Homo sapiens Variation. Homo sapiens

The trace amine-associated receptor 1 (TAAR1) is expressed across brain areas involved in emotions, reward and cognition. The human gene for TAAR1 maps to locus 6q23, within a region associated with major mental disorders. We screened a cohort of patients with major mental disorders and a group of healthy controls for TAAR1 variants. We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs 1, 1 variant in both groups, p < 0.01). In silico analysis identified 4 dysfunctional variants, all in patients. In heterozygosity, 3 of these – R23C, Y131C, C263R – substantially dampened Gs signaling in response to PEA, and, more robustly, to T1AM. Disruptions of TAAR1 activity may be relevant to the pathophysiology of mental disorders.

微量胺相关受体1（Trace amine-associated receptor 1，TAAR1）在参与情绪、奖赏与认知功能的多个脑区中均有表达。TAAR1的人类基因定位于6q23染色体区域，该区域与多种重性精神障碍相关联。本研究针对重性精神障碍患者队列与健康对照人群，开展了TAAR1基因变异筛查。研究团队在TAAR1编码区中共检测到13个错义变异，患者组的变异携带率显著高于健康对照组（患者组11个，对照组1个，两组共有变异1个，p < 0.01）。计算机模拟分析鉴定出4个功能异常变异，且所有变异均来自患者组。在杂合子状态下，其中3个变异——R23C、Y131C、C263R——可显著抑制Gs蛋白信号通路对PEA的响应，且对T1AM的抑制效果更为强劲。TAAR1功能异常或与精神障碍的病理生理机制密切相关。