The First Robust Genetic Markers for ADHD Are Reported

The First Robust Genetic Markers for ADHD Are Reported

Posted: July 11, 2019
The First Robust Genetic Markers for ADHD Are Reported

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A large international team has for the first time pinpointed specific locations in the human genome—12 in all—in which DNA variations are robustly associated with risk for ADHD.


After years of trying, researchers say they have now succeeded in discovering specific areas of the human genome that contain variations in DNA sequence that are robustly associated with risk for ADHD (attention-deficit hyperactivity disorder).

Reporting their findings in Nature Genetics, a large international team that included 10 BBRF grantees and prizewinners identified, mapped, and analyzed the potential biological significance of 12 “significant risk loci” associated with ADHD.

Nine years ago, a major effort to identify common DNA variations—single-DNA “letter” variations, called SNPs—found many variations that differed between people with ADHD and unaffected individuals. The problem was that none of these rose to a mathematical threshold called “genome-wide significance.” This standard is vitally important, for each of us harbors thousands, if not millions of SNPs, a fact that implies that most SNPs have no impact on health.

The problem is that some SNPs do affect health, a fact that is inferred from decades of genetic research. While a small number of relatively rare SNPs can alone cause a serious illness—cystic fibrosis, for example—the difficult question in brain and behavior disorders and other genetically “complex” conditions concerns “common” SNPs, those that occur frequently across the human population.

ADHD is quite common, affecting 5 children in every 100 and about 2 adults per 100, and many researchers believe that a significant portion of risk traces to the collection of SNPs that an individual happens to be born with. Each commonly occurring SNP which affects risk for illness has a tiny impact on total risk. It takes several or many such common SNPs to put an individual at significant risk, in combination with a range of environmental factors.

In contrast the to 2010 study, which assessed SNPs in several thousand people, the new assessment was massive, involving a total of 20,183 individuals diagnosed with ADHD and 35,191 controls. These were assembled from 12 different cohorts from Europe, North America, and China. The study was a meta-analysis, a study of previously collected data, a procedure that adds statistical power to the analysis.

In all, over 8 million SNPs were included in the meta-analysis. Of these, 304 SNPs concentrated in 12 “loci”—locations on 11 of the 23 human chromosomes—rose to genome-wide significance for ADHD. Loci are stretches of thousands of DNA letters, most of which contain many genes, as well as other areas where DNA regulates the activity of nearby genes. Thus, finding “loci” is only the beginning of the discovery process. The 12 reported loci are the first genomic “risk” sites for ADHD that survive mathematical tests of robustness.

Risk areas on chromosomes 2, 7, and 10 converged on single genes. These genes have roles in development of the brain, and are active when synapses between neurons are being formed, in neuronal development, and in neural mechanisms involved in the development of speech and learning.

By correlating their results with other large genetic studies, the researchers showed that the set of SNPs that increase risk for ADHD are correlated with the sets of SNPs that put people at risk for depression, learning difficulties, obesity, and other conditions that had been associated with ADHD in prior clinical, family and twin studies.

Consistent with the theory that combinations of small-effect SNPs contribute variously to overall risk in any given individual, the genetic evidence from the study suggested that ADHD is at the far end of a broad continuum of symptoms, meaning that they appear in different combinations and intensities across the broad population, with only individuals at one extreme of the continuum actually meeting the diagnostic criteria for ADHD.

The research team was co-led by Stephen Faraone, Ph.D., Anders Borglum, Ph.D., and Benjamin Neale, Ph.D., and included: Stephan Ripke, M.D., Ph.D., 2015 BBRF Young Investigator and 2014 Baer Prizewinner; Daniel Geschwind, M.D., Ph.D., 1999 BBRF Young Investigator, 2012 Ruane Prizewinner and 2015 Distinguished Investigator; Patrick Sullivan, M.D., FRANZP, 2014 Lieber Prizewinner and 2010 BBRF Distinguished Investigator; the late Pamela Sklar, M.D., Ph.D., 2016 Colvin Prizewinner, 2006 BBRF Independent Investigator and 1995 and 1998 Young Investigator; Anita Thapar, Ph.D., MBBCh, 2014 Ruane Prizewinner; Sarah Medland, Ph.D., 2017 BBRF Independent Investigator; Panos Roussos, M.D., Ph.D., 2013 BBRF Young Investigator; Dorret Boomsma, Ph.D., 2011 BBRF Distinguished Investigator; Hyejung Wong, Ph.D., 2018 BBRF Young Investigator; and Elise Robinson, ScD, MPH, 2014 BBRF Young Investigator.