Summary: A new study reports genetic variants that are critical for the development of the brain during fetal development are also frequently found in psychiatric disorders.
Source: Aarhus University.
Particular genetic variants in the human genome that are important for the development of the brain early in the life of the foetus are frequently found in psychiatric disorders. This is shown by a study carried out by iPSYCH.
Researchers studied a total of eight million genetic variants and in connection with this they found that a number of these variants occur particularly often in people who have one of more of the following psychiatric disorders: schizophrenia, depression, bipolar disorder, autism and ADHD.
This background is provided by Professor Thomas Werge from the Mental Health Services & University of Copenhagen and the Lundbeck Foundation’s Initiative for Integrated Psychiatric Research, commonly referred to as iPSYCH, which has received a total of DKK 361 million in funding from the Lundbeck Foundation. He explains:
“When we take a closer look at these genetic variants, one of the things we can ascertain is that they are tied to genes which are active in connection with the establishing of synapses in the brain during the prenatal stage – that is to say the formation of the ‘wiring’ that runs from nerve cell to nerve cell. And this means that the causes of mental disorders may actually originate all the way back from the point during pregnancy where the brain of the foetus was being formed.”
Thomas Werge has headed the study which has just been published in the scientific journal Nature Neuroscience. The Danish contribution has involved researchers from Aarhus University, Statens Serum Institut (SSI) and the Technical University of Denmark. Researchers from Australia, Switzerland and USA also took part.
Enormous battery of blood tests
Researchers who study psychiatric disorders have long held an assumption that across psychiatric diagnoses there will be common characteristics in the form of specific genetic variants. An assumption that has also built on the fact that a ‘range’ of psychiatric disorders can often be seen to appear at the same time – both in families and individuals.
Whether or not this is the case has been tested in a range of different studies, but never in a way that actually involves an entire population, explains Thomas Werge:
“And that is exactly what we have done, because we have looked at a whole population in Denmark. By doing things in this way, you can achieve the highest possible degree of statistical certainty, as it’s now possible to exclude a long list of biases and thus chance findings, which have to do with factors such as the selection of material for the study. At the same time, we get a very detailed picture of all the forms of mental disorders that can affect a person.
The study behind the article in Nature Neuroscience is based on the blood samples that are taken from nearly all new-born babies in Denmark, though only with parental consent. These heel prick samples or PKU tests, as they are known, are accessible for research work but only in anonymised form.
The PKU archive is the only one of its kind in the world and by looking at the DNA profiles from all samples taken during the period between 1980 and 2005, Thomas Werge and his colleagues were able to carry out a unique study:
The samples were correlated with the Danish healthcare system’s CPR (civil registration number) registrations, which is to say that the journal behind the individual PKU sample – in addition to containing the DNA of the person in question – would also contain in anonymised form much of the health information on that person that is stored in the Danish public healthcare system, including information on psychiatric diagnoses.
“In 2012, when we looked at the registers holding detailed information on all of the PKU samples taken in the period 1980-2005 – approximately one-and-a-half million in total – we could therefore see that 46,000 people from this group had during that time received one of more of the major psychiatric diagnoses. We then compared their DNA with the DNA from a sufficiently large number of persons in the register who had not received a psychiatric diagnosis,” explains Professor Thomas Werge.
A question of vulnerability
What do these discoveries mean then? Is it the case that the genetic variants in the study which were shown to appear especially frequently in people diagnosed with one of the five major psychiatric disorders will necessarily trigger the disease?
“No, it’s not that simple,” says Professor Thomas Werge: “But knowledge of specific predisposing processes enables us to carry out a qualified search for ‘matching’ environmental factors that are active in the same time period during foetal brain development, and that may make particularly vulnerable people ill but have little effect on less liable individuals.”
An additional factor is mentioned by the scientific article’s first author, lead scientist Andrew Schork from iPSYCH: “Our study shows that the foundation for both early and late-stage mental disorders is in part located in the foetal stage; that is to say, very, very early in life and long before the disorders present clinically.”
According to Thomas Werge, it ought to be possible to utilise knowledge of the correlation between mental vulnerability and genetics in preventative contexts:
“Hopefully this knowledge can help us to identify damaging or protective environmental factors enabling us to provide improved guideline on do’s and don’ts during pregnancy.
Funding: Lundbeck fondation funded this study.
Source: Thomas Werge – Aarhus University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment” by Andrew J. Schork, Hyejung Won, Vivek Appadurai, Ron Nudel, Mike Gandal, Olivier Delaneau, Malene Revsbech Christiansen, David M. Hougaard, Marie Bækved-Hansen, Jonas Bybjerg-Grauholm, Marianne Giørtz Pedersen, Esben Agerbo, Carsten Bøcker Pedersen, Benjamin M. Neale, Mark J. Daly, Naomi R. Wray, Merete Nordentoft, Ole Mors, Anders D. Børglum, Preben Bo Mortensen, Alfonso Buil, Wesley K. Thompson, Daniel H. Geschwind & Thomas Werge in Nature Neuroscience. Published January 28 2019.
A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment
There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.