Zai Clement C H, Tiwari Arun K, Chowdhury Nabilah I, Brandl Eva J, Shaikh Sajid A, Freeman Natalie, Lieberman Jeffrey A, Meltzer Herbert Y, Müller Daniel J, Kennedy James L
From the *Neurogenetics Section, Centre for Addiction and Mental Health; †Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; ‡Department of Psychiatry and Psychotherapy, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany; §Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, Lieber Center for Schizophrenia Research, New York Presbyterian Hospital & Columbia University Medical Center, New York, NY; and ║Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL.
J Clin Psychopharmacol. 2015 Feb;35(1):7-12. doi: 10.1097/JCP.0000000000000261.
Schizophrenia treatment has been hampered by undesirable adverse effects, including weight gain and associated complications. Recent candidate gene studies have been exploring the appetite regulation pathways in antipsychotic-associated weight gain (AAWG) with some promising leads. Genome-wide association studies of obesity have pointed to a number of potential candidate genes, such as MC4R, that were later found to be shared with AAWG. GABAA α2 receptor subunit (GABRA2) was another potential candidate gene for obesity from genome-wide association studies; however, it has not been explored in AAWG. We examined 9 single nucleotide polymorphisms across the GABRA2 gene. Prospective weight change was assessed for a total of 160 schizophrenia patients of European ancestry. The rs279858 marker was associated with percent weight change, with the patients homozygous for the TT genotype experiencing higher percentage weight gain on average than the C allele carriers (P = 0.009). When we performed the analysis considering each clinical site using a meta-analytic method, the results remained statistically significant (P = 1.4e-4). These findings became even more significant when we considered only patients taking clozapine or olanzapine, the 2 medications with higher risk for weight gain (P < 1e-10). GABRA2 genetic variants may play a role in predicting AAWG. However, replication in larger and independent samples is required.
精神分裂症的治疗一直受到不良副作用的阻碍，这些副作用包括体重增加及相关并发症。最近的候选基因研究一直在探索抗精神病药物所致体重增加（AAWG）中的食欲调节途径，并取得了一些有前景的线索。肥胖的全基因组关联研究已指出一些潜在的候选基因，如黑皮质素4受体（MC4R），后来发现这些基因也与AAWG有关。γ-氨基丁酸A受体α2亚基（GABRA2）是全基因组关联研究中发现的另一个肥胖潜在候选基因；然而，尚未在AAWG中对其进行研究。我们检测了GABRA2基因上的9个单核苷酸多态性。对总共160名欧洲血统的精神分裂症患者的体重变化进行了前瞻性评估。rs279858标记与体重变化百分比相关，TT基因型纯合子患者的平均体重增加百分比高于C等位基因携带者（P = 0.009）。当我们使用荟萃分析方法对每个临床位点进行分析时，结果仍具有统计学意义（P = 1.4×10⁻⁴）。当我们仅考虑服用氯氮平或奥氮平的患者时，这些发现变得更加显著，这两种药物导致体重增加的风险更高（P < 1×10⁻¹⁰）。GABRA2基因变异可能在预测AAWG中起作用。然而，需要在更大的独立样本中进行重复验证。
