Working Memory and Vigilance as Multivariate Endophenotypes Related to Common Genetic Risk for Attention-Deficit/Hyperactivity Disorder

Joel T. Nigg, Hanna C. Gustafsson, Sarah L. Karalunas, Peter Ryabinin, Shannon K. McWeeney, Stephen V. Faraone, Michael A. Mooney, Damien A. Fair, Beth Wilmot

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Objective: Understanding the role of endophenotypes is essential for process models of psychopathology. This study examined which candidate cognitive endophenotypes statistically mediate common variant genetic risk for attention-deficit/hyperactivity disorder (ADHD). Method: A case-control design using community-recruited volunteer children 7 to 11 years of age (n = 656, n = 435 ADHD), of whom 514 were of homogenous European ancestry for the primary models (n = 337 ADHD, 177 non-ADHD). Children were assessed with a multi-informant, best-estimate diagnostic procedure and laboratory measures of working memory, response inhibition, executive functioning, arousal/attention, temporal information processing, and processing speed. Latent variables were created for the candidate cognitive measures and for parent- and teacher-rated ADHD dimensions. Polygenic risk scores (PGS) were computed using a discovery sample of 20,183 individuals with ADHD and 35,191 controls from the Psychiatric Genetics Consortium. Cognitive measures that survived multiple testing correction for association with the PGS were evaluated for mediation with ADHD using structural equation models. Results: Results were essentially identical in the homogeneous European ancestry subgroup (n = 514) and in the full sample (N = 656). For the European population, the PGS was associated with ADHD diagnosis (Nagelkerke R2 = 0.045; β = 0.233, SE = 0.053, p =.000011) and multi-indicator dimensional ADHD latent variables by parent report (β = 0.185, SE = 0.043) and teacher report (β = 0.165, SE = 0.042). The PGS effect was statistically mediated by working memory (indirect effect, β = 0.101, SE = 0.029, 95% CI = 0.05, 0.16, p =.00049, 43% of genetic effect accounted for) and arousal/alertness (indirect effect β = 0.115, 95% CI = 0.04, 0.20, SE = 0.041, p =.005, 49% of genetic effect accounted for). Conclusion: This is the first clear demonstration from molecular genetic data that working memory and arousal regulation are promising cognitive endophenotypes for ADHD with regard to mediating genetic risk from common genetic variants.

Original languageEnglish (US)
Pages (from-to)175-182
Number of pages8
JournalJournal of the American Academy of Child and Adolescent Psychiatry
Issue number3
StatePublished - Mar 2018
Externally publishedYes

Bibliographical note

Funding Information:
Disclosure: Dr. Nigg has received royalties from Guilford Press for What Causes ADHD (2007) and Getting Ahead of ADHD (2017). Dr. Faraone has received grant or research support from the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, the University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development, and demonstration, the European Union’s Horizon 2020 research and innovation programme, and the National Institute of Mental Health. He has received income, potential income, travel expenses, continuing education support, research support from, and/or has served on the advisory boards of/as a consultant to Lundbeck, Rhodes, Arbor, KenPharm, Ironshore, Neurovance, Impact, Takeda, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, Sunovion, Genomind, and NeuroLifeSciences. In previous years, he has received income or research support from Shire, Neurovance, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly and Co. He has served as editor of the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. His institution (SUNY) has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He has received royalties from books published by Guilford Press (Straight Talk about Your Child’s Mental Health), Oxford University Press (Schizophrenia: The Facts), and Elsevier (ADHD: Non-Pharmacologic Interventions). He has held stock in CogCubed and Ironshore. He is the principal investigator of . Drs. Gustafsson, Karalunas, Ryabinin, McWeeney, Mooney, Fair, and Wilmot report no biomedical financial interests or potential conflicts of interest.

Funding Information:
This project was supported by National Institute of Mental Health grants R01-MH099064 and R01-MH5104.

Publisher Copyright:
© 2018 American Academy of Child and Adolescent Psychiatry


  • ADHD
  • endophenotype
  • executive function
  • polygenic score
  • working memory


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