Search

Low back (LBP) and chronic widespread musculoskeletal pain (CWP) both have a significant genetic component and are associated with increased body mass index (BMI). We examined whether LBP and CWP share common genetic factors, and to what extent this correlation is modified by the genetic factors influencing BMI. Genetic analysis of binary traits such as pain is not simple, particularly if their risk is associated with age or other quantitative traits. Implementing Falconer's polygenic threshold concept for dichotomous traits inheritance, we developed new software to examine the extent of the genetic influence on LBP and CWP under age and BMI dependence. The analysis was conducted on 3266 and 2256 UK female twins, assessed for LBP and CWP, respectively. Analysis of the liability scores with threshold to LBP and CWP established substantial contribution of genetic factors to their variation (h(2)0.60, p0.004-0.0003) and covariation (p=3.1E-08). Some 39% of the CWP and 70% of the LBP heritability estimates were attributable to genetic effects shared by both phenotypes, and 40% and 67% of the residual variation is caused by environmental factors simultaneously affecting both pain syndromes. However, contribution of BMI to variation/covariation of both pain phenotypes-although statistically highly significant (p∼10-7)-was not determinative.

A high melanocytic nevi count is the strongest known risk factor for cutaneous melanoma. We conducted a genome-wide association study for nevus count using 297,108 SNPs in 1,524 twins, with validation in an independent cohort of 4,107 individuals. We identified strongly associated variants in MTAP, a gene adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (rs4636294, combined P = 3.4 x 10(-15)), as well as in PLA2G6 on 22q13.1 (rs2284063, combined P = 3.4 x 10(-8)). In addition, variants in these two loci showed association with melanoma risk in 3,131 melanoma cases from two independent studies, including rs10757257 at 9p21, combined P = 3.4 x 10(-8), OR = 1.23 (95% CI = 1.15-1.30) and rs132985 at 22q13.1, combined P = 2.6 x 10(-7), OR = 1.23 (95% CI = 1.15-1.30). This provides the first report of common variants associated to nevus number and demonstrates association of these variants with melanoma susceptibility.