Importance People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown. Objective To assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them. Design, Setting, and Participants Using a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018. Main Outcomes and Measures The primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways. Results Genome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways. Conclusions and Relevance In this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

中文翻译：

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体重指数和主要精神疾病之间的共享遗传基因座：全基因组关联研究。

重要性患有严重精神疾病（MPD）的人的寿命比其他人群要短10至20年，而这种差异主要是由于合并症引起的。全基因组关联研究已经确定了与精神分裂症（SCZ），躁郁症（BIP）和重度抑郁症（MD）和体重指数（BMI）有关的常见变异，这是心脏代谢的关键危险因素。但是，共同影响MPD和BMI的遗传变异仍然未知。目的评估MPD和BMI的遗传结构之间的重叠程度，并确定它们之间共享的遗传基因座。设计，设置和参与者使用条件错误发现率统计框架，有关SCZ（n = 82 315），BIP（n = 51 710），MD（n = 480 359），和BMI（n = 795640）进行了分析。MD数据集排除了英国生物库研究组（n = 29 740），以避免样品重叠。数据收集自2017年8月至2018年5月，分析于2018年7月开始。主要结果和措施主要结果是BMI和MPD之间共享的基因位点列表及其功能途径。结果分析了来自1 380 284名参与者的全基因组关联研究数据，BMI和MPD之间的遗传相关性发生了变化（SCZ：r代表遗传= -0.11，P = 2.1×10-10； BIP：r代表遗传= -0.06 ，P = .0103； MD：遗传的r = 0.12，P = 6.7×10-10）。总体上，BMI和SCZ，BIP和MD分别共享的63、17和32个基因座的联合虚假发现率小于0.01。在共享位置中，SCZ中占34％（213个中的73个），BIP中占52％（69个中的36个），MD中有57％（99个中的56个）具有与较高BMI相关的风险等位基因（联合虚假发现率<0.05），而其他人则具有相反的关联方向。功能分析表明，重叠的基因座涉及多个途径，包括神经发育，神经递质信号传导和细胞内过程，并且具有一致和相反关联方向的基因座主要指向不同的途径。结论与相关性在这项全基因组关联研究中，发现BMI与SCZ，BIP和MD之间存在广泛的多基因重叠，并鉴定出111个共有的遗传基因座，这暗示了新的功能机制。SCZ和BMI中存在关联方向的混合，尽管有很多不一致的方向。