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ADHD Risk Variants Identified

NEW YORK (GenomeWeb) – A dozen distinct loci appear to contribute to attention deficit/hyperactivity disorder (ADHD), according to new research from an international team led by investigators in Denmark and the US.

As they reported online today in Nature Genetics, the researchers conducted a genome-wide association study based on data from 20,183 individuals with ADHD and 35,191 unaffected controls from 12 cohorts enrolled in Europe, North America, or China. They identified 304 suspicious variants at 12 risk loci for ADHD that were over-represented at highly conserved sites in the genome and regulatory marks that mediate gene expression in the brain. 

The top associations were supported by replication analyses done using data for tens of thousands of additional ADHD cases and hundreds of thousands of additional unaffected controls evaluated by Decode Genetics, 23andMe, and the "Early Lifecourse and Genetic Epidemiology" and QIMR Berghofer Medical Research Institute consortia.

With the help of gene function, expression quantitative trait locus, and interaction data gleaned from Hi-C analyses, the team found that many of the ADHD-associated variants fell in or around genes from biological pathways involved in synaptic function, neuronal development, neurotransmitter regulation, and other brain-related processes.

The group also saw potential variant overlap with loci linked to intellectual disability, schizophrenia, depression, and other conditions — findings supported by pairwise genetic correlations done to estimate the genetic ties between ADHD and 219 other phenotypes. The team saw signs of apparent genetic overlap between ADHD and risk for 43 phenotypes from major depressive disorder or anorexia nervosa to education outcomes and smoking habits.

"The GWAS meta-analysis implicates FOXP2 and other biologically informative genes as well as constrained regions of the genome as important contributors to the etiology of ADHD," the authors wrote. "The results also highlight strong overlap with the genetics of ADHD-related traits and health risk behaviors in the population, encouraging a dimensional view of ADHD as the extreme end of a continuum of symptoms."

The findings offer an advance in ADHD research, the authors noted, since prior GWAS had not identified individual common variants with strong genetic ties to ADHD. Still, they added, prior SNP heritability estimates have suggested that "common variants comprise a significant fraction of the risk underlying ADHD and that with increasing sample size, and thus, increasing statistical power, genome-wide significant loci will emerge."

Past findings suggest polygenic ADHD risk "has previously been associated with inattentive and hyperactive/impulsive trait variation below clinical threshold in the population," they concluded, writing, "We observe strong concordance between the GWAS of ADHD and the previous GWAS of ADHD-related traits in the population, both in terms of genome-wide genetic correlation and concordance at individual loci."

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