title: TPH2 G/T polymorphism is associated with hyperphagia, IQ, and internalizing problems in Prader-Willi syndrome.
abstract: BACKGROUND
  Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by intellectual disabilities, growth hormone dysregulation, hyperphagia, increased risks of morbid obesity, compulsive behaviors, and irritability. As aberrant serotonergic functioning is strongly implicated in PWS, we examined associations between the PWS phenotype and polymorphisms in tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the biosynthesis of serotonin in the brain.
  
  
  METHODS
  Ninety-two individuals with PWS aged 4 to 50 years (M = 21.97) were genotyped for the TPH2 G703-T polymorphism. IQ testing was conducted in offspring, and parents completed questionnaires that tapped their child's compulsivity, hyperphagia, and other behavior problems.
  
  
  RESULTS
  As expected, the frequency of G/T or T/T polymorphisms in participants with PWS (39%) was similar to rates found in the general population (38%). Compared to those with a homozygous (G/G) genotype, individuals with a T allele had significantly higher hyperphagic behavior, drive, and severity scores, and they also had a younger age of onset of hyperphagia. Those with a T allele also had higher IQ scores than their counterparts. Females with a T allele had significantly higher internalizing symptoms, primarily anxiety and depression, than all others.
  
  
  CONCLUSIONS
  TPH2 G/T polymorphisms, and presumed loss of enzyme function, were associated with specific aspects of the PWS phenotype. Aberrant serotonergic functioning is strongly implicated in hyperphagia in PWS, and females with TPH2 T alleles may be at higher risk for affective or mood disorders. Findings hold promise for examining other serotonin-altering genes in PWS, and for future serotonin-altering treatment trials.
authors.affiliation: Vanderbilt Kennedy Center for Research on Human Development, Departments of Psychology and Human Development, Psychiatry, and Pediatrics, Vanderbilt University, Nashville, TN, USA. elisabeth.dykens@vanderbilt.edu
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Dykens
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Roof
authors.forename: Douglas
authors.initials: D
authors.lastname: Bittel
authors.forename: Merlin G
authors.initials: MG
authors.lastname: Butler
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D006963:Hyperphagia / Q000235:genetics*; D007360:Intelligence / Q000235:genetics*; D007389:Internal-External Control; D008297:Male; D008875:Middle Aged; D009035:Mothers; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000523:psychology*; D011795:Surveys and Questionnaires; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D055815:Young Adult
chemical_list: C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase