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Association of Genetic Risk for Rheumatoid Arthritis with Cognitive and Psychiatric Phenotypes Across Childhood and Adolescence

Research output: Contribution to journalArticle

Original languageEnglish
Article numbere196118
Number of pages12
JournalJAMA Network Open
Issue number6
DateAccepted/In press - 6 May 2019
DatePublished (current) - 21 Jun 2019


The association of rheumatoid arthritis (RA) with cognitive and psychiatric phenotypes has been recognised. However, it is not known whether these phenotypes are a consequence of disease related factors, such as pain, or reflect shared aetiological factors.
To investigate whether genomic risk for RA is associated with cognitive and psychiatric symptoms in children and adolescents.
Design, Setting, and Participants:
A general population cohort study of adolescents from the Avon Longitudinal Study of Parents and Children birth cohort initially consisting of 14,062 children. Clinical and questionnaire data were collected periodically from September 6, 1990, with collection ongoing, and analyzed from August 21, 2017 to May 21, 2018.
Polygenic risk scores (PRSs) for RA.
Main Outcomes and Measures:
Measures of cognition (including IQ, working memory, verbal learning, processing speed, problem solving, selective attention and attentional control) and psychopathology (including anxiety, depression, negative symptoms, psychotic experiences, ADHD and hyperactive and inattentive symptoms) in childhood and adolescence (N = 3296-5936 depending on the outcome).
PRSs for RA were generated for 7977 individuals (48.7% female). Of these 7977 individuals, 9 (0.11%) had a known diagnosis of RA at age 22 years. Increased polygenic risk for RA was associated with lower total (s.d. change in total IQ per s.d. increase in PRS [β]), -0.05; 95% confidence interval (CI), -0.07, -0.02; P < 0.001), performance (β, -0.03; 95% CI, -0.06, -0.005; P = 0.02) and verbal IQ (β, -0.05; 95% CI, -0.08, -0.02; P < 0.001) at age 8 years (mean age of 8.6 (0.3) years) and symptoms of hyperactivity and inattention from age 4-16 years (strongest evidence of association: age 13 years [mean age of 13.2 (0.2) years]; odds ratio per s.d. increase in PRS, 1.25; 95% CI, 1.12, 1.39, P < 0.001). There was little evidence of association between the RA PRS and other measures of cognition and psychopathology. Gene-based analyses indicated that polygenic signal for RA was enriched for immune pathways (q ≤ 0.05). No equivalent associations were seen for polygenic risk associated with inflammatory bowel disease or multiple sclerosis.
Conclusions and relevance:
These findings support an association between genetic risk for RA and neural phenotypes, and suggests that cognitive impairment in RA is not simply secondary to disease-related processes or treatment effects. These results may suggest that genetic susceptibility for RA might impact on psychological wellbeing in early life and reinforces the emerging link between mental health and the immune system.

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