title: Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia.
abstract: 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.
authors.affiliation: Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, India.
authors.forename: Jibin
authors.initials: J
authors.lastname: John
authors.affiliation: Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, India.
authors.forename: Prachi
authors.initials: P
authors.lastname: Kukshal
authors.affiliation: Department of Psychiatry, PGIMER-Dr. RML Hospital, New Delhi 110 001, India.
authors.forename: Triptish
authors.initials: T
authors.lastname: Bhatia
authors.affiliation: Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara Street,Pittsburgh, PA 15213, USA.
authors.forename: K V
authors.initials: KV
authors.lastname: Chowdari
authors.affiliation: Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara Street,Pittsburgh, PA 15213, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, DeSoto St, Pittsburgh, PA 15213, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Nimgaonkar
authors.affiliation: Department of Psychiatry, PGIMER-Dr. RML Hospital, New Delhi 110 001, India.
authors.forename: S N
authors.initials: SN
authors.lastname: Deshpande
authors.affiliation: Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, India. Electronic address: thelmabk@gmail.com.
authors.forename: B K
authors.initials: BK
authors.lastname: Thelma
mesh_terms: D015331:Cohort Studies; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D000095383:Trace Amine-Associated Receptors
chemical_list: D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors
keywords: Association; Exome sequencing; Psychiatry; Rare variants; SNPs; TAAR1