Genome-wide association study of pain sensitivity assessed by questionnaire and the cold pressor test

Abstract

We deployed an online pain sensitivity questionnaire (PSQ) and an at-home version of the cold pressor test (CPT) in a large genotyped cohort. We performed genome-wide association studies on the PSQ score (25,321 participants) and CPT duration (6853). We identified one new genome-wide significant locus associated with the PSQ score, which was located in the TSSC1 (also known as EIPR1) gene (rs58194899, OR 5 0.950 [0.933-0.967], P-value 5 1.9 3 10 28 ). Although high pain sensitivity measured by both PSQ and CPT was associated with individual history of chronic and acute pains, genetic correlation analyses surprisingly suggested an opposite direction: PSQ score was inversely genetically correlated with neck and shoulder pain (r g 5 20.71), rheumatoid arthritis (20.68), and osteoarthritis (20.38), and with known risk factors, such as the length of working week (20.65), smoking (20.36), or extreme BMI (20.23). Gene-based analysis followed by pathway analysis showed that genome-wide association studies results were enriched for genes expressed in the brain and involved in neuronal development and glutamatergic synapse signaling pathways. Finally, we confirmed that females with red hair were more sensitive to pain and found that genetic variation in the MC1R gene was associated with an increase in self-perceived pain sensitivity as assessed by the PSQ.

We need to talk: The urgent conversation on chronic pain, mental health, prescribing patterns and the opioid crisis

“…As is common with multifactorial, complex phenotypes, the genetic and environmental risk factors that underlie the co-occurrence of internalising conditions and chronic pain are likely to be numerous. Identified environmental risk factors that impinge on both pain and internalisation include early-life adversities such as childhood parental loss (You et al, 2019), and examples of credible candidate genetic risk factors for both anxiety and pain include the acid-sensing ion channels genes family (Battaglia et al, 2019; Cittaro et al, 2016; Fontanillas et al, 2022; Giannese et al, 2018; Taugher et al, 2014; Wemmie et al, 2013).…”

A shared genetic signature for common chronic pain conditions and its impact on biopsychosocial traits

“…Further work is required including: (i) genetic epidemiology studies collecting data on more specific chronic pain diagnoses, clinical traits (e.g., pro- & anti-nociceptive phenotypes, quantitative sensory testing, 70–73 medication/treatment responses 52,74 ) and epigenetic factors 75 (e.g., early life stress, physical activity); (ii) replication in other large genotyped datasets, 5,19 particularly population samples with non-European ancestry; and (iii) incorporating putative transdiagnostic subtypes and genetic risk stratification of placebo/control groups in clinical trials of chronic pain interventions. 3,4,27,52,76…”

A systematic review of genome-wide association studies for pain, nociception, neuropathy, and pain treatment responses

“…Fontanillas et al 34 conducted the first GWAS on pain sensitivity. Two phenotypes were used to measure pain sensitivity: a pain questionnaire (n 5 25,321) and a cold pressor test (n 5 6853).…”

“…Indeed, GWASes have identified many putative causal genes other than the previously described candidate genes, which shed new light on the mechanism of pain development. 34 Unfortunately, most candidate and genome-wide association studies on pain report inconsistent results, which is partly due to the low statistical power of the studies. Therefore, few findings are convincing enough to be investigated further.…”