Punchaichira Toyanji Joseph, Kukshal Prachi, Bhatia Triptish, Deshpande Smita Neelkanth, Thelma B K
Department of Genetics, University of Delhi South Campus, Benito Juarez Road.
Department of Psychiatry, Postgraduate Institute of Medical Education and Research-Dr. Ram Manohar Lohia Hospital, Baba Kharak Singh Marg, Connaught Place, New Delhi, India.
Psychiatr Genet. 2020 Oct;30(5):125-135. doi: 10.1097/YPG.0000000000000258.
The aim of the study is to test the association of a functional variant each in DRD2 and COMT genes with schizophrenia and its endophenotypes.
Effect of two functional variants rs1076560 in DRD2 and rs4680 in COMT on (1) schizophrenia (502 cases, 448 controls) diagnosed by Diagnostic and Statistical Manual of Mental Disorders-IV criteria and in subsets with (2) tardive dyskinesia (80 positive, 103 negative), assessed by Abnormal Involuntary Movement Scale (AIMS), positive and negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) and (3) cognition (299 cases, 245 controls), estimated by Penn Computerized Neurocognitive Battery, were analysed either using analysis of variance (ANOVA) or regression analysis.
No association of two SNPs with schizophrenia, but association of rs4680 (P < 0.05) with tardive dyskinesia was observed. On ANOVA, main effect of smoking [F(2,148) = 16.3; P = 3.9 × 10]; rs4680 [F(2,148) = 3.3; P = 0.04] and interaction effect of tardive dyskinesia-statusSmoking [F(2,148) = 5.4, P = 0.006]; Smokingrs1076560 [F(3,148) = 3.6; P = 0.01]; Smoking*rs4680 [F(4,148) = 5.3; P = 4.7 × 10] were significant with AIMS tardive dyskinesia score. The main effect of rs1076560 [F(2,148) = 4.5; P = 0.013] and rs4680 [F(2,148) = 4.0; P = 0.02] were significant with limb truncal tardive dyskinesia. Allelic/genotypic (P = 0.004/P = 0.01) association of rs1076560 with negative scale of PANSS in tardive dyskinesia-negative; diminished expression factor of PANSS in tardive dyskinesia-negative subcohort (allelic/genotypic P = 3.3 × 10/6.6 × 10) and tardive dyskinesia cohorts (P = 0.003/0.002); genotypic association (P = 0.05) with disorganised/concrete factor in tardive dyskinesia-positive subcohorts were observed by regression analysis using gPLINKv2.050. Further allelic/genotypic (P = 0.02) association of rs4680 with depressed factor of PANSS in tardive dyskinesia cohort was observed. Allelic/genotypic association of rs1076560 with abstraction and mental flexibilityaccuracy (P = 0.03/0.04), abstraction and mental flexibilityefficiency (P = 0.01/0.02); allelic association with spatial abilityprocessing speed (P = 0.03), emotionefficiency (P = 0.05); and with spatial abilityefficiency (genotypic, P = 0.05) in healthy controls and allelic association of rs4680 with emotionefficiency in cases with schizophrenia (P = 0.04) were notable.
Dopaminergic genes seem to contribute to tardive dyskinesia and cognition warranting replication.
本研究旨在测试多巴胺D2受体基因（DRD2）和儿茶酚-O-甲基转移酶基因（COMT）中的功能变异与精神分裂症及其内表型之间的关联。
采用方差分析（ANOVA）或回归分析，分析DRD2基因中的rs1076560和COMT基因中的rs4680这两个功能变异对以下方面的影响：（1）根据《精神疾病诊断与统计手册》第四版标准诊断的精神分裂症（502例患者，448名对照），以及在亚组中（2）迟发性运动障碍（80例阳性，103例阴性），通过异常不自主运动量表（AIMS）评估，通过阳性和阴性症状量表（PANSS）评估阳性和阴性症状，以及（3）认知（299例患者，245名对照），通过宾夕法尼亚计算机化神经认知测试电池进行评估。
未观察到两个单核苷酸多态性（SNP）与精神分裂症之间的关联，但观察到rs4680与迟发性运动障碍存在关联（P < 0.05）。在方差分析中，吸烟的主效应[F(2,148) = 16.3；P = 3.9 × 10⁻⁴]；rs4680[F(2,148) = 3.3；P = 0.04]以及迟发性运动障碍状态吸烟的交互效应[F(2,148) = 5.4，P = 0.006]；吸烟rs1076560[F(3,148) = 3.6；P = 0.01]；吸烟*rs4680[F(4,148) = 5.3；P = 4.7 × 10⁻³]与AIMS迟发性运动障碍评分显著相关。rs1076560[F(2,148) = 4.5；P = 0.013]和rs4680[F(2,148) = 4.0；P = 0.02]对肢体躯干迟发性运动障碍的主效应显著。在迟发性运动障碍阴性组中，rs1076560与PANSS阴性量表的等位基因/基因型关联（P = 0.004/P = 0.01）；在迟发性运动障碍阴性亚组（等位基因/基因型P = 3.3 × 10⁻³/6.6 × 10⁻⁴）和迟发性运动障碍组（P = 0.003/0.002）中PANSS的表达降低因子；通过使用gPLINKv2.050进行回归分析，在迟发性运动障碍阳性亚组中观察到与紊乱/具体因子的基因型关联（P = 0.05）。进一步观察到rs4680与迟发性运动障碍组中PANSS抑郁因子的等位基因/基因型关联（P = 0.02）。在健康对照中，rs1076560与抽象和心理灵活性准确性（P = 0.03/0.04）、抽象和心理灵活性效率（P = 0.01/0.02）的等位基因/基因型关联；与空间能力处理速度（P = 0.03）、情绪效率（P = 0.05）的等位基因关联；以及与空间能力效率（基因型，P = 0.05）的关联，以及rs4680与精神分裂症患者情绪效率的等位基因关联（P = 0.04）值得注意。
多巴胺能基因似乎与迟发性运动障碍和认知有关，有待重复验证。
