TPH2 G/T polymorphism is associated with hyperphagia, IQ, and internalizing problems in Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a relatively rare genetic disorder well-known for its genetic and phenotypic complexities. Seen in approximately 1 in 15,000 births, PWS is characterized by mild to moderate levels of intellectual disability, growth hormone dysregulation, hyperphagia, and increased risks of morbid obesity (Cassidy & Driscoll, 2009). The PWS behavioral phenotype includes high rate of repetitive, compulsive behaviors, as well as irritability, negative and labile moods, impulsivity, and tantrums (Dykens, Summar, & Roof, 2005). These problems, coupled with hyperphagia, necessitate that affected individuals receive lifelong supervision and supports. PWS is caused by a lack of paternally-derived imprinted material on chromosome 15q11-q13. In approximately 70% of cases, PWS is due to a paternal deletion at 15q11-q13, and deletions can be further characterized according to size, with Type I deletions being about 500 kb larger than Type II deletions. Approximately 25% of PWS cases are due to maternal uniparental disomy (mUPD), or when both copies of chromosome 15 are inherited from the mother, and 5% to translocations or imprinting center mutations. Genetic causes of PWS aside, a growing literature on biomarkers suggests that genetic variation outside of the PWS critical region may greatly influence phenotypic expression in PWS. Based on converging clinical and genetic findings, for example, aberrant serotonergic functioning is strongly implicated in PWS. Individuals with PWS are prone to disorders or symptoms regulated by serotonin, including aberrant appetite and sleep, affective illness and mood disorders, and compulsive behaviors that are similar to those seen in autism spectrum disorders or obsessive-compulsive disorder (Clarke et al., 2002; Dykens, Cassidy, & Leckman, 1996). More severe symptoms or disorders (e.g., psychosis) are typically manifest in those with mUPD (e.g., Soni et al., 2007; Vogels et al., 2003). Treatment with selective serotonin reuptake inhibitors (SSRI’s) is widely used and in some people, reduces irritability, moodiness, outbursts, and compulsions (Dykens & Shah, 2003). The PWS critical region is also implicated in the production of serotonin. A small nucleolar RNA (snoRNA), HBII-52 (SNORD115), located in the 15q11-q13 region, has been shown to regulate the processing of the mRNA of the serotonin 2C receptor, located elsewhere on the genome (Kishore & Stamm, 2006). Several mouse models of PWS exist, including mice deleted for HBII-52 (Ding et al., 2008), or with altered 2C receptor mRNA functioning (Morabito et al., 2010). As with other PWS models, these mice are hyperphagic but not obese. Sahoo et al. (2008) reported a boy with features consistent with the diagnosis of PWS who had a small deletion of only the snoRNA HBII-85 (SNORD116) and part of HBII-52 (SNORD115) region, strongly implicating these clusters in the PWS phenotype. Lack of HBII-52 expression in PWS may lead to altered processing of serotonin 2C receptor mRNA, which may impact the efficacy of SSRIs in this population. Treatments with SSRI’s are not consistently beneficial in PWS, with some persons showing a worsening of target symptoms (Dykens & Shah, 2003). This variability in treatment response suggests that the PWS phenotype may also be influenced by genes that are known to alter serotonin production among people in general. Although many genes are involved in the production of serotonin, we selected tryptophan hydroxylase (TPH2) for initial study, as it is the first-step and rate-limiting enzyme in the biosynthesis of serotonin in the brain. While TPH1 is expressed mostly in cells of the gut, TPH2 is expressed predominantly in the brainstem and is responsible for the production of serotonin in the brain (Walther & Bader, 2003). Polymorphisms in TPH2 are implicated in depression, anxiety, and aggression, as well as in the regulation of mood, attention, appetite, and sleep; all of these processes are disrupted in PWS (Cassidy & Driscoll, 2009). Associations have been reported between sequence variants (single nucleotide polymorphisms, SNPs) in the TPH2 promoter (G-703T; dbSNP accession number rs4570625) and children with OCD (Mosser et al., 2006), autism (Coon et al., 2005), and ADHD (Walitza et al., 2005), and in adult depression or bi-polar disorder (Harvey et al., 2004; Zhang et al., 2005). Other investigators have examined the effects of the TPH2, G-703T polymorphisms on broader personality traits or emotional reactivity. Compared to those homozygous for the G allele, Brown et al. (2005) identified increased amygdala activation in response to angry or fearful faces in healthy adults with the T allele. Canli et al. (2005) subsequently demonstrated increased amygdala activation in participants with the T allele versus G/G allele in response to faces depicting both negative and positive affect. The TPH2 -703 T allele may thus modulate emotional arousal in general, and is implicated in disorders involving emotional dysregulation. This study identified TPH2 G/T allele status in a large cohort of 92 participants with genetically confirmed PWS, and compared salient features of PWS across those with or without polymorphisms in this allele. We predicted that the frequency of polymorphisms in the TPH2 G/T allele in PWS would be similar to those found in the general population. We also hypothesized that, compared to participants who are homozygous for the G/G allele, those with a loss of TPH2 enzyme function, or with a G/T or T/T allele, would show significantly more behavioral, mood, or emotional problems. Finally, although gender differences are rarely reported in PWS, gender by genotype differences may exist as females in the general population are more prone to mood disorders (Kessler et al., 2003). Significant gender effects of the TPH2 T/G allele have been identified in the emotional startle response (Ambruster et al., 2010), susceptibility to depression (Utge et al., 2010), and panic disorder (Maron et al., 2007). As such, we reasoned that females with PWS may be more vulnerable to the effects of the T polymorphism and reduced serotonin production.