PubMed Highlight: Genes contributing to pain sensitivity in the normal population: an exome sequencing study

This interesting study applies exome sequencing to determine rare variants associated with pain sensitivity. The approach used by the authors relies both on twins study design (they tested two groups of about 200 healthy volunteers from the Twin UK project) and selection of extreme phenotypes (authors compared individuals performing at the extreme ranges of standard pain tests). Angiotensin related pathway emerged as a good candidate for pain sensitivity modulation.

Genes contributing to pain sensitivity in the normal population: an exome sequencing study

PLoS Genet. 2012 Dec;8(12)

Williams FM, Scollen S, Cao D, Memari Y, Hyde CL, Zhang B, Sidders B, Ziemek D, Shi Y, Harris J, Harrow I, Dougherty B, Malarstig A, McEwen R, Stephens JC, Patel K, Menni C, Shin SY, Hodgkiss D, Surdulescu G, He W, Jin X, McMahon SB, Soranzo N, John S, Wang J, Spector TD.

Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. 

Abstract

Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF<5%) influencing pain sensitivity, we explored the genetic variation in individuals' responses to experimental pain. Quantitative sensory testing to heat pain was performed in 2,500 volunteers from TwinsUK (TUK): exome sequencing to a depth of 70× was carried out on DNA from singletons at the high and low ends of the heat pain sensitivity distribution in two separate subsamples. Thus in TUK1, 101 pain-sensitive and 102 pain-insensitive were examined, while in TUK2 there were 114 and 96 individuals respectively. A combination of methods was used to test the association between rare variants and pain sensitivity, and the function of the genes identified was explored using network analysis. Using causal reasoning analysis on the genes with different patterns of SNVs by pain sensitivity status, we observed a significant enrichment of variants in genes of the angiotensin pathway (Bonferroni corrected p = 3.8×10(-4)). This pathway is already implicated in animal models and human studies of pain, supporting the notion that it may provide fruitful new targets in pain management. The approach of sequencing extreme exome variation in normal individuals has provided important insights into gene networks mediating pain sensitivity in humans and will be applicable to other common complex traits.