NEW YORK — Researchers have uncovered shared genetic liability between autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), but also genetic distinctions between the conditions.
ASD and ADHD are common neurodevelopmental disorders affecting children that may last into adulthood. They are also highly heritable and polygenic, and previous studies have suggested the two conditions are genetically correlated.
To look into just which genetic variants are shared by the conditions, an international team of researchers led by Aarhus University's Anders Børglum conducted genome-wide association studies using the Psychiatric Genomics Consortium (PGC) and the Lundbeck Foundation for Integrative Psychiatric Research (iPSYCH) cohorts. As they reported in Nature Genetics on Monday, they found seven loci shared by ASD and ADHD but also five loci that differentiate them.
"[W]e have disentangled the shared and differentiating genetic liability underlying ASD and ADHD, identifying shared and disorder-specific risk variants providing information on pathophysiology," Børglum, director of the iPSYCH program, and colleagues wrote in their paper.
The researchers conducted a combined genome-wide association study of diagnosed ASD or ADHD in a cohort of 34,462 cases and 41,201 controls. After identifying more than 260 SNPs in seven distinct loci, the researchers conducted a transcriptome-wide association study to home in on putative causal shared genes. This identified five genes or isoforms that were differentially expressed between the case and control groups. Further gene-based analysis using the tool MAGMA confirmed those TWAS findings and identified two additional shared loci, for a total of seven genetic loci shared between ASD and ADHD.
These shared loci tended to be pleiotropic and had been identified in previous GWAS of related disorders or cross-disorder studies, the researchers noted.
Meanwhile, to identify loci that differ between ASD and ADHD, the researchers performed an ADHD versus ASD GWAS using 9,315 ASD-only and 11,964 ADHD-only cases from the iPSYCH cohort. This analysis uncovered five genome-wide significant loci, three of which had not previously been tied to either ASD or ADHD.
Those loci, though, have been linked to related disorders or traits, particularly cognitive traits. Four of the loci, for instance, have been associated with cognitive ability or neuroticism, and two with educational attainment. The lead variants further exhibited opposite direction of effect in the two conditions.
In a TWAS, the top gene or isoform identified that differentiated the disorders was HIST1H2BD-201, located on chromosome 6. Deleterious or de novo variants in histone-modifying or histone-related genes have previously been linked to autism and developmental delay with features of autism. Here, the researchers found that the expression of HIST1H2BD-201 was lower in ASD compared to ADHD. Further, the ASD risk allele of the lead SNP there was linked to better educational performance and increased volume of the left globus pallidus in the brain.
The researchers proposed that the ADHD-ASD differentiating locus on chromosome 6 affects the expression of HIST1H2BD-201 and left globus pallidus volume and, in turn, traits like educational performance, social interaction, and motor impairments. This pushes the disorder presentation toward ASD or ADHD.
The researchers additionally conducted a GWAS of 2,304 individuals diagnosed with both ASD and ADHD, as well as a polygenic risk score-based analysis. They found that these comorbid cases had an ASD-PRS load similar to that of ASD-only cases as well as an ADHD-PRS load similar to that of ADHD-only cases, indicating they are "double-loaded" with genetic predispositions for both disorders. This provides support, they noted, for the recent change in diagnostic guidelines allowing for the diagnosis of both ASD and ADHD in the same individual.
"The results advance our understanding of the complex etiologic basis of ASD and ADHD and the relationship between the two disorders, toward the long-term goals of better diagnosis and treatment of these disorders," the authors wrote.