Identification of three new genes associated to serum Butyrylcholinesterase activity by GWAS in two genetically distant isolated populations.

Introduction: Great interest in the physiological role of BuChE has been given since it was demonstrated the correlation of its serum activity levels with Metabolic Syndrome (MS). Many variants in the BuChE locus have been described which influence the serum activity level and more recently other QTL were identified by GWAS in a large cohorts of outbreed populations. However it is not known the genetic link between this enzyme and the MS. Objectives: To investigate the phenotypic correlation between serum BuChE activity levels and MS endophenotypes and to identify genetic determinants of the trait in homogeneous populations. Methods: We analyzed 2,500 participants from two Italian isolated populations representing the Ogliastra (N=1272) and Friuli Venezia Giulia (N=1226) Genetic Parks. A comparison of continuous variables was performed by ANOVA. Factor Analyses to illustrate the relationship between BuChe activity and other variables was performed using Principal Components method. GWAS was carried out in each cohort with 2.5M genotyped or imputed SNPs using a mixed linear regression model taking into account sex, age, BMI and genomic kinship. In conditional analyses SNPs with the GWAS lowest P values were selected and included as covariates in the linear regression. Meta-analyses were conducted using the inverse variance weighted method. Results: A significant (P<0.05) phenotypic correlation was detected between BuChE levels and BMI, LDL and HDL cholesterol, fasting glucose, triglycerides, diastolic and systolic blood pressure, MS (ATPIII). Factor analysis confirmed these results. We identified five genome wide significant loci: two (rs1803274 BuChE K variant P=4.7e-68 on 3q26 and rs11686036 ABI2-RAPH1P=2.2e-9 on 2q33) described in recently GWAS and three (rs2911262 ANKRD11 P=6.1e-9 on 16q24, rs1244509 TAF3 P=3.4e-8 on 10p15 and rs4308478 SPOCK1 P=1.7e-8 on 5q31) novel. Some of the several suggestive loci reached a significant P value in meta-analysis with previously published GWAS data. We tested the effects of loci previously reported to affect MS components such as GALNT and LPIN (P<0.01 bonferroni corrected). Conclusions: We confirmed a strong correlation of BuChE activity with MS. We add new genetic data which may help to better understand the BuChE pathway complexity. Additional Next-gen sequencing and functional studies are required to elucidate the role of this increasingly interesting enzyme in physiology and disease.