Infant Body Composition and Other Early Life Determinants of Obesity and Adult Diseases

Introduction: Chronic pain and pain sensitivity are complex traits with a variety of potential determinants. Although not yet fully elucidated, pain sensitivity and the risk for chronic pain are thought to be partly genetic. In our study, we attempt to further elucidate the genetic predisposition of pain sensitivity. Methods: In a total number of 3,795 participants from the Rotterdam study (a large prospective population based cohort) heat pain thresholds (HPT) were determined. We estimated the total additive genetic influence on HPT measurements due to common genetic variation using GCTA, and we performed a genome wide association study (GWAS) to identify new loci associated with HPT in the general population. Finally, we reviewed the literature for previously reported DNA variants associated with experimental pain thresholds and tried to replicate these findings in our dataset. Results: The overall heritability estimate of HPT was 19%. In individuals without chronic pain, this estimate was 32% compared to 9% in individuals with chronic pain. In addition, the heritability was higher in women compared to men. Our GWAS revealed one genome-wide significant signal (1:176688345:D) which is located in the twelfth intron of the PAPPA2 gene (p= 2.48*10). Additionally, we found six suggestive signals (P<1.0*10). Genetic variants previously associated with pain sensitivity were not replicated in our study. Conclusion: A significant proportion of the variability of HPT is explained by genetics. The extent to which HPT is genetically determined is higher when individuals do not experience chronic pain. Future genetic studies on pain sensitivity should take the presence of chronic pain into account since it influences the phenotype substantially. This largest genetic screen for pain sensitivity up to date provides new potential genetic loci for further research. Genetic of Heat Pain Threshold 27