Phenylthiocarbamide (PTC) perception in patients with schizophrenia and first-degree family members: Relationship to clinical symptomatology and psychophysical olfactory performance Paul J. Moberg a,b,���, Colleen McGue a, Stephen J. Kanes a,b, David R. Roalf a, Catherine C. Balderston a, Raquel E. Gur a, Christian G. Kohler a, Bruce I. Turetsky a,b a Schizophrenia Research Center, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, United States b Smell and Taste Center, Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, United States Received 18 May 2006 received in revised form 18 November 2006 accepted 26 November 2006 Available online 8 January 2007 Abstract The inability to taste phenylthiocarbamide (PTC ���taste-blindness���) has been associated with a number of medical and neurological illnesses not typically related to taste. We examined PTC sensitivity in 67 schizophrenia patients, 30 healthy controls, and 30 first-degree relatives to determine whether taster status could represent a simple vulnerability marker. A higher prevalence of non-tasters was seen in patients and family members relative to healthy controls. Among patients, non-tasters exhibited increased levels of negative and first-rank symptoms as well as poorer right nostril odor identification skills relative to PTC tasters. These differences were not explained by age, sex, education, smoking, or intensity differences. Phenotypic variation in PTC sensitivity is thought to be genetic in origin and suggests greater illness risk for those subjects with recessive taster alleles. �� 2006 Elsevier B.V. All rights reserved. Keywords: Schizophrenia Family Taste Phenylthiocarbamide PTC Genetics 1. Introduction Sensitivity to the bitter-tasting compound phenyl- thiocarbamide (PTC) has long been believed to be a simple Mendelian recessive trait, with tasters defined as having at least one dominant allele, (i.e., TT or Tt) and non-tasters displaying a double recessive genotype (i.e., tt) (Bartoshuk et al., 1994 Blakeslee, 1932 Drayna, 2005 Fox, 1931 Kim et al., 2003 Snyder, 1931). The strong genetic basis for sensitivity to PTC has been used as a tool to trace family lineages and population migration patterns (Guo and Reed, 2001 Mattes, 2004). Previous studies have demonstrated that in the U.S. population, approximately 30% are non-tasters of PTC, whereas 70% are tasters of this substance (Drayna, 2005 Guo and Reed, 2001). In a landmark study of PTC sensitivity in the Utah Genetic Reference Project families, a single major locus on chromosome 7 was Schizophrenia Research 90 (2007) 221���228 www.elsevier.com/locate/schres ��� Corresponding author. Brain-Behavior Laboratory, Department of Psychiatry, 10th Floor, Gates Building, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, United States. Tel.: +1 215 615 3608 fax: +1 215 662 7903. E-mail address: moberg@bbl.med.upenn.edu (P.J. Moberg). 0920-9964/$ - see front matter �� 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.11.014

found to be responsible for most of the phenotypic variation that exists in the population (Drayna et al., 2003). In addition, a modest linkage score between PTC taste ability and markers on chromosome 16p has been reported (Reed, 2000). Recent investigations of PTC tasting have focused on the intracellular activation of various G proteins. In an extensive genetic survey of the chromosome 7 linkage region, Kim and colleagues found that the PTC gene encodes for a specific G protein taste receptor, TAS2R38 (7q35���36), which accounts for all of the bimodality in PTC taste perception (Kim et al., 2003). The observed differences in taste perception of PTC are hypothesized to be due to variations in types of G proteins activated by TAS2R38 haplotypes (Bufe et al., 2005). In addition to taste, G protein-dysregulation has been strongly linked to mental illnesses such as major depressive disorder, manic depression, and schizophrenia (Schreiber and Avissar, 2000). Indeed, heterotrimeric G proteins are crucial elements in post-receptor information transduction and have been implicated in the biochemical mechanism of many of the drugs used to treat psychiatric disorders (Schreiber and Avissar, 2003). In studies of the role of G proteins in mental illness, the chief focus has been on the role of dopamine (DA) in the cortex. Dopa- mine receptor subtypes couple to multiple G proteins intracellularly, and it is hypothesized that slight altera- tions in DA subtypes during critical developmental periods may underlie the imbalance displayed in schizo- phrenia (Gainetdinov et al., 2004 Sidhu and Niznik, 2000). These G protein-coupling imbalances have been mimicked in animal models, producing cognitive deficits that closely resemble many endophenotypes of schizo- phrenia. For example, transgenic mice expressing constitutively active Gs��-coupled dopamine receptors displayed deficits in pre-pulse inhibition, which modeled deficits seen in patients with schizophrenia (Gould et al., 2004). Additionally, studies of schizophrenia patients prior to drug treatment also showed an increase in Gs when compared to healthy controls as well as increases in overall positive and negative symptom presentation when compared within patient groups (Schreiber and Avissar, 2003). PTC tasting status has been linked to a myriad of medical illnesses ranging from epilepsy to gastrointes- tinal ulcers, though consistent findings among these disorders have been rare (Guo and Reed, 2001 Pal et al., 2004). In contrast, the handful of studies examining PTC perception in schizophrenia have been generally consistent in showing an increase in the prevalence of non-tasters in patients (Constantinidis, 1958 Freire- Maia et al., 1968 Schlosberg and Baruch, 1992). We recently reported an increased prevalence of PTC non- tasters among schizophrenia patients and their non-ill first-degree relatives compared to healthy controls (Moberg et al., 2005). We hypothesized that the increased number of non-tasters in patients and non-ill first-degree family members might reflect abnormalities in the function and/or expression of G protein-signaling that interact with other genetic or environmental factors to produce an increased vulnerability to illness. Based on these prior findings, we sought to replicate the finding of an increased prevalence of non-tasters in patients and family members in a larger independent sample, and to examine any possible clinical and symptom correlates of taster status in patients with schizophrenia. In addition, because of the propinquity of smell and taste functions as well as similarities in the underlying neuroanatomy, it was hypothesized that that the well-documented deficits in olfactory function seen in schizophrenia might cluster together with PTC taster status. 2. Method 2.1. Participants Sixty-seven patients with DSM-IV (APA, 1994) criteria for schizophrenia (49 male, 18 female), 30 healthy controls (18 male, 12 female), and 30 healthy first-degree relatives of patients (15 male, 15 female), were recruited from the Schizophrenia Research Center (SRC) at the University of Pennsylvania Medical Center, Philadelphia, PA. The non-ill family members consisted of 8 parents, 19 siblings, and 3 children of probands. The groups did not differ in age (F[2,124]=1.3, p=0.26) or in sex distribution (��2 =5.2, df=2, p=0.074). They did, however, differ with regard to ethnic background (��2 =15.2, df=4, p=0.004), largely driven by a greater proportion of African���American subjects in the patient group. As expected, patients and family members had lower educational attainment than controls (F[2,119]= 12.3, pb0.001). Smoking was evaluated by computing a pack-years score, based upon the number of cigarettes smoked per day and the number of years a particular individual had been a smoker. Since pack-years of smoking were not normally distributed, the nonparamet- ric Kruskal���Wallis test was used to compare smoking history among the three groups. A significant difference in smoking exposure was noted (��2 =2.83, df =2, pb0.001), with both patients and family members smoking more than healthy controls. Demographic and clinical information for the study sample is presented in Table 1. 222 P.J. Moberg et al. / Schizophrenia Research 90 (2007) 221���228