title: Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone.
abstract: BACKGROUND
  The genetic background of Growth Hormone (GH) secretion is not well understood. Mutations giving rise to a stop codon have a high likelihood of affecting protein function.
  
  
  OBJECTIVE
  To analyze likely functional stop codon mutations that are associated with fasting plasma concentration of Growth Hormone.
  
  
  METHODS
  We analyzed stop codon mutations in 5451 individuals in the Malmö Diet and Cancer study by genotyping the Illumina Exome Chip. To enrich for stop codon mutations with likely functional effects on protein function, we focused on those disrupting >80% of the predicted amino acid sequence, which were carried by ≥ 10 individuals. Such mutations were related to GH concentration, measured with a high sensitivity assay (hs-GH) and, if nominally significant, to GH related phenotypes, using linear regression analysis.
  
  
  RESULTS
  Two stop codon mutations were associated with the fasting concentration of hs-GH. rs121909305 (NP_005370.1:p.R93*) [Minor Allele Frequency (MAF) = 0.8%] in the Myosin 1A gene (MYO1A) was associated with a 0.36 (95%CI, 0.04 to 0.54; p=0.02) increment of the standardized value of the natural logarithm of hs-GH per 1 minor allele and rs35699176 (NP_067040.1:p.Q100*) in the Zink Finger protein 77 gene (ZNF77) (MAF = 4.8%) was associated with a 0.12 (95%CI, 0.02 to 0.22; p = 0.02) increase of hs-GH. The mutated high hs-GH associated allele of MYO1A was related to lower BMI (β-coefficient, -0.22; p = 0.05), waist (β-coefficient, -0.22; p = 0.04), body fat percentage (β-coefficient, -0.23; p = 0.03) and with higher HDL (β-coefficient, 0.23; p = 0.04). The ZNF77 stop codon was associated with height (β-coefficient, 0.11; p = 0.02) but not with cardiometabolic risk factors.
  
  
  CONCLUSIONS
  We here suggest that a stop codon of MYO1A, disrupting 91% of the predicted amino acid sequence, is associated with higher hs-GH and GH-related traits suggesting that MYO1A is involved in GH metabolism and possibly body fat distribution. However, our results are preliminary and need replication in independent populations.
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Hallengren
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Engström
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Persson
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
mesh_terms: D018388:Codon, Terminator / Q000235:genetics*; D005215:Fasting / Q000097:blood* / Q000502:physiology; D005260:Female; D019382:Human Growth Hormone / Q000097:blood* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics / Q000502:physiology; D024461:Myosin Type I / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide
chemical_list: D018388:Codon, Terminator; C062291:MYO1A protein, human; D019382:Human Growth Hormone; D024461:Myosin Type I; D018995:Myosin Heavy Chains