Summary: An international research collaboration has identified specific genetic variants that raise the risk of attention deficit hyperactivity disorder (ADHD), offering new biological insight into the condition.
Source: Aarhus University.
Researchers from the Danish iPSYCH project together with teams at the Broad Institute of Harvard and MIT, Massachusetts General Hospital, SUNY Upstate Medical University, and the Psychiatric Genomics Consortium have, for the first time, identified genome-wide significant loci that increase the risk of ADHD. These discoveries reveal new biological pathways involved in ADHD.
Genetic factors play a major role in the development of many mental disorders, including ADHD, where heritability accounts for a large portion of risk. Until now, locating robust genetic risk factors for ADHD had proved difficult. In this new genome-wide association meta-analysis, researchers compared DNA variation across the entire genome from more than 20,000 individuals diagnosed with ADHD and over 35,000 control subjects, and identified twelve independent genomic regions where specific variants are associated with increased ADHD risk.
The study is published in the scientific journal Nature Genetics.
“By substantially increasing the number of participants, we were able to detect genomic locations where people with ADHD differ from those without. Previous efforts lacked sufficient sample size to produce consistent findings. This study included a large contribution from the Danish iPSYCH cohort, which accounted for more than two-thirds of the international sample and markedly improved our statistical power,” explains Associate Professor Ditte Demontis from Aarhus University, one of the study’s lead authors.
Ditte Demontis and Raymond Walters of Massachusetts General Hospital led the analysis as part of the ADHD working group of the Psychiatric Genomics Consortium, a broad international effort focused on discovering genetic contributors to ADHD.
These genetic findings provide fresh insights into the biological mechanisms that can lead to ADHD. Several implicated genes are involved in neuronal communication, while others relate to cognitive functions such as language and learning. Overall, the identified risk variants tend to influence gene expression levels, and many of the affected genes are predominantly expressed in the brain, indicating regulation of brain function as a central theme.
Same genetic variants influence attention and impulsivity across the population
The researchers also compared their results with genetic studies that measure ADHD-related behaviors continuously in the general population. They found that the same variants linked to an ADHD diagnosis also correlate with inattention and impulsivity among people who do not have a formal diagnosis. This supports the idea that clinical ADHD represents the extreme end of continuous, heritable traits present across the population.
“These risk variants are common in the population: the greater the number of risk alleles a person carries, the higher their tendency toward ADHD-like characteristics and the greater their risk of receiving an ADHD diagnosis,” says Professor Anders Børglum from Aarhus University, research head at iPSYCH and a senior investigator on the study, together with Professors Stephen Faraone and Benjamin Neale.
The analysis also explored genetic overlap between ADHD and other traits. The investigators observed a strong negative genetic correlation between ADHD and educational attainment, meaning genetic variants that increase ADHD risk tend to be associated with lower performance in educational measures in the general population. Conversely, they found positive genetic correlations between ADHD and obesity-related traits, including increased body mass index (BMI) and type 2 diabetes, indicating that some genetic risks are shared across these conditions.
“The scale of collaboration and data sharing was essential to these discoveries,” says Dr. Benjamin Neale. “Only by pooling large datasets across many groups were we able to detect these genome-wide significant signals.”
Anders Børglum adds: “After years of research, we now have robust genetic findings that point to the underlying biology of ADHD and to genetic links with traits and disorders that often co-occur with ADHD. This work lays a foundation for targeted follow-up studies to understand how these risk genes influence brain development and behavior, with the long-term goal of improving diagnosis and treatment.”
Professor Stephen Faraone notes: “This study lays the groundwork for future research that will examine how genetic susceptibility interacts with environmental exposures to cause ADHD. As those pieces come together, we expect progress in clinical care and interventions.”
Type of study:
The research used a genome-wide association approach, comparing common genetic variants across the genomes of a large cohort of individuals diagnosed with ADHD versus control subjects. When a variant is significantly more frequent in cases than in controls, it is inferred to contribute to disease risk. The meta-analysis included data from 20,183 individuals with ADHD and 35,191 controls, with a substantial contribution from the iPSYCH cohort (14,584 ADHD cases and 22,492 controls) that enhanced the study’s statistical power.
Funding: The research received support from the Lundbeck Foundation and several international funders, including foundations and public research agencies.
Source: Ditte Demontis – Aarhus University
Publisher: Organized by NeuroscienceNews.com.
Image Source: Image in the public domain.
Original Research: Abstract for “Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder” by D. Demontis et al., published in Nature Genetics on November 26, 2018.
Aarhus University. “First Risk Genes for ADHD Discovered.” NeuroscienceNews, 27 November 2018.
Abstract
Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder that affects approximately 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but until this study no variants had been robustly associated with the disorder. The genome-wide association meta-analysis of 20,183 people diagnosed with ADHD and 35,191 controls identified variants reaching genome-wide significance at 12 independent loci, providing new insights into ADHD biology. The associations are enriched in evolutionarily constrained genomic regions and genes intolerant to loss-of-function, and in regulatory marks active in brain tissue. Replication analyses across clinical and population-based samples supported the results and emphasized that clinical ADHD represents the extreme end of continuous heritable traits related to attention and impulsivity.