We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms in taars have emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, several taars (especially taar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.
Trace amine-associated receptors (TAARs) belong to the family of G-protein-coupled receptors (GPCRs) (Zucchi et al. 2006; Grandy 2007). GPCRs, also known as seven-transmembrane receptors, represent the most versatile family of membrane receptors, as they respond to a broad range of stimuli, such as light, odorants, hormones, and several types of chemical messengers, including neurotransmitters (Pierce et al. 2002). The presence of a DRY motif (i.e. aspartate-arginine-tyrosine: unless otherwise specified, we are using single letter codes for amino acid residues) in the third transmembrane domain allocates TAARs to the largest class of GPCRs, known as Class A or Rhodopsin-like family (Borowsky 2001).
In mammals, the genes coding for TAARs (henceforward indicated as taars) are characterized by high homology, all cluster in a small region of a unique chromosome, with consistent transcriptional orientations across orthologs (Lindemann et al. 2005). All members of the taar family generate short (~ 1000-bp-long) intronless transcripts, with the exception of taar2 which contains two exons. According to molecular evolutionary analyses, an ancestral gene emerged in the see lamprey (Eyun et al. 2016). Then, several species-specific events of gene duplications and pseudogenizations occurred, so that the number of taars is highly diverse among mammals, ranging from 0 in dolphins to 26 in the flying fox (Eyun et al. 2016). The receptors are classified into nine subfamilies (TAAR1 to TAAR9) (Hashiguchi and Nishida 2007). The oldest subfamily includes TAAR1, which is the only TAAR that is not expressed in the olfactory epithelium and does not function as an olfactory receptor (Eyun et al. 2016). Therefore, it appears that the divergence of younger TAARs from TAAR1 was accompanied by a change in their expression pattern (Eyun et al. 2016). From the functional point of view, receptors in the TAAR1-4 cluster detect primary amines, while those in the TAAR5-9 cluster, which are specific to therian mammals, are predominantly stimulated by tertiary amines (Ferrero et al. 2012).
While most genomes contain a single well-conserved copy of the more anciently emerged taar subfamily genes (taar1-4), the latest subfamilies (taar5-9) underwent multiple species-specific duplications, with positive selection, e.g. in taar7 (Eyun et al. 2016). On the contrary, primate genomes are characterized by a small number of taars, with accelerated pseudogenization of taar repertoires (Eyun 2018). In particular, the human genome encompasses six taars, all present as single-copy genes, and mapping to a small genomic region of 108 kb located in chromosome 6q23 (Vladimirov et al. 2007). Functional TAAR3, TAAR4, and TAAR7 have been lost (Lindemann et al. 2005; Eyun et al. 2016), before humans diverged from gorillas (Fig. 1) (Staubert et al. 2010).
Schematic representation of the human 108-kb genomic region in chromosome 6q23, containing the genes coding for trace amine-associated receptors (taars). The location of the genes refers to the most recent Genome Reference Consortium assembly (February 2019), i.e. GRCh38.p13. The human genome encompasses six taars (dark blue) all present as single-copy genes. TAAR3, TAAR4, and TAAR7 (light blue) underwent pseudogenization before humans diverged from gorillas. All members of the taar family generate short (~ 1000-bp-long) intronless transcripts, with the exception of taar2, which contains two exons. This small genomic region has been repeatedly observed to be in genetic linkage with schizophrenia and bipolar disorder. Linkage studies pointed to a rather wide chromosomal region at 6q to contain one or more susceptibility loci for schizophrenia (~ 102–180 cM from the pter). The polymorphic markers showing the higher peaks in linkage with schizophrenia (black) or bipolar disorder (blue) are depicted in the lower part of the figure
TAARs were identified while searching for novel biogenic amine receptors, but turned out to respond to trace amines, instead (Borowsky 2001; Bunzow 2001). The term trace amines refers to endogenous amines, namely β-phenylethylamine, p-tyramine, tryptamine, octopamine, and synephrine. They derive from aromatic amino acids and are physiologically present in tissues at much lower concentrations (< 100 ng/g tissue) (Boulton 1974) than the classic biogenic amines, such as dopamine, serotonin, norepinephrine, and histamine. While trace amines are major chemical messengers in invertebrates, in mammals they were originally believed to act as “false transmitters”, i.e. displacing classic biogenic amines from their stores and inhibiting their transporters (Parker and Cubeddu 1986). With the discovery of TAARs, it became clear that trace amines may exert actions in their own respect (Borowsky 2001; Berry 2004; Geracitano et al. 2004). Furthermore, some TAARs (notably TAAR1 and TAAR5) bind with high affinity to another class of endogenous amines, i.e. thyronamines, probably representing a novel branch of thyroid hormone signalling (Scanlan et al. 2004; Zucchi et al. 2014; Hoefig et al. 2016; Kohrle and Biebermann 2019). As a matter of fact, binding to trace amines has not been demonstrated for all TAAR subtypes, and this is the reason why the acronym TAAR has been accepted by the Human Genome Organization (HUGO) Gene Nomenclature Committee, although the International Union of Pharmacology (IUPHAR) still recommends the original denomination of trace amine receptors (Maguire et al. 2009).
As mentioned above, most TAARs are chiefly expressed in the olfactory epithelium and it has been argued that they might play a crucial role in sensing important ethological signals, such as predator and prey odours, spoiled food, migratory cues, and pheromones, thereby activating appropriate behaviours (Ferrero et al. 2011). For instance, β-phenylethylamine, which is ligand for TAAR1 and TAAR4, is a carnivore odour from mountain lions, tigers and jaguars (Ferrero et al. 2011; Dewan et al. 2013). Taar gene dynamics might be affected by environmental and evolutionary factors. Indeed, taar duplications and positive selection might have helped therian mammals to adapt to ground-living and discriminate among a wide number of volatile amines. On the other hand, taars deteriorated as a consequence of relaxed selection in those primates who adapted to arboreality, therefore relying less on olfaction for survival (Eyun 2018).
Notably, TAAR1 is also stimulated, with EC50 in the nanomolar to micromolar range, by a wide array of psychoactive drugs, such as amphetamine, 3,4-methylenedioxymethamphetamine, known as “ecstasy” (Bunzow 2001; Miller et al. 2005; Simmler et al. 2016), D-lysergic acid diethylamide, bromocriptine, lisuride, nomifensine, apomorphine, ractopamin, clonidine, guanabenz, idozoxan, aminoindanes (2-aminoindane and 5-iodo-2-aminoindane), and m-chlorophenylpiperazine (Bunzow 2001; Hu et al. 2009; Liu et al. 2014; Sukhanov et al. 2014; Simmler et al. 2016).
On the whole, it has been speculated that TAARs could play an important role in the central nervous system function, and possibly contribute an etiological role to the pathogenesis of mental disorders. This review will cover the efforts made, under a genetic perspective, to unravel the association between TAARs and psychopathology. The small genomic region on chromosome 6 where taars are located has been repeatedly observed to be in genetic linkage with schizophrenia and bipolar disorder. Fine mapping association studies were subsequently integrated with genome-wide association studies. Recent technological advances allowed large-scale sequencing of taars, as well as of the whole genomes of patients. Finally, the use of gene expression profiling and peptidome analyses has been used to identify TAAR dysregulation in specific diseases.
In linkage analysis, no assumptions about specific genes are made. Polymorphic markers scattered over the genome at approximately equal distances, i.e. microsatellites with di- or tri-nucleotide repeats, are genotyped in family members, to determine whether they segregated with the disease (Bray and O’Donovan 2019). Markers are usually indicated by symbols such as DXS000, where D stands for DNA, X is a number that identifies chromosomal assignment, S denotes that it is a unique DNA sequence, and the final number is a specific identifier (Fig. 1). Chromosomal location may be expressed with cytogenetic notation, where chromosome number is followed by the letter “p” (indicating the short arm) or “q” (indicating the long arm) and by a number that denotes microscope-identified bands and sub-bands. Distances between genes can be calculated on the basis of recombination frequencies, which are related to chromosomal crossover at meiosis and are expressed in centiMorgans (cM), where 1 cM corresponds to a frequency of 1% per generation. Distances can be also expressed as number of base-pairs calculated through sequencing, and in general in humans 1 cM corresponds to about one million base-pairs (1 Mbp). However, this is only an approximation, since recombination frequency is not the same in all regions.