Discovery of genome-wide significant risk loci for attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental psychiatric disorder that affects ~5% of children and adolescents and ~2.5% of adults worldwide; 50 years ago ADHD was rare, but the frequency has changed, perhaps due to unknown environmental factors, plus diagnostic criteria have softened. ADHD can cause harmful outcomes (e.g. injuries, traffic accidents, increased healthcare needs, substance abuse, criminality, unemployment, divorce, suicide, enhanced risk of AIDS, and premature mortality). Epidemiologic and clinical studies implicate a combination of genetic and environmental risk factors — affecting the structure and functional capacity of brain networks involved in behavior and cognition (mental process of acquiring knowledge, understanding through thought, perception, experience, and the senses).

Consensus estimates from more than 30 twin studies suggest that the heritability of ADHD is as high as 70–80%, and that environmental risks are those not shared by siblings. Twin studies also suggest genetic overlap between ADHD and other conditions (including antisocial personality disorder/behaviors, cognitive impairment, autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder). Thus far, genome-wide association studies (GWAS) — to identify common DNA variants that increase ADHD risk have not been successful — probably due to small sample size. Nevertheless, genome-wide single-nucleotide variant (SNV) heritability (variance explainted/revealed) estimates range from 0.10–0.28, supporting the notion that common variants comprise a significant fraction of the risk underlying ADHD. Therefore, by increasing the sample size (which would enhance the statistical power of detecting low-effect-contributing genes), genome-wide significant loci will emerge.

Authors [see attached report] describe a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD, plus 35,191 controls — identifying statistically significant variants in 12 independent loci — which provides new important information about the underlying biology of ADHD (and thus could lead to new drug development for treating ADHD). [For anyone interested in seeing whether or not “their favorite gene” is listed among these 12 loci, please check Table 1 of attached article.]

These newly discovered variants are located in constrained (i.e. resistant to evolutionary change; little difference in DNA sequence between human and gorilla or chimpanzee) genomic regions, and loss-of-function-intolerant (i.e. critical for survival of the organism) genes, and around brain-expressed regulatory regions. Analyses of three replication studies (a cohort of individuals diagnosed with ADHD; a self-reported ADHD sample; and a meta-analysis of quantitative measures of ADHD symptoms in the population) support these findings — while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms also confirms the concept that clinical diagnosis of ADHD is an extreme expression of continuous heritable phenotypes (i.e. traits seen in everyone) — in all human populations.


Nat Genet Jan 2019; 51: 63–75

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.