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

Hum Mol Genet. 2011 Nov 15;20(22):4504-14. doi: 10.1093/hmg/ddr375. Epub 2011 Aug 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adolescent
  • Adult
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Aminopeptidases / genetics
  • Butyrylcholinesterase / genetics*
  • Carrier Proteins / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods*
  • Genotype
  • Glucuronosyltransferase / genetics
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Proteins / genetics
  • Risk Factors
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GCKR protein, human
  • Membrane Proteins
  • Proteins
  • RAPH1 protein, human
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Butyrylcholinesterase
  • Aminopeptidases
  • aminopeptidase B