Association of Genetic Risk Variants With Attention-Deficit/Hyperactivity Disorder Trajectories in the General Population.
OBJECTIVE
Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder that shows clinical and genetic overlap with other childhood neurodevelopmental disorders. Levels of ADHD symptoms typically decline across childhood and adolescence, although they remain elevated for some individuals. The determinants of symptom persistence and decline are not yet fully understood.


OBJECTIVE
To test the hypothesis that genetic risk variant load for ADHD (indexed by polygenic risk scores [PRS]), but not for other psychiatric disorders, is associated with population-based ADHD symptom trajectories across childhood and adolescence, and to examine whether higher genetic liability for ADHD is correlated with total number of additional neurodevelopmental disorders (multimorbidity) in childhood.


METHODS
The Avon Longitudinal Study of Parents and Children, an ongoing prospective population-based cohort study, has been collecting data on 14 701 children, including 9757 with data on symptoms of ADHD at multiple time points, since September 6, 1990. The primary exposure variables, PRS, were generated using results of a genome-wide association study from the Psychiatric Genomics Consortium. Childhood multimorbidity scores (ages 7-9 years) were measured by total impairments in 4 domains known to share genetic liability with ADHD: IQ, social communication, pragmatic language, and conduct. Data analysis was conducted from March 1 to September 8, 2016.


METHODS
Attention-deficit/hyperactivity disorder symptom trajectories from ages 4 to 17 years (7 time points).


RESULTS
Among 9757 children with data on symptoms of ADHD at multiple time points (age range, 4-17 years; 4968 boys and 4789 girls), 4 ADHD symptom trajectories were identified: low (82.6%), intermediate (7.7%), childhood-limited (5.8%), and persistent (3.9%). Mean (SE) PRS for ADHD were higher in children in the persistent trajectory (0.254 [0.069]) compared with each of the other 3 trajectories (low, -0.018 [0.014], χ21 = 14.67, P < .001, odds ratio, 1.31; intermediate, 0.054 [0.055], χ21 = 4.70, P = .03, odds ratio, 1.22; and childhood-limited, 0.017 [0.060], χ21 = 6.50, P = .01, odds ratio, 1.27). Findings were specific to PRS for ADHD; PRS for other psychiatric conditions did not differ across trajectories. The proportion of children with multimorbidity was also highest in those in the persistent trajectory (42.5%; 95% CI, 33.9%-51.1%; P < .001) and was associated with persistence of ADHD symptoms independent of PRS.


CONCLUSIONS
Persistence of ADHD symptoms across childhood and adolescence in the general population is associated with higher PRS for ADHD. Childhood multimorbidity was also associated with persistence of ADHD symptoms and may help to identify children with ADHD whose symptoms are most likely to continue into adolescence.
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Lucy
L
Riglin
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Stephan
S
Collishaw
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Ajay K
AK
Thapar
National Centre for Register-Based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark3The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
Søren
S
Dalsgaard
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom4School of Psychology, Cardiff University, Cardiff, United Kingdom.
Kate
K
Langley
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
George Davey
GD
Smith
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom6School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom.
Evie
E
Stergiakouli
MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London, United Kingdom.
Barbara
B
Maughan
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Michael C
MC
O'Donovan
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Anita
A
Thapar
D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D015897:Comorbidity; D019955:Conduct Disorder / Q000453:epidemiology / Q000235:genetics; D004739:England; D005260:Female; D040741:Genetic Load; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005828:Genetics, Population; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D065886:Neurodevelopmental Disorders / Q000453:epidemiology / Q000235:genetics; D011159:Population Surveillance