Association of the trace amine associated receptor 6 (TAAR6) gene with schizophrenia and bipolar disorder in a Korean case control sample

Pae, Chi‐Un; Yu, Hye-Sook; Amann, Daniela; Kim, Jung-Jin; Lee, Chang-Uk; Lee, Soo-Jung; Jun, Tae‐Youn; Lee, Chul; Paik, In‐Ho; Patkar, Ashwin A.; Lerer, Bernard

doi:10.1016/j.jpsychires.2006.09.011

Cited by 35 publications

(18 citation statements)

References 25 publications

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“…Further efforts to replicate these findings in 265 multiplex families of Irish origin identified additional genotypic and haplotypic association with disease (Vladimirov et al, 2007). This finding was not replicated in an Irish case-control study carried out by the same group (Vladimirov et al, 2009), in Chinese (Duan et al, 2006) and in Japanese populations (Ikeda et al, 2005), but genotypic and haplotypic association of TAAR6 SNPs with SZ and bipolar disorder were reported in Korean case-control cohorts (Pae et al, 2008). TAAR1 is a known modulator of dopaminergic (Lindemann et al, 2008), serotoninergic, and glutamatergic (Revel et al, 2011) pathways and its role in SZ etiology is amply evidenced in literature.…”

Section: Discussionmentioning

confidence: 84%

Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia

John

Kukshal

Bhatia

et al. 2017

Schizophrenia Research

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Schizophrenia (SZ) is a chronic mental illness with behavioral abnormalities. Recent common variant based genome wide association studies and rare variant detection using next generation sequencing approaches have identified numerous variants that confer risk for SZ, but etiology remains unclear propelling continuing investigations. Using whole exome sequencing, we identified a rare heterozygous variant (c.545G > T; p.Cys182Phe) in Trace amine associated receptor 1 gene (TAAR1 6q23.2) in three affected members in a small SZ family. The variant predicted to be damaging by 15 prediction tools, causes breakage of a conserved disulfide bond in this G-protein-coupled receptor. On screening this intronless gene for additional variant(s) in ~800 sporadic SZ patients, we identified six rare protein altering variants (MAF < 0.001) namely p.Ser47Cys, p.Phe51Leu, p.Tyr294Ter, p.Leu295Ser in four unrelated north Indian cases (n = 475); p.Ala109Thr and p.Val250Ala in two independent Caucasian/African-American patients (n = 310). Five of these variants were also predicted to be damaging. Besides, a rare synonymous variant was observed in SZ patients. These rare variants were absent in north Indian healthy controls (n = 410) but significantly enriched in patients (p = 0.036). Conversely, three common coding SNPs (rs8192621, rs8192620 and rs8192619) and a promoter SNP (rs60266355) tested for association with SZ in the north Indian cohort were not significant (P > 0.05). TAAR1 is a modulator of monoaminergic pathways and interacts with AKT signaling pathways. Substantial animal model based pharmacological and functional data implying its relevance in SZ are also available. However, this is the first report suggestive of the likely contribution of rare variants in this gene to SZ.

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Section: Discussionmentioning

confidence: 84%

Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia

John

Kukshal

Bhatia

et al. 2017

Schizophrenia Research

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“…Pae et al (2006) found an association of polymorphisms in human TAAR6 with schizophrenia and bipolar disorder in a Korean case control sample but Venken et al (2006) could find no such evidence of an association of with bipolar disorder in a northern Swedish population.…”

Section: Mental Healthmentioning

confidence: 88%

Trace amine-associated receptor 1—Family archetype or iconoclast?

Grandy

2007

Pharmacology & Therapeutics

178

211

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Interest has recently been rekindled in receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the 'trace amines' (TAs) β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of two publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers as TA1 (Borowsky et al., 2001) and TAR1 (Bunzow et al., 2001). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines recombinant rodent and human TA receptors dosedependently couple to the stimulation of cAMP production. Structure-activity profiling based on this functional response has revealed that in addition to the TAs, other biologically active compounds containing a 2 carbon aliphatic side chain linking an amino group to at least one benzene ring are potent and efficacious TA receptor agonists with amphetamine, methamphetamine, 3-iodothyronamine, thyronamine, and dopamine among the most notable. Almost 100 years after the search for TA receptors began numerous TA1/TAR1-related sequences, now called Trace AmineAssociated Receptors (TAARs), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TA receptor a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCRs. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.

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“…Despite minimal knowledge on the biology and physiologic role(s) of TAAR6, several studies have identified single nucleotide polymorphisms (Duan et al, 2004;Chang et al, 2015) and other genetic variants (Pae et al, 2010) in patients with schizophrenia (Duan et al, 2004;Pae et al, 2008a) and affective disorders (Abou Jamra et al, 2005;Pae et al, 2008bPae et al, , 2010. Particularly interesting are the investigations of the potential role of TAAR6 single nucleotide polymorphisms in schizophrenia etiology and treatment, even though results of these studies are somewhat conflicting.…”

Section: Trace Amine-associated Receptormentioning

confidence: 99%