GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors

Abstract

Serum butyrylcholinesterase (BCHE) activity is associated with obesity, blood pressure and biomarkers of cardiovascular and diabetes risk. We have conducted a genome-wide association scan to discover genetic variants affecting BCHE activity, and to clarify whether the associations between BCHE activity and cardiometabolic risk factors are caused by variation in BCHE or whether BCHE variation is secondary to the metabolic abnormalities. We measured serum BCHE in adolescents and adults from three cohorts of Australian twin and family studies. The genotypes from ∼2.4 million single-nucleotide polymorphisms (SNPs) were available in 8791 participants with BCHE measurements. We detected significant associations with BCHE activity at three independent groups of SNPs at the BCHE locus (P = 5.8 × 10(-262), 7.8 × 10(-47), 2.9 × 10(-12)) and at four other loci: RNPEP (P = 9.4 × 10(-16)), RAPH1-ABI2 (P = 4.1 × 10(-18)), UGT1A1 (P = 4.0 × 10(-8)) and an intergenic region on chromosome 8 (P = 1.4 × 10(-8)). These loci affecting BCHE activity were not associated with metabolic risk factors. On the other hand, SNPs in genes previously associated with metabolic risk had effects on BCHE activity more often than can be explained by chance. In particular, SNPs within FTO and GCKR were associated with BCHE activity, but their effects were partly mediated by body mass index and triglycerides, respectively. We conclude that variation in BCHE activity is due to multiple variants across the spectrum from uncommon/large effect to common/small effect, and partly results from (rather than causes) metabolic abnormalities.

Figure 1.

Clustering of phenotypes related to metabolic risk for cardiovascular disease and type 2 diabetes and BCHE activity, measured in the 2000–2005 Adult Studies. X- and Y-axes show the factor loadings from PCs analysis for each phenotype for Factor 1 and Factor 2.

Figure 2.

Manhattan plots for initial association analysis, and after adding rs1803274 (BCHE K variant) and then rs2668196 genotype as covariates.

Figure 3.

Detailed plots of associations with SNPs at the BCHE locus. (A1) Initial results; (A2) after covariate adjustment for rs1803274 genotype; (A3) after covariate adjustment for rs1803274 and rs2668196 genotypes.

Figure 4.

Detailed plots of associations with SNPs at other loci. (A) RAPH1-ABI2 locus on chromosome 1; (B): RNPEP locus on chromosome 2; (C): UGT1A locus on chromosome 2 after covariate adjustment for rs1803274 genotype; (D): chromosome 8 locus after covariate adjustment for rs1803274 genotype.

Figure 5.

Quantile–quantile plot of observed against expected P-values for allelic associations with BCHE activity, for 203 SNPs previously reported as showing associations at P < 5.0 × 10⁻⁷ with one or more components of the metabolic syndrome. The grey shaded area represents the 95% confidence interval.