Catechol-O-methyltransferase (COMT) located on chromosome 22q11.2 is one candidate gene for schizophrenia that has received widespread attention due to its role in prefrontal dopamine degradation. A relatively common deletion at chromosome 22q11.2, encompassing the entire COMT gene, is responsible for DiGeorge Syndrome (also known as velocardiofacial syndrome or VCFS), which manifests in adults with a high prevalence of a schizophrenia-like psychosis (Murphy, 2002). Consistent with this, genome-wide scans of rare copy number variants (CNVs) have revealed that microdeletions at chromosome 22q11.2 confer significant risk for schizophrenia (Karayiorgou et al., 1995; Levinson et al., 2011; Vacic et al., 2011). A common functional polymorphism of the COMT gene consists of a guanine to adenine transition at codon 158 in the membrane-bound isoform of the enzyme and at codon 108 in the short soluble form, which results in a valine (Val) to methionine (Met) amino acid mutation. The higher thermostability of the Val allele results in a four-fold increase in the rate of dopamine catabolism and significantly lower synaptic dopamine levels, compared to the thermolabile Met allele (Lachman et al., 1996). Mounting evidence from neuropsychological, structural and functional imaging studies have indicated that this biallelic single nucleotide polymorphism influences the cognitive and emotional disturbances seen in the illness. Though the nature of these impairments have been debated, there is general consensus that the Val allele is associated with greater working memory dysfunction, while the Met allele is associated with increased treatment resistance and limbic dysfunction (for a review, see: Bilder, Volavka, Lachman, & Grace, 2004).

COMT has been investigated extensively in schizophrenia due to its location on chromosome 22q, where a deletion encompassing the COMT gene results in the development of VCFS, a disorder associated with a high prevalence of schizophrenia-like psychotic symptoms (Murphy, 2002). VCFS is characterized by cardiovascular and craniofacial dysmorphology, as well as olfactory impairment (Romanos, et al., 2011). Individuals with schizophrenia have similarly shown minor midline physical anomalies (e.g., increased palate height, cleft palate; O’Callaghan, Larkin, Kinsella, & Waddington, 1991), as well as abnormalities on structural and functional olfactory indices (Moberg et al., 2006; Moberg, et al., 2004; Turetsky, Crutchley, Walker, Gur, & Moberg, 2009; Turetsky et al., 2007; Turetsky et al., 2000). Notably, the face, olfactory structures, and forebrain develop embryologically in close association with each other (Carstens, 2002; Diewert, Lozanoff, & Choy, 1993), and these early morphogenetic processes are affected in a dose-related fashion to diminished 22q11 genes (Meechan, Maynard, Tucker, & LaMantia, 2011; Meechan, Tucker, Maynard, & LaMantia, 2009). Thus, it is plausible that genetic disruption influences neurogenesis and, in turn, contributes to the observed abnormalities in the structure and function of olfactory regions observed in both schizophrenia and VCFS.

Alternatively, dopaminergic transmission in the prefrontal cortex may influence olfactory signal transduction. Olfactory receptor neurons (ORN) embedded in the nasal epithelium transduce and relay odor signals to the olfactory bulb (OB). Within the OB, the ORNs arborize within the glomeruli and terminate on mitral and tufted cell dendrites. It is here that the first point of olfactory information integration is initiated (for a review, see: Wachowiak & Shipley, 2006). In the glomerular layer, dopamine D2 receptors are highly expressed in juxtaglomerular neurons, which are involved in lateral inhibitory interactions within and between glomeruli. Though it is not entirely clear how dopamine influences transmission of olfactory signals, evidence from the extant animal literature indicates that dopamine suppresses the transmission of olfactory signals at the level of the OB via presynaptic action on ORN terminals (Berkowicz & Trombley, 2000; Ennis et al., 2001). Dopamine receptor agonists disrupt odor-induced metabolic activity in the OB glomeruli (Sallaz & Jourdan, 1992), reduce ORN to mitral cell synaptic transmission (Hsia, Vincent, & Lledo, 1999), and impair odor detection ability (Doty & Risser, 1989). These disruptive effects appear to be mediated specifically through D2 receptors, as they can be blocked by pre-treatment with selective D2 antagonists (Doty & Risser, 1989). In humans, the indirect dopamine receptor agonist, methylphenidate, has been shown to negatively affect olfactory performance. Children with attention-deficit/hyperactivity disorder (ADHD) exhibit enhanced abilities to detect and discriminate between odors, relative to healthy children, but this is attenuated following treatment with methylphenidate (Romanos et al., 2008; Schecklmann et al., 2011). Also, post-mortem studies of patients with Parkinson’s disease show a 100% increase in dopaminergic neurons in the olfactory bulb (Huisman, Uylings, & Hoogland, 2004). This dopaminergic increase was theorized to explain the olfactory impairment well-described in the illness.

In the current study, Val¹⁵⁸ homozygote schizophrenia patients, who presumably have reduced levels of available dopamine, were significantly better at identifying odors compared to Met homozygotes. This is consistent with findings in VCFS patients (Bassett, et al., 2007) and with available research on the role of dopamine in olfactory processing. However, several studies examining correlates of the COMT val158met polymorphism in schizophrenia have found that the Val/Val genotype is generally associated with poorer performance on cognitive tasks reflecting prefrontal cortical activity (for a review, see: Kurnianingsih et al., 2011). Since accurate odor identification involves accessing the necessary verbal information from semantic stores, the task is thought to rely partly on verbal and executive functions (Hedner, Larsson, Arnold, Zucco, & Hummel, 2010) and we might therefore expect the Val¹⁵⁸ homozygote patients to perform worse, rather than better. That this was not the case suggests that decreased prefrontal dopamine levels do not interfere with the verbal and executive components of odor identification performance in patients. This hypothesis is further supported by the finding that picture identification scores did not differ by group or COMT genotype status. Rather, it strongly suggests that the effect of the val158met polymorphism is a direct reflection of altered dopamine levels within the afferent olfactory neurocircuitry. It also implies that olfactory impairment in schizophrenia is not a byproduct of antipsychotic medications. Based on these findings, treatment with antipsychotic medications might actually enhance olfactory performance.

It is important to also note that the effect of the val158met polymorphism on olfactory performance was not observed in our healthy control sample. The reason for this is unclear. It may be that healthy subjects have sufficient olfactory reserve capacity, such that the lower dopamine levels associated with Val¹⁵⁸ homozygote status does not result in impaired performance. Alternatively, the impact of the polymorphism may only manifest itself in the broader context of appropriate gene-gene or gene-environment interactions that exert a greater effect on olfactory function (Wishart et al., 2011). So, for example, altered dopaminergic modulation coupled with altered excitatory glutamate transmission could result in an observable deficit (e.g., Vorstman et al., 2009). Addressing the question of such interactions, however, requires much larger samples than those available for this study.

Several other limitations must be noted. The current study only employed one behavioral measure of olfactory processing. Odor identification tasks, like the one used here, are considered the most highly standardized and reliable of psychophysical olfactory processing measures in humans. Other olfactory measures, such as odor detection threshold and odor discrimination, typically load on one broad olfactory domain with odor identification (Doty, Smith, McKeown, & Raj, 1994). Nevertheless, studies like the aforementioned investigations by Romanos et al. (2008) and Schecklmann et al. (2011) have shown that methylphenidate differentially affects some aspects of olfactory performance, but not others. Thus, certain olfactory measures may be more sensitive to the influence of dopamine on odor processing despite sharing a common source of variance in the overall olfactory domain. Use of a broader olfactory battery would therefore be of interest in future studies. It would also be useful to examine the extent to which other structural and functional olfactory measures shown to be abnormal in schizophrenia (e.g., posterior nasal volume, olfactory sulcus depth, olfactory bulb volume, and olfactory event-related potentials) are influenced by COMT genotype status. Finally, as noted above, multiple gene interactions across multiple neural networks are tied to dopamine and olfactory processing in schizophrenia. While the current findings provide strong inferential support, replication and inclusion of additional functional COMT haplotypes and the examination of other candidate schizophrenia genes will be necessary to determine the extent to which the current findings are unique to the COMT val158met polymorphism.