title: Genes contributing to pain sensitivity in the normal population: an exome sequencing study.
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.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Frances M K
authors.initials: FM
authors.lastname: Williams
authors.forename: Serena
authors.initials: S
authors.lastname: Scollen
authors.forename: Dandan
authors.initials: D
authors.lastname: Cao
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.forename: Craig L
authors.initials: CL
authors.lastname: Hyde
authors.forename: Baohong
authors.initials: B
authors.lastname: Zhang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sidders
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
authors.forename: Yujian
authors.initials: Y
authors.lastname: Shi
authors.forename: Juliette
authors.initials: J
authors.lastname: Harris
authors.forename: Ian
authors.initials: I
authors.lastname: Harrow
authors.forename: Brian
authors.initials: B
authors.lastname: Dougherty
authors.forename: Anders
authors.initials: A
authors.lastname: Malarstig
authors.forename: Robert
authors.initials: R
authors.lastname: McEwen
authors.forename: Joel C
authors.initials: JC
authors.lastname: Stephens
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Dylan
authors.initials: D
authors.lastname: Hodgkiss
authors.forename: Gabriela
authors.initials: G
authors.lastname: Surdulescu
authors.forename: Wen
authors.initials: W
authors.lastname: He
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Sally
authors.initials: S
authors.lastname: John
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000328:Adult; D000809:Angiotensins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D059472:Exome / Q000235:genetics*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006358:Hot Temperature; D006801:Humans; D008297:Male; D010146:Pain / Q000235:genetics / Q000503:physiopathology; D017288:Pain Threshold; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D000809:Angiotensins