Genetic Patterning for Psychopathology Is Distinct in Children and Adults
Key findings
- This analysis of prospective data from 11,875 participants in the multicenter Adolescent Brain Cognitive Development Study evaluated relationships of disease-specific and cross-disorder polygenic scores (PGS) to psychopathology at ages 9–10 and 11–12
- A "Neurodevelopmental" PGS was more sensitive than any disease-specific PGS or other cross-disorder PGS in capturing variance in psychopathology across numerous domains
- The Neurodevelopmental score represents genetic risk primarily shared among early neurodevelopmental disorders (autism, attention-deficit/hyperactivity disorder and Tourette's syndrome), along with major depressive disorder
- The findings were replicated using data on 1,850 participants in the Generation R Study, a European prospective birth cohort study
- Future observations of when, and in whom, clinical sequelae of the Neurodevelopmental PGS are supplanted by disorder-specific PGS may allow refinement of predictive algorithms for youth who show non-specific early symptoms
Polygenic scores (PGS) have provided novel insights into the biological origins of neuropsychiatric disorders and even allow calculations of an individual's risk of developing such a disorder. However, PGS are of limited applicability to children, partly because the studies used to derive them have largely or exclusively enrolled adults.
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Furthermore, even more so than in adults, psychiatric symptoms in children tend not to conform with discrete diagnostic categories. Researchers at Massachusetts General Hospital have determined that a PGS accounting for overlapping risk among neurodevelopmental disorders is better suited than disorder-specific PGS scores for capturing psychopathology in children.
Dylan E. Hughes, of the Department of Psychiatry, Joshua L. Roffman, MD, MMSc, director of the Mass General Early Brain Development Initiative and co-director of Mass General Neuroscience, and colleagues report the findings in Nature Neuroscience.
Methods
The researchers analyzed data from the Adolescent Brain Cognitive Development (ABCD) Study, which enrolled 11,875 children, ages 9 to 10, at 22 U.S. centers. They included complete data from the baseline assessments and the year 2 assessments (ages 11–12; n=8,076), which became available in June 2022.
Dimensions of psychopathology were measured at both time points using the:
- Child Behavior Checklist (CBCL)—Items are organized into eight individual syndrome scales (anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior and aggressive behavior) and three broader scales (internalizing, externalizing and total symptoms), all reported by parents
- Prodromal Questionnaire–Brief Child version—Establishes the presence or absence of symptoms of prodromal psychosis as reported by the child, with a rating of distress for each endorsed item
Genotype data from 4,462 youth in the ABCD Study were used to calculate PGS for eight psychiatric illnesses: anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ), and Tourette's syndrome (TS).
Disorder-specific PGS were obtained from various studies conducted by the Psychiatric Genomics Consortium. The researchers also used cross-disorder PGS identified from the latest Psychiatric Genomics Consortium cross-disorders study:
- Compulsive—Incorporates the AN, OCD and TS PGS
- Mood–Psychotic—Incorporates the BPD, MDD and SCZ PGS
- Neurodevelopmental—Incorporates the ADHD, ASD, MDD and TS PGS
Principal Analysis
Among the three cross-disorder scores, the Neurodevelopmental PGS predicted the widest range of psychopathology. Compulsive and Mood–Psychotic contributed only minimally to variance in CBCL total score at ages 9 to 10 and even less so at ages 11 to 12.
Moreover, at both time points, Neurodevelopmental accounted for significantly more variance in CBCL broader scales and psychosis spectrum symptoms than any other PGS, except that MDD predicted internalizing symptoms.
When comparing the top to bottom quintiles, Neurodevelopmental was the only measure of genetic risk (either disorder-specific or cross-disorder) consistently associated with higher odds of both:
- Clinically significant psychopathology (CBCL total score ≥64) at ages 9–10 (OR, 1.88; P=0.002)
- Newly emergent clinically significant psychopathology at ages 11–12 (OR, 2.30; P=0.02)
Replication
To try to replicate the findings, the researchers examined data from the Generation R Study, a European prospective birth cohort study that's following the offspring of 9,778 mothers from fetal life to adulthood. The team used June 2022 data on 1,850 children at age 9 and 1,791 at age 13.
The results were similar to those in the primary analysis. At both ages, Neurodevelopmental was associated with the widest spectrum of psychopathology. At age 13, Neurodevelopmental outperformed all PGS except ADHD in predicting CBCL total, externalizing, internalizing and psychosis spectrum symptoms.
Questions for Future Research
For adults, disorder-specific PGS most strongly predict the risk of a psychiatric diagnosis, even though there's extensive genetic overlap across major psychiatric disorders. As participants in the ABCD Study approach adulthood and psychopathology becomes further differentiated, it will be interesting to follow whether disease-specific PGS account for more variance in symptoms than they do currently.
Prospectively observing when, and in whom, clinical sequelae of the Neurodevelopmental PGS are supplanted by disorder-specific PGS may allow refinement of predictive algorithms for youth who show non-specific early symptoms.
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