First common risk genes discovered for autism

A study headed by researchers from the Danish project iPSYCH and the Broad Institute, USA, has found the first common genetic risk variants for autism and uncovered genetic differences in clinical subgroups of autism. The discovery means that we will in future be able to determine the genes which separate the diagnostic groups, make more precise diagnoses, and provide better counselling for the individual person suffering from autism disorders.

Autism is not a new phenomenon as we have historical records describing individuals with symptoms that today are associated with the group of disorders that today is known as autism. It was not until 1938 that the first person was given that diagnosis though. Ever since then researchers have tried to explain where the disorder stems from. There have been many suggestions, but one factor has long been established – that genes play a very important role.

A large-scale international collaboration headed by the Danish iPSYCH project and Broad Institute together with several international groups organized in the Psychiatric Genomics Consortium has now identified the first common genetic risk variants for autism and for the first time found the genetic differences between different types of autism.

“When we look at autism, there is a heredity factor of up to eighty percent, so genes have a great deal of impact overall. Nevertheless, despite many years of work, identifying precisely which genes are involved has been very challenging,” says Professor Mark Daly from Broad Institute and Institute for Molecular Medicine Finland who is one of the leading scientists of the study.

In the study, researchers have compared the genome of 20,415 people with autism and 174,280 healthy control subjects, and in this way they have been able to determine five different genetic variants which increase the risk of autism. The results have recently been published in the scientific journal Nature Genetics.

“It is known that there are very rare genetic variants that carry a high risk for autism, but they do not explain many cases. However, according to our estimates, there are common variants that do that when enough of them act together. In this study we have examined all the approximately nine million frequent variants that can be found in the genome of the people who are included in our study. These are genetic variants which are common in the population at large and where the individual variant’s contribution to the risk is very small,” explains Associate Professor Jakob Grove from Aarhus University. He is the lead author of the study and a member of the iPSYCH research project.

The genetic findings provide an entirely new insight into the biological processes involved in the development of autism.

“By comparing the genetic risk variants with the genes’ expression and the 3D structure of the genome in the developing brain, we can show that the identified risk genes are important for the development of the brain and in particular the development of the cerebral cortex,” explains Professor Anders Børglum from Aarhus University, who is research head at iPSYCH and directed the study together with Dr. Daly.

The researchers have also found a significant overlap between the genetic background for autism and other mental disorders such as schizophrenia and depression – though also with positive cognitive characteristics such as educational attainment and IQ.

“The positive correlation with educational attainment might seem paradoxical because some autistic people have reduced cognitive function and on average, fewer people with an autism diagnosis end up with a higher education. The correlation is seen in several previous studies, and in our data we can confirm that in general, this correlation between the genes for autism and genes that predispose for longer education does exist,” says Jakob Grove and continues:

“However, we can demonstrate that this does not apply to all subsets of autism. We see that people with Asperger’s syndrome or infantile autism on average have more of the genes that are beneficial for taking an education, while this is not the case for people with so-called atypical autism or unspecified autism disorders.”

Autism refers to a very mixed group with different autism disorders. Some have very pervasive developmental disorders with mental retardation, while others may be cognitively well-functioning with a normal or high IQ.

“Thanks to a new and highly sensitive method that we’ve developed, we can for the first time establish genetic differences between the various diagnostic subgroups. This indicates that larger studies in the future will be able to pinpoint genes that separate the diagnostic groups and enable more precise diagnosis and advice for the individual person suffering from an autism disorder. We also hope that the genes we identify can provide an opportunity for developing actual treatment or prevention of the condition, which is something that we unfortunately cannot offer at present,” says Anders Børglum.

The national research project iPSYCH – which is financed by the Lundbeck Foundation – was established back in 2012 with the purpose of carrying out research into and finding the causes of five of the most serious mental disorders: schizophrenia, bipolar disorder (formerly manic depression), autism, ADHD and depression. iPSYCH’s purpose was – and still is – to lay the foundations for better treatment and prevention of mental disorders by mapping the factors that play a role for these diseases. By examining genetic and risk factors in more than 80,000 Danes both with and without mental disorders, iPSYCH sheds light on the complex interaction between heredity factors and the environment, which for some people result in them developing a mental disorder. The project examines the diseases from various angles, ranging from genes and cells to population studies, prenatal life to adult patient and from cause to symptom. iPSYCH is a national collaborative project between Aarhus University, the University of Copenhagen, the Central Denmark Region and the Capital Region of Denmark, as well as SSI, the Danish State Serum Institute.

Today iPSYCH is one of the world’s largest studies of genetic and environmental causes of mental disorders and it now comprises more than 150 researchers within psychiatry, genetics and register-based research.

Type of study: Researchers scan the entire genome of a large number of people with autism and a large number of healthy control subjects. When a genetic variation is significantly more frequent in people with autism than in the healthy control group, it is possible to conclude that the variant increases the risk of suffering from the disorder. In the iPSYCH project, researchers have collected genetic information on 13,076 autists and 22,644 control subjects. The results where combined with the results from an additional 5,305 people with autism and 5,305 control subjects from an international multi-centre study under the auspices of The Psychiatric Genomics Consortium, and a follow-up was also carried out on 2,119 people with autism and 142,379 control persons from, among other places, deCODE in Iceland.

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External funding: The Lundbeck Foundation and several international foundations including the Stanley Foundation, NIH/NIMH.

Partners: Primarily researchers from The Broad Institute at Harvard and MIT together with Massachusetts General Hospital in Boston, but also a number of international researchers and institutions who are organised in The Psychiatric Genomics Consortium.

The scientific article ‘Identification of common genetic risk variants for autism spectrum disorder’ was published in Nature Genetics, February 2019.

Associate Professor Jakob Grove

Aarhus University, Institut for BIomedicin

Tel.: (+45) 2980 1768

Email [email protected]

Professor & Centre Director Anders Børglum

Aarhus University, Institut for BIomedicin

Tel.: (+45) 6020 2720

Email [email protected]

Professor Mark Daly

Tel.: (+1) 617 643 3290?

Email [email protected]