TY - JOUR
T1 - Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample
AU - Moses, Mia
AU - Tiego, Jeggan
AU - Demontis, Ditte
AU - Bragi Walters, G.
AU - Stefansson, Hreinn
AU - Stefansson, Kari
AU - Børglum, Anders D.
AU - Arnatkeviciute, Aurina
AU - Bellgrove, Mark A.
N1 - Funding Information:
MAB was supported by a National Health and Medical Research Council of Australia Senior Research Fellowship. AA was funded by a grant from the Australian Research Council (ARC) under its Linkage Project scheme (LP160101592). JT was supported by a Turner Impact Fellowships from the Turner Institute for Brain and Mental Health at Monash University. Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study ( https://abcdstudy.org ), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children age 9-10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html . A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/ . ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. The ABCD data repository grows and changes over time. The ABCD genetic data used in this report came from ABCD release 2.0; https://nda.nih.gov/study.html?id=634 . The ABCD behavioural/cognitive data used in this report came from ABCD release 3.0; https://nda.nih.gov/study.html?id=901 . SM ®
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition, and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain Cognitive DevelopmentSM Study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.
AB - Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition, and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain Cognitive DevelopmentSM Study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.
UR - http://www.scopus.com/inward/record.url?scp=85138728280&partnerID=8YFLogxK
U2 - 10.1038/s41380-022-01775-5
DO - 10.1038/s41380-022-01775-5
M3 - Article
C2 - 36151456
AN - SCOPUS:85138728280
SN - 1359-4184
VL - 27
SP - 5028
EP - 5037
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 12
ER -
