Sex differences in gene expression related to antipsychotic induced weight gain

Antipsychotics are crucial for the treatment of schizophrenia and contribute to weight gain in psychosis, particularly during early phases. Antipsychotic Induced Weight Gain (AIWG) might contribute to reduce the quality of life, drug compliance and to increase mortality. To characterize sex differences of gene expression related to AIWG, we sequenced total mRNA from blood samples of schizophrenia patients, before and after 3 months of antipsychotic-treatment. We analyzed schizophrenia patients according to their sex (38 males and 39 females) and their BMI increase after medication, characterizing the differential gene expression before and after medication. Individuals in each group were categorized in patients who gain weight and those whose do not gain weight. The “weight gain” groups included patients with an increase of body mass index (BMI) > 1.0 points (27 males and 23 females with a median BMI increase of 2.68 and 2.32 respectively). The “no weight gain” groups included patients with a change of BMI between -1.0 points (11 males and 16 females with a median BMI increase of 0.21 and 0.16 respectively). The males had 331 genes with significant differential expression in the weight gain group and 24 genes in the no weight gain group. The females had 119 genes with significant differential expression in the weight gain group and 75 genes in the no weight gain group. Both weight gain groups were significantly enriched with “obesity” genes (Fisher; p = 1.1E-09 and p = 0.0001 respectively), according to the Gene Reference into Function (GeneRIF) database.In conclusion, we characterized genes with differential expression associated to AIWG that are specific to males, to females and common to both sexes. These genes are good candidates to depict the biological processes involved in AIWG and provide additional evidence of the genetic links between weight gain and the immune system.抗精神病药物（Antipsychotics）是治疗精神分裂症的核心用药，同时可引发精神病性障碍患者的体重增加，尤以治疗早期阶段最为明显。抗精神病药物诱导体重增加（Antipsychotic Induced Weight Gain, AIWG）可能会降低患者的生活质量与药物依从性，甚至增加死亡风险。为明确与AIWG相关的基因表达性别差异，本研究对精神分裂症患者接受抗精神病药物治疗前、后3个月的血液样本进行了总mRNA测序。本研究按性别（38名男性、39名女性）及服药后的身体质量指数（Body Mass Index, BMI）变化对患者进行分组，分析了患者服药前后的差异基因表达情况。每组患者进一步分为体重增加组与体重未增加组：体重增加组定义为BMI升高≥1.0的患者，其中男性27名、女性23名，中位BMI升高值分别为2.68与2.32；体重未增加组定义为BMI变化幅度介于-1.0至1.0之间的患者，其中男性11名、女性16名，中位BMI升高值分别为0.21与0.16。男性体重增加组中存在331个显著差异表达基因，体重未增加组则有24个显著差异表达基因；女性体重增加组中存在119个显著差异表达基因，体重未增加组则有75个显著差异表达基因。根据基因功能参考数据库（Gene Reference into Function, GeneRIF）的分析结果，两组体重增加组均显著富集于肥胖相关基因（Fisher精确检验；P值分别为1.1×10^-9与0.0001）。综上，本研究明确了与AIWG相关的差异表达基因，这些基因可分为男性特异性、女性特异性以及两性共有三类。上述基因可作为阐释AIWG相关生物学过程的优质候选靶点，同时也为体重增加与免疫系统之间的遗传关联提供了新的实验证据。