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.

Trace Amines and Their Receptors

“…TAAR1 is expressed in brain structures associated with psychiatric disorders, in particular in key areas where modulation of dopamine [ventral tegmental area (VTA)] and serotonin [dorsal raphe nuclei (DRN)] occurs (Table 4), and the presence of TAAR1 variants was recently reported to be associated with schizophrenia (John et al, 2017). In the periphery, TAAR1 expression suggests putative roles in regulating immune system responses and controlling energy metabolism.…”

Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouringde novomutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

“…More recent whole exome sequencing (WES)/whole genome sequencing in small/modest sized multiplex families have added to the list of inherited rare protein coding variants. These include variants in previously analyzed candidate genes namely RELN (Zhou et al, 2016), UNC13B (Egawa et al, 2016), GRM5, LRP1B, and PPEF2 (Timms et al, 2013),GRIN3B (Hornig et al, 2017), SHANK2 and SMARCA1 (Homann et al, 2016), ANKK1 (Shirzad et al, 2016), RBM12 (Steinberg et al, 2017), TAAR1 (John et al, 2017), TIMP2 (John et al, 2018)and PTPRA (John et al, 2018).These insightful studies suggest the importance of such variants with large/moderate effects in disease development or in increasing the risk in the respective families with disease clustering.…”

“…In this study 11 non consanguineous families with multiple members affected with SZ were recruited from Dr. RML Hospital New Delhi, following the diagnosis and sample recruitment procedure detailed previously (John et al, 2018(John et al, , 2017(John et al, , 2016Kukshal et al, 2013). Details of the families used in the study are given in Supplementary Figure 1.…”

Rare PDCD11 variations are not associated with risk of schizophrenia in Japan

“…WES and whole‐genome sequencing studies of multiplex schizophrenia families may be useful in identifying rare risk variations with large effcts . Recently, we performed WES with three families that each included a proband, an affected sibling, and parents .…”

“…12 WES and whole-genome sequencing studies of multiplex schizophrenia families may be useful in identifying rare risk variations with large effcts. [13][14][15][16][17] Recently, we performed WES with three families that each included a proband, an affected sibling, and parents. 18 We identified a total of 15 rare truncating (nonsense and frameshift) variations, but no rare de novo non-synonymous variations.…”