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Scientists discover first risk genes for ADHD

Tristan Manalac
06 Dec 2018

For the first time, researchers have reported genome-wide significant risk loci associated with attention deficit/hyperactivity disorder (ADHD).

“The GWAS (genome-wide association studies) meta-analysis implicates FOXP2 and other biologically informative genes as well as constrained regions of the genome as important contributors to the aetiology of ADHD. The results also highlight strong overlap with the genetics of ADHD-related traits and health risk behaviours in the population, encouraging a dimensional view of ADHD as the extreme end of a continuum of symptoms,” said researchers.

Using genotype array of 20,183 individuals with ADHD and 35,191 controls, researchers identified 304 genetic variants spread across 12 loci that met the criteria for genome-wide significance (p<5×10-8). [Nat Genet 2018;doi:10.1038/s41588-018-0269-7]

At each of the 12 significant loci, researchers defined Bayesian credible sets to identify the putative genetic variants that were most likely to have causal effects. The most credible variants were then annotated to determine functional and regulatory importance.

One of the 12 loci was located on chromosome 7, in which the credible sets were localized to FOXP2, a gene known to be involved in synapse formation and neural mechanisms. On chromosome 10, the ADHD association was found on the SORCS3 gene, which encodes a transmembrane receptor found in the brain.

Other credible sets localized to more than one genetic element. For example, the credible set in chromosome 12 includes the DUSP6 gene as well as an insertion around its transcription start site and a missense variant in the first exon.

“The 12 significant loci are compelling but only capture a tiny fraction of common variant risk for ADHD,” said researchers, pointing out that these alleles correspond to only modest elevations in odds ratios, which range from 1.077–1.198. This is consistent with the observed values for other psychiatric disorders such as schizophrenia. [Nature 2014;511:421-427]

Evolutionary pressures are also important determinants in ADHD genetics, researchers continued. For instance, some risk variants are much more common in genomic regions conserved in mammals, while others are associated with having more children and having them at younger ages. [Nature 2011;378:476-482]

In terms of phenotypes, ADHD has also been found to share genetic correlations with major depressive disorder and other depressive symptoms as well as various health risks such as smoking, obesity, insomnia and other sleep disturbances. [Nat Genet 2013;45:45:984-994; Clin Psychol Rev 2011;31:328-341; J Can Acad Child Adolesc Psychiatry 2009;18:92-102]

“The observed genetic correlations with educational outcomes and other phenotypes suggest a strong genetic component to the epidemiological correlates of ADHD,” researchers noted.

Overall, “[o]ur GWAS meta-analysis of ADHD identified the first genome-wide significant risk loci and indicates an important role for common variants in the polygenic architecture of ADHD. Several of the loci are located in or near genes that implicate neurodevelopmental processes that are likely to be relevant to ADHD,” they added.

Future studies should focus on more accurately determining the source of the strong association within each locus. In addition, studies about rare variants or fecundity might provide valuable insights about selective pressure on genetic loci associated with ADHD.

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