Curious about twin research

One twin is healthy, the other is ill – despite having the same genes. Identical DNA makes identical twins the perfect research subjects for studying how our genetic heritage and our environment affect us.

Twin girls in a field of sunflowers
Twin girls in a field of sunflowers. Photo: Svenska Tvillingregistret

Identical twins share the same DNA and have, in principal, the same set of genes. But they already start to differ while in the womb. When they are born, they are no longer identical – they do not, for example, have the same fingerprints. This is due to minute changes in the womb's environment and to other random events.

The fact that twins are of special scientific interest was highlighted as early as the 1870s by the British scientist Francis Galton. One of his theories was that intelligence was hereditary, an idea that was controversial at the time. He proposed to compare twins who had grown up in different environments as a method to study this. He was especially interested in twins who were very similar he compared them to the double yolks that can occur in a hen's egg.

Eventually, the genetic difference between identical twins, who share 100 per cent of their DNA, and fraternal twins, who only share 50 per cent, was discovered. This allowed twin research to enter a new phase if identical twins are more similar than fraternal twins, you could conclude that genetic heritage is of significance. The method is currently a standard model in epidemiological research, where results from twin studies are considered very reliable.

Includes almost 180,000 persons

At the start of the 1960s, the foundation was laid for the Swedish Twin Registry, which today is the most comprehensive twin register in the world. It includes almost 180,000 persons, born from 1886 onwards. The registry is administered by Karolinska Institutet and was originally founded to research whether or not smoking was dangerous – something that was not considered scientifically proven 50 years ago.

Since the registry was founded, tens of thousands of twins have completed comprehensive surveys concerning their lifestyles, undergone medical exams and been interviewed. There is a large number of collected biobank samples, including almost 15,000 blood samples and more than 30,000 saliva samples.

Nancy Pedersen. Photo: Jacob Forsell

"This is a veritable gold mine from a scientific perspective, and we get a great number of requests from both Swedish and foreign researchers who want to utilise our data," says Nancy Pedersen, Professor of Genetic Epidemiology at the Department of Medical Epidemiology and Biostatistics, and one of the researchers who uses the registry.

Today it is considered to be proven that genetics explains around 70 per cent of the differences that exist between individuals, as far as intelligence is concerned.

"In other words, genetics is fairly important, but you should remember that environmental factors are also important. After all, we can influence our memory and our risk for developing dementia through exercise, both physical and mental," says Nancy Pedersen.

When it comes to other character traits, such as being jolly or extrovert, hereditary factors are estimated to account for roughly 40 per cent of individual differences in this regard, the environment to which one has been exposed whilst growing up plays a much bigger part.

To allocate quotas concerning genes and environment in different contexts has always been a fundamental issue for twin research. This applies not only to various diseases, but also to character traits. For example, twin studies have shown that the hereditary component of ADHD can be estimated at between 45 and 90 per cent. Autism, alcoholism, asthma, bipolar disorder, schizophrenia and physique are also considered to be largely dependent on hereditary factors. Other information based on the register includes the fact that smoking not only damages the lungs but also causes cardiovascular diseases – a revelation that was ground-breaking in the 1970s.

More than 30 research projects

Currently, there are more than 30 research projects being conducted on Swedish twins. They concern everything from behavioural problems in children to cardiovascular disease and schizophrenia in adults. Several studies concern diseases among the elderly. Some of them are based on a special set of data that is especially exciting for the scientists, for various reasons. This is the data concerning approximately 900 pairs of identical twins who have grown up in different homes. Of these, many have participated in surveys or interviews, some upwards of ten times.

These twins are now elderly, and many of them are ill. In many cases, only one of the twins has become ill, which gives researchers a unique opportunity to study how their different childhood environments may have influenced them.

Previous twin studies have concluded that the susceptibility to Alzheimer's disease is around 80 per cent due to hereditary factors; it is therefore extremely interesting to try to understand which environmental factors constitute the remaining 20 per cent. Major risk factors that have been identified so far include obesity in midlife.

Other interesting discoveries have also been made, such as the fact that the influence of our genes and our environment changes throughout our lives. This means that the same individual can be more influenced by hereditary factors during their childhood, and later in life be influenced more by their environment.

"For some abilities, for example problem solving, the genetic factors seem to lose importance as one gets older. This may indicate that epigenetic effects are more noticeable later in life," says Nancy Pedersen.

The epigenetic effects to which she refers concern the grey area between genes and environment. What happens in the body when a hereditary propensity for a disease is activated in one individual but remains dormant in another? When, how and why can some genes be activated and switched on, while others remain passive and shut off? To study identical twins is of special interest in these cases, as they have the same genes.

"In cases where the genetic dispositions are identical, the individuals are affected by something else. Epigenetics can explain how these factors affect us as it encompasses everything that a person has been exposed to, such as various infections, traumas, diet, smoking, sedentary lifestyle or environmental toxins," says Tomas Ekström, Professor of Molecular Cell Biology at the Department of Clinical Neuroscience, Karolinska Institutet.

Two epigenetic mechanisms that are considered fairly well investigated are DNA methylation, where methyl groups attach directly to the DNA string, and histone modifications, where the proteins around which the DNA string is wound are modified. In both of these cases, the expressions of nearby genes are affected they become activated or deactivated, depending on the nature of the modification. It is also known that RNA molecules have an epigenetic significance, due to their important role in regulating genes and transferring information from the mother cell to the daughter cells during mitosis.

Epigenetic issues

But so far it has been far from established what controls the epigenetic processes in various tissues and cell types. Within cancer research, epigenetic issues have been in the spotlight for several years, but within, for example, diabetes research, rheumatology and neurology, it is still a far younger field of research.

Tomas Ekström uses twins to study epigenetic issues associated with systemic autoimmune diseases. This narrow field of research is beset by practical difficulties – it requires a great deal of patience to collect a large number of identical twins, where only one twin in each pair has developed a relatively rare disease. For example, last year saw the publication of an article in the renowned medical journal 'Nature' based on only three pairs of identical twins, where one twin had MS and their sibling did not. The study garnered a lot of attention, despite researchers not being able to identify any epigenetic differences that could explain why only one person in each pair had the disease.

Tomas Ekström. Photo: Stefan Zimmerman

Thanks to collaboration between several research groups at Karolinska Institutet, it has been possible to amass 25 pairs of identical twins, where one twin in each pair has developed rheumatoid arthritis. Half of these have an especially aggressive version of rheumatic arthritis and are what is known as ACPA positive. One research group headed by Tomas Ekström has studied white blood cells from these identical twins and made several interesting discoveries.

"There are clear epigenetic differences in genes that are of functional interest for the disease," he says.

However, an obvious problem in these studies is that there is no way of telling if the observed differences are a consequence of the disease or if they are the cause of the disease. Nor is it possible to see when differences have arisen and what environmental factors caused them.

"It could have happened in the womb," says Tomas Ekström.

Modified genes

In the long term, the goal is to understand how the epigenetic processes play out in the genes that are important in terms of various diseases, such as rheumatic arthritis. Hopefully it will be possible to tell which genes are activated or deactivated and how this is done. And as the epigenome, i.e., the modified genes, is changeable, it should be possible to reverse the process.

"This is a possible treatment strategy that lies far in the future. If we can, for example, reverse DNA methylation or histone modification so that relevant cells no longer express that which causes the disease, this could be a possible route to treating the diseases. But this only applies when the disease is caused by an epigenetic change - if it is caused by a mutation, the DNA sequence is modified and it cannot be reversed," says Tomas Ekström.

A few years ago, identical twins Emma Sandgren and Sofia Sandgren were contacted by researchers at Karolinska Institutet. They were asked to participate in a study concerning behavioural genetics. The study would, among other things, concern risk-taking. They accepted – an easy choice to make, they say.

"It feels good to help with research. And it wasn't particularly hard – we got to sit in a large room and answer questions, and then give a saliva sample. The only thing that was strange was that the room was full of twins – that was a bit strange," says Sofia Sandgren.

The questions were about how much money they would be willing to bet in various hypothetical scenarios. They were also asked about the colour and brand of car they preferred. Directly after leaving the room they compared their answers, which turned out to be practically identical.

"Of course it was exciting to find that out. We are alike in many ways, but not all," says Emma Sandgren.

They have stuck together throughout their school years and are now both working as resident physicians at Varberg Hospital. They are now planning to go their own ways: Emma will eventually specialise in cardiology, whilst Sofia plans to be a neurologist.

"I think it will be nice not to spend all our time together. It gives us the chance to develop our own personalities," says Sofia

Text: Annika Lund. This article was first published in Swedish in the magazine Medicinsk Vetenskap no 4/2012. A second English edition was published in the magazine Medical Science in 2013.

The world's largest twin registry

The Swedish Twin Registry, managed by Karolinska Institutet is the largest of its kind and has become an invaluable resource for medical research. The Registry was established in the 1960s and contains information about some 87 000 twin pairs for which zygosity is known, both mono- and dizygotic pairs.

At present there are around 30 projects ongoing based on its data. The studies cover a variety of topics on public health issues such as allergies, cancer, dementia and cardiovascular disease.

More about the Swedish Twin Registry