide, of which 12 million are males and 9 million are females, and the disease commonly appears earlier in men than women. Although the symptoms are treatable with medication and psychosocial support, more than half of sufferers do not access proper treatment, which can result in serious problems such as: hospitalization, strained relationships and social interactions, and difficulties in maintaining employment. Overall, individuals with schizophrenia are 2 to 2.5 times more likely to die earlier than members of the general population due to an increased risk of other illnesses e.g., cardiovascular, metabolic and infectious diseases.
Although it is widely accepted that interactions between genes and a host of environmental factors contribute to the onset of schizophrenia, extensive research efforts since the beginning of the 20th century have not yet revealed the cause of this devastating disease. While many genes are associated with an increased risk of developing schizophrenia, no single gene is believed to be the cause, and it is not yet possible to predict the disease by genetic testing. Some of the environmental factors implicated in schizophrenia in genetically susceptible individuals include maternal malnutrition during pregnancy, birth complications, exposure to certain viruses, and psychosocial factors.
Decades worth of family, twin and adoption studies have pointed to a strong genetic component in the risk of developing schizophrenia. However, until the emergence of advanced high throughput sequencing and genotyping technologies in the last decade, it has been extremely challenging to move from familial observations to identifying genes involved in the disease.
The explosion in DNA-based technologies has revealed that schizophrenia is not only a highly complex polygenic disease, but that it also shares considerable genetic overlap with other mental disorders, such as bipolar disorder and autism spectrum disorders, to name a few. This overlap may complicate the diagnosis of schizophrenia and related disorders, highlighting the need for new ways to distinguish these diseases from each other with high confidence.
Like many other diseases with a genetic component to their etiology, schizophrenia is known to run in families. To date, the greatest single risk factor is having a first-degree relative with the disease (about 1 in 15 chance). With one parent affected, an individual’s risk is approximately 1 in 7, while this increases to 1 in 2 if both parents have the disease. The inheritance of schizophrenia is far from straightforward because many individuals will develop the disorder without having any affected family members, while others with multiple affected family members will not develop schizophrenia themselves.
As alluded to above, twins are valuable research ‘tools’ in genetic studies because they allow us to investigate how environmental factors and genetic makeup influence susceptibility to given traits or disease. While non-identical or dizygotic twins share about half of their genes (like all non-twin siblings), monozygotic twins are almost 100 % genetically identical. The latter infers that the majority of differences that arise between a set of so-called identical twins e.g., height, personality, hobbies, are explained by environmental factors rather than genetics.
Besides sharing DNA, twins also share many environmental aspects during the gestational period and early childhood because they are born into the same family at the same time, and are therefore exposed to very similar environmental influences e.g., maternal nutrition, the uterine environment, antibodies in breast milk, parenting style, and family traditions. For these reasons, twin research is considered one of the key tools in fields ranging from basic biology to psychology.
The presence of a given genetic trait or disease in only one member of a pair of identical twins, known as discordance, provides an excellent opportunity for researchers to examine the role of environmental factors in traits or diseases that are also found in the broader population. Of all the traits and diseases investigated via twin studies to date, schizophrenia is probably the best-known example. The concordance rate (the risk of both members of a twin pair having a trait/disease) of schizophrenia in monozygotic twins is estimated at approximately 40-60 % worldwide, highlighting the critical role played by environmental factors in the onset of this disease.
Schizophrenia – Insights from Danish Twin Studies
In the largest study of its kind used in schizophrenia research to date, a group of researchers from the University of Copenhagen, Denmark, analyzed 31,524 sets of twins that were born in Denmark between 1951-2000 and followed up until June 2011. Results of the study published this month provide evidence that almost 80 % of the risk of developing schizophrenia is down to genetics (Hilker et al., 2018).
The study by Hilker et al. used advanced statistical approaches that make these author’s estimates likely to be the most accurate thus far. Firstly, their study differed to previous studies in that it accounted for the possibility that healthy individuals at risk of developing schizophrenia could develop the disease after the study was completed. Most previous studies had not taken this possibility into account, requiring that all study participants be classified as either having the disease or not. Furthermore, Hilker et al. estimated susceptibility to schizophrenia taking into account other related disorders (collectively referred to as schizophrenia spectrum disorder), and even with these considerations their estimate was 73%, highlighting once again the importance of genetic factors in the risk of developing schizophrenia.
Personalized Medicine: Will It Help Patients?
Some would argue that the current approach to treating schizophrenia is personalized, in the sense that treatments, their outcomes, and associated side effects vary considerably among patients. However, this take on personalized medicine is a far cry from the rapidly emerging genetic-driven immunotherapies that seem to dominate the personalized medicine space today. So, will modern day personalized approaches to therapy ever help schizophrenia patients?
Advances made in genetic-driven personalized treatments for cystic fibrosis and cancer give us a cause to be optimistic that similar approaches might one day become a reality for schizophrenia. Indeed, the genetic risk rate of 80 % predicted by Hilker et al., which is close to the highest estimates made in previous studies, supports ongoing efforts to identify genes and variants involved in the disease. However, as pointed out by many, difficulties in classifying schizophrenia and lack of a clearly defined etiology are likely to challenge and delay the development of personalized treatments for prevention or cure. Nevertheless, the ability to predict susceptibility to the disease before it manifests could greatly improve the prognosis for the many sufferers who don’t appropriate treatment, given that one of the reasons for lack of access to treatment is that people with schizophrenia are less likely to seek care than the general population, according to the WHO. So, while we can’t yet say whether or not personalized medicine will help schizophrenia patients in the future, we are not in doubt that efforts to understand the genetics of the disease are a critical step in the right direction!
Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, Nordentoft M, Glenthøj B. 2018. Heritability of schizophrenia and schizophrenia spectrum on the nationwide Danish Twin Register. Biol. Psychiatry. 83(6):492-498.
Kavanagh DH, Tansey KE, O’Donovan MC, Owen MJ. 2015. Schizophrenia genetics: emerging themes for a complex disorder. Mol. Psychiatry. 20(1):72-6.
Buckley PT, Miller, BJ. 2017. Editorial: Personalized medicine for schizophrenia. npj Schizophrenia 3, Article number: 2.
Article by Karen O’Hanlon Cohrt PhD. Contact Karen at firstname.lastname@example.org.
Karen O’Hanlon Cohrt is a Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen moved to Denmark and held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for writing helps her to keep abreast of exciting research developments as they unfold. Follow Karen on Twitter @KarenOHCohrt. Karen has been a science writer since 2014; you can find her other work on her portfolio.