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Identifying novel subtypes of irritability using a developmental genetic approach

By Lucy Riglin, Olga Eyre, Ajay K Thapar, Argyris Stringaris, Ellen Leibenluft, Daniel Pine, Kate Tilling, George Davey Smith, Michael C O'Donovan, Anita Thapar

Posted 02 Oct 2018
bioRxiv DOI: 10.1101/433342 (published DOI: 10.1176/appi.ajp.2019.18101134)

Objective. Irritability is a common reason for referral to services, strongly associated with impairment and negative outcomes, but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. This study used a developmental approach to test the hypothesis that there are several forms of irritability, including a 'neurodevelopmental/ADHD-like' subtype with onset in childhood and a 'depression/mood' subtype with onset in adolescence. Method. Data were analyzed in the Avon Longitudinal Study of Parents and Children, a prospective UK population-based cohort. Irritability trajectory-classes were estimated for 7924 individuals with data at multiple time-points across childhood and adolescence (4 possible time-points from approximately ages 7 to 15 years). Psychiatric diagnoses were assessed at approximately ages 7 and 15 years. Psychiatric genetic risk was indexed by polygenic risk scores (PRS) for attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) derived using large genome-wide association study results. Results. Five irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%) and high-persistent (2.4%). The early-onset, high-persistent trajectory was associated with male preponderance, childhood ADHD (OR=108.64 (57.45-204.41), p<0.001) and ADHD PRS (OR=1.31 (1.09-1.58), p=0.005); the adolescent-onset, increasing trajectory was associated with female preponderance, adolescent MDD (OR=5.14 (2.47-10.73), p<0.001) and MDD PRS (OR=1.20, (1.05-1.38), p=0.009). Both trajectory classes were associated with MDD diagnosis and ADHD genetic risk. Conclusions. The developmental context of irritability may be important in its conceptualization: early-onset persistent irritability maybe more 'neurodevelopmental/ADHD-like' and later-onset irritability more 'depression/mood-like'. This has implications for treatment as well as nosology.

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