Study: Rheumatoid Arthritis Associated with Neural Phenotypes

Jeremy Hall, PhD

New research associates genetic risk for rheumatoid arthritis (RA) with neural phenotypes despite RA’s current conceptualization as a connective tissue disorder.

Jeremy Hall, PhD, of the Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, UK, led the team of investigators. Their research strongly suggests a link between early-life cognitive difficulties and the potential for diagnosis of RA later in life. These findings could lead to new therapeutic approaches for cognitive impairments in RA and/or attention deficit hyperactivity disorder (ADHD).

The study population included 3296 to 5936 adolescents (depending on outcome) within the Avon Longitudinal Study of Parents and Children (ALSPAC) longitudinal birth cohort. Each subject’s health was assessed in detail since birth (with parental permission) for the purpose of the study. Investigators collected data periodically from September 1990 through the present, then analyzed said data from August 21, 2017 to May 21, 2018.

Genome-wide association studies (GWAS) determined 7977 subjects’ polygenic risk scores (PRSs) for RA, inflammatory bowel disease (IBD), and multiple sclerosis (MS). Of the study’s subjects, 48.7% were female and .11% had a known diagnosis of RA at age 22.

At age 8, subjects with a high PRS for RA displayed lower total, verbal, and (to a lesser degree) performance IQ, as well as working memory, verbal learning, processing speed, and problem solving, according to the Wechsler Intelligence Scale for Children. From ages 4-16, high PRS subjects also displayed symptoms of hyperactivity and inattention which were especially concentrated at age 13.

This was not the case when using PRSs based upon single-nucleotide polymorphism, but investigators emphasized that this secondary data did not detract from the primary finding via alternate PRS. Neither IBS nor MS presented equivalent associations at all.

Alongside PRS, investigators performed gene-based analyses using results of Multi-marker Analysis of GenoMic Annotation, which tested 7321 geneontology gene sets for enriched RA genes. Hierarchical clustering analysis also identified gene sets based on shared gene overlap. After correcting for multiple testing, results indicated 106 gene sets being associated with RA, which extended the formerly reported pathway analysis.

The study did, admittedly, have its limitations. Investigators noted that they couldn’t account for potential parental RA effects on child outcomes such as effects on the child’s upbringing but given the mean age of RA onset and the age group studied, this data’s effect was likely negligible. Reliance upon ALSPAC cohorts also inevitably lead to underrepresentation of lower social classes, potentially leading to selection bias.

Nevertheless, the study demonstrated multiple strengths, namely a large, well-characterized longitudinal cohort, as well as multiple self-report- and interview-based measures of cognition and psychopathology.

The collective results strongly suggest that RA, which is currently considered a multisystem connective tissue disorder, has deeper neurological impacts and associations than have been adequately explored, particularly relating to cognition. Future studies likely will examine the role of immune pathways in regulating cognitive function.

The study, “Association of Genetic Risk for Rheumatoid Arthritis With Cognitive and Psychiatric Phenotypes Across Childhood and Adolescence,” was published by JAMA Network Open.