A distinctive profile of family genetic risk scores in a Swedish national sample of cases of fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome compared to rheumatoid arthritis and major depression

Abstract

Background Functional somatic disorders (FSD) feature medical symptoms of unclear etiology. Attempts to clarify their origin have been hampered by a lack of rigorous research designs. We sought to clarify the etiology of the FSD by examining the genetic risk patterns for FSD and other related disorders. Methods This study was performed in 5 829 186 individuals from Swedish national registers. We quantified familial genetic risk for FSD, internalizing disorders, and somatic disorders in cases of chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS), using a novel method based on aggregate risk in first to fifth degree relatives, adjusting for cohabitation. We compared these profiles with those of a prototypic internalizing psychiatric – major depression (MD) – and a somatic/autoimmune disorder: rheumatoid arthritis (RA). Results Patients with FM carry substantial genetic risks not only for FM, but also for pain syndromes and internalizing, autoimmune and sleep disorders. The genetic risk profiles for IBS and CFS are also widely distributed although with lower average risks. By contrast, genetic risk profiles of MD and RA are much more restricted to related conditions. Conclusion Patients with FM have a relatively unique family genetic risk score profile with elevated genetic risk across a range of disorders that differs markedly from the profiles of a classic autoimmune disorder (RA) and internalizing disorder (MD). A similar less marked pattern of genetic risks was seen for IBS and CFS. FSD arise from a distinctive pattern of genetic liability for a diversity of psychiatric, autoimmune, pain, sleep, and functional somatic disorders.

The multi-generational familial aggregation of interstitial cystitis, other chronic nociplastic pain disorders, depression, and panic disorder

“…Our findings are consistent with the previous twin (Kato et al, 2009; Vehof et al, 2014) and family based (Kendler et al, 2022) studies addressing the question of heritable and genetic overlap of these disorders. Though previous studies differed in methodological aspects (e.g.…”

“…Some support for this hypothesis is provided by several family studies that have found increased risk for other nociplastic disorders in relatives of patients with IC (Allen-Brady, Norton, & Cannon-Albright, 2015; Kendler, Rosmalen, Ohlsson, Sundquist, & Sundquist, 2022; Warren, Jackson, Langenberg, Meyers, & Xu, 2004; Weissman et al, 2004) suggesting common heritable components. Two population-based twin studies have also found evidence for shared genetic contributions among several nociplastic pain disorders (Kato, Sullivan, Evengard, & Pedersen, 2009; Vehof, Zavos, Lachance, Hammond, & Williams, 2014), as has a family-based study using pedigree-based genetic risk scores (Kendler et al, 2022), though none of these included specific data on IC.…”

Relationship of Family Genetic Risk Score With Diagnostic Trajectory in a Swedish National Sample of Incident Cases of Major Depression, Bipolar Disorder, Other Nonaffective Psychosis, and Schizophrenia

“…Fourth, the FGRS, a family phenotype-based method to assess quantitative genetic risk, has been now widely published, with prior reports demonstrating that this score is not highly sensitive to the various assumptions involved in its calculation, that the correction for cohabitation effects performs appropriately, and the method agrees well with other similar, although statistically distinct, approaches …”

Proinflammatory cytokines and their receptors as druggable targets to alleviate pathological pain

“…Despite specific genetic risk profiles, chronic inflammatory diseases, such as rheumatoid arthritis (RA) or irritable bowel syndrome, and, more recently, even fibromyalgia syndrome not only share pain as a long-lasting symptom, reducing patients' quality of life, but also share signatures of central sensitization and an involvement of proinflammatory cytokines in pain pathogenesis. 6,11,173,255,277,375,376 Neuroinflammation and specifically proinflammatory cytokines are further critical regulators of neuropathic pain resulting from nerve damage, such as traumatic nerve lesions or complex regional pain syndrome (CRPS), as well as antineoplastic chemotherapies, diabetes, or postherpetic neuralgia. 26,42,148,195,212,303 Emerging evidence supports the idea that cytokines may even be relevant at brain level for the development of mental comorbidities.…”