An international research effort headed by scientists from the Danish iPSYCH initiative and the Broad Institute has identified the first common genetic risk factors for autism spectrum disorder (ASD). The genome-wide association meta-analysis, involving more than 18,000 individuals with ASD and nearly 30,000 controls, also identified genetic variations between different types of autism. The researchers suggest their findings could ultimately lead to new diagnostic and therapeutic approaches.

“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,” said Aarhus University’s Anders Børglum, who is research head at iPSYCH and is co-director of the study, which is reported in Nature Genetics. “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.”

The collaborating researchers, including international groups with the Psychiatric Genomics Consortium, reported their findings in a paper titled, “Identification of common genetic risk variants for autism spectrum disorder.

ASD is an umbrella term for a group of “highly heritable and heterogeneous” neurodevelopmental disorders that are characterized by impaired social and communication skills, together with repetitive and restrictive behaviors, the authors explained. The disorder is diagnosed in more than 1% of children, and may feature severe intellectual disability (ID), or above-average intelligence quotient (IQ) and high academic functioning.

Although the collective effects of many common genetic variants are believed to underpin ASD susceptibility, “to date no individual variants have been robustly associated with ASD,” the authors pointed out. The largest previously reported genome-wide association study (GWAS) involving 7,387 cases provided evidence that the common variants impacts on disease risk, but couldn’t conclusively identify single variants. “These results underscore that common variants, as in other complex diseases such as schizophrenia, individually have low impact and that a substantial scale-up in sample numbers would be needed,” the researchers suggested.

“It is known that there are very rare genetic variants that carry a high risk for autism, but they do not explain many cases,” commented Jakob Grove, PhD, associate professor at Aarhus University, member of the iPSYCH project, and lead author of the published paper in Nature Genetics. “However, according to our estimates, there are common variants that do that when enough of them act together.”

For their reported study the team turned to data from the Danish national iPSYCH project, which was established in 2012 to carry out research into five of the most serious psychological and psychiatric disorders, schizophrenia, bipolar disorder, ASD, attention deficit hyperactivity disorder (ADHD), and depression. The initiative is evaluating genetic and other risk factors in more 80,000 individuals in Denmark with and without mental disorders.

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

The researchers’ primary analysis, comparing the genomes of 18,381 individuals with ASD and another 27,969 controls, identified five genome-wide-significant loci associated with ASD. “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,” Grove added. “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.” The team then broadened their study to include GWAS data on schizophrenia, major depression, and educational attainment, “three phenotypes with significantly overlapping genetic architectures,” and identified seven additional regions.

Interestingly, there was a correlation between ASD and positive cognitive characteristics such as educational attainment and IQ, but not across all subtypes of ASD. “In particular, the excess of alleles associated with higher intelligence and educational attainment was observed only in the higher-functioning categories (particularly in individuals with Asperger’s syndrome and individuals without comorbid ID) …” the researchers commented.

“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,” Grove further explained. “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. 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.”

There was genetic heterogeneity across different subcategories of ASD, including childhood autism, atypical autism, and Asperger’s syndrome. Notably, common genetic variations associated with ASD were located in regions involved in brain development. “In most GWAS studies, there has been little evidence of heterogeneity of association across phenotypic subgroups,” the authors stated. “In this study, however, we observed strong heterogeneity of genetic overlap with other traits when our ASD samples were divided into distinct subsets.”

“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,” Børglum commented.

In total, the studies and analyses combined the iPHSYCH cohort data with results from an additional 5,305 individuals with autism and 5,305 controls from an international multi-center study under the auspices of The Psychiatric Genomics Consortium. A follow-up was also carried out on 2,119 people with autism and 142,379 controls from cohorts including individuals in the deCODE resource in Iceland.

“Here we report what are, to our knowledge, the first reported common risk variants robustly associated with ASD…” the researchers concluded. “… we established an initial robust set of common variant associations in ASD and have begun laying the groundwork through which the biology of ASD and related phenotypes will inevitably be better articulated … These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.”

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