Trace amine associated receptor 1: predicted effects of single nucleotide variants on structure-function in geographically diverse populations.

IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Human Genomics Pub Date : 2024-06-11 DOI:10.1186/s40246-024-00620-w
Britto Shajan, Shashikanth Marri, Tarun Bastiampillai, Karen J Gregory, Shane D Hellyer, Pramod C Nair
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Abstract

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants (SNV) have been found in patients with schizophrenia and metabolic disorders. However, the frequency of variants in geographically diverse populations and the functional effects of such variants are unknown. In this study, we aimed to characterise the distribution of TAAR1 SNVs in five different WHO regions using the Database of Genotypes and Phenotypes (dbGaP) and conducted a critical computational analysis using available TAAR1 structural data to identify SNVs affecting ligand binding and/or functional regions. Our analysis shows 19 orthosteric, 9 signalling and 16 micro-switch SNVs hypothesised to critically influence the agonist induced TAAR1 activation. These SNVs may non-proportionally influence populations from discrete regions and differentially influence the activity of TAAR1-targeting therapeutics in genetically and geographically diverse populations. Notably, our dataset presented with orthosteric SNVs D1033.32N (found only in the South-East Asian Region and Western Pacific Region) and T1945.42A (found only in South-East Asian Region), and 2 signalling SNVs (V1253.54A/T2526.36A, found in African Region and commonly, respectively), all of which have previously demonstrated to influence ligand induced functions of TAAR1. Furthermore, bioinformatics analysis using SIFT4G, MutationTaster 2, PROVEAN and MutationAssessor predicted all 16 micro-switch SNVs are damaging and may further influence the agonist activation of TAAR1, thereby possibly impacting upon clinical outcomes. Understanding the genetic basis of TAAR1 function and the impact of common mutations within clinical populations is important for the safe and effective utilisation of novel and existing pharmacotherapies.

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痕量胺相关受体 1:单核苷酸变异对不同地域人群结构-功能的预测影响。
痕量胺相关受体 1(TAAR1)是一种新型药物靶点,目前正在研究用于治疗多种神经精神疾病。在精神分裂症和代谢紊乱患者中发现了 TAAR1 单核苷酸变异(SNV)。然而,变异在不同地域人群中的频率及其功能影响尚不清楚。在这项研究中,我们旨在利用基因型和表型数据库(dbGaP)描述世界卫生组织五个不同地区 TAAR1 SNV 的分布特征,并利用现有的 TAAR1 结构数据进行关键的计算分析,以确定影响配体结合和/或功能区域的 SNV。我们的分析显示了 19 个正交、9 个信号和 16 个微开关 SNV,假设这些 SNV 对激动剂诱导的 TAAR1 激活有重要影响。这些 SNV 可能会对来自不同地区的人群产生非比例影响,并对 TAAR1 靶向疗法在不同基因和地域人群中的活性产生不同影响。值得注意的是,我们的数据集中出现了正交 SNV D1033.32N(仅在东南亚地区和西太平洋地区发现)和 T1945.42A(仅在东南亚地区发现),以及 2 个信号 SNV(V1253.54A/T2526.36A,分别在非洲地区和常见地区发现),所有这些 SNV 以前都被证明会影响 TAAR1 的配体诱导功能。此外,利用 SIFT4G、MutationTaster 2、PROVEAN 和 MutationAssessor 进行的生物信息学分析预测,所有 16 个微开关 SNV 都具有损伤性,可能会进一步影响 TAAR1 的激动剂激活,从而可能影响临床结果。了解 TAAR1 功能的遗传基础以及临床人群中常见突变的影响对于安全有效地利用新型和现有药物疗法非常重要。
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来源期刊
Human Genomics
Human Genomics GENETICS & HEREDITY-
CiteScore
6.00
自引率
2.20%
发文量
55
审稿时长
11 weeks
期刊介绍: Human Genomics is a peer-reviewed, open access, online journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics. Topics covered by the journal include, but are not limited to: pharmacogenomics, genome-wide association studies, genome-wide sequencing, exome sequencing, next-generation deep-sequencing, functional genomics, epigenomics, translational genomics, expression profiling, proteomics, bioinformatics, animal models, statistical genetics, genetic epidemiology, human population genetics and comparative genomics.
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