Ter Hark Sophie E, Jamain Stéphane, Schijven Dick, Lin Bochao D, Bakker Mark K, Boland-Auge Anne, Deleuze Jean-François, Troudet Réjane, Malhotra Anil K, Gülöksüz Sinan, Vinkers Christiaan H, Ebdrup Bjørn H, Kahn René S, Leboyer Marion, Luykx Jurjen J
Department of Translational Neuroscience, Utrecht University, Utrecht, The Netherlands.
Psychiatrie Translationnelle, Inserm U955, Créteil, France.
J Psychopharmacol. 2020 May;34(5):524-531. doi: 10.1177/0269881120907972. Epub 2020 Mar 4.
Antipsychotic-induced weight gain is a common and debilitating side effect of antipsychotics. Although genome-wide association studies of antipsychotic-induced weight gain have been performed, few genome-wide loci have been discovered. Moreover, these genome-wide association studies have included a wide variety of antipsychotic compounds.
We aim to gain more insight in the genomic loci affecting antipsychotic-induced weight gain. Given the variable pharmacological properties of antipsychotics, we hypothesized that targeting a single antipsychotic compound would provide new clues about genomic loci affecting antipsychotic-induced weight gain.
All subjects included for this genome-wide association study (=339) were first-episode schizophrenia spectrum disorder patients treated with amisulpride and were minimally medicated (defined as antipsychotic use <2 weeks in the previous year and/or <6 weeks lifetime). Weight gain was defined as the increase in body mass index from before until approximately 1 month after amisulpride treatment.
Our genome-wide association analyses for antipsychotic-induced weight gain yielded one genome-wide significant hit (rs78310016; β=1.05; =3.66 × 10; =206) in a locus not previously associated with antipsychotic-induced weight gain or body mass index. Minor allele carriers had an odds ratio of 3.98 (=1.0 × 10) for clinically meaningful antipsychotic-induced weight gain (⩾7% of baseline weight). In silico analysis elucidated a chromatin interaction with In an attempt to replicate single-nucleotide polymorphisms previously associated with antipsychotic-induced weight gain, we found none were associated with amisulpride-induced weight gain.
Our findings suggest the involvement of rs78310016 and possibly in antipsychotic-induced weight gain. In line with the unique binding profile of this atypical antipsychotic, our findings furthermore hint that biological mechanisms underlying amisulpride-induced weight gain differ from antipsychotic-induced weight gain by other atypical antipsychotics.
抗精神病药物所致体重增加是抗精神病药物常见且使人衰弱的副作用。尽管已经开展了抗精神病药物所致体重增加的全基因组关联研究，但发现的全基因组位点很少。此外，这些全基因组关联研究涵盖了多种抗精神病药物化合物。
我们旨在更深入了解影响抗精神病药物所致体重增加的基因组位点。鉴于抗精神病药物药理学特性的差异，我们推测针对单一抗精神病药物化合物进行研究将为影响抗精神病药物所致体重增加的基因组位点提供新线索。
纳入本全基因组关联研究的所有受试者（n = 339）均为首次发作的精神分裂症谱系障碍患者，接受氨磺必利治疗且用药极少（定义为前一年抗精神病药物使用时间<2周和/或终生使用时间<6周）。体重增加定义为从氨磺必利治疗前到治疗后约1个月期间体重指数的增加。
我们针对抗精神病药物所致体重增加的全基因组关联分析在一个先前与抗精神病药物所致体重增加或体重指数无关的位点产生了一个全基因组显著关联信号（rs78310016；β = 1.05；P = 3.66 × 10⁻⁸；n = 206）。次要等位基因携带者出现具有临床意义的抗精神病药物所致体重增加（≥基线体重的7%）的比值比为3.98（P = 1.0 × 10⁻⁴）。电子分析阐明了与……的染色质相互作用。为了重复先前与抗精神病药物所致体重增加相关的单核苷酸多态性，我们发现没有一个与氨磺必利所致体重增加相关。
我们的研究结果提示rs78310016以及可能的……参与了抗精神病药物所致体重增加。与这种非典型抗精神病药物独特的结合谱一致，我们的研究结果还提示氨磺必利所致体重增加的生物学机制与其他非典型抗精神病药物所致体重增加不同。
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