Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap—pleiotropy—between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.

精神分裂症（SCZ）和双相情感障碍（BD）等精神疾病代表进化悖论，因为它们对健康表现出强烈的负面影响，例如生育力降低和早期死亡率下降，但在全世界的患病率仍约为1％。影响寿命的分子机制在具有适应性影响的复杂疾病中可能很普遍，可以通过对人类长寿的全基因组关联研究（GWAS）以及任何相关疾病的数据进行综合分析，来研究影响寿命的分子机制。在这里，我们报道了此类研究的第一篇，着重研究了两种寿命缩短的精神疾病（SCZ和BD）与人类父母寿命（PLS）之间的遗传重叠（多效性），以替代预期寿命。我们的结果是双重的：首先，我们证明了SCZ和PLS之间广泛的多基因重叠，而BD和PLS之间的重叠程度较小。其次，我们确定了PLS和SCZ之间共享的新基因座（n  = 39）和BD（n  = 8）。尽管大多数已鉴定的SCZ（66％）和BD（62％）多效性风险等位基因与寿命缩短相关，但我们还检测到一些与寿命较短相关的拮抗保护性等位基因。实际上，与SCZ密切相关的SNP似乎比许多其他威胁生命的疾病，包括2型糖尿病和大多数癌症，更能解释寿命变异解释（LVE），这可能是由于与吸烟相关的途径高度重叠。总体而言，我们的研究提供了由SCZ人群过早死亡驱动的遗传负担的证据，这对于理解并潜在治疗与该精神病相关的死亡率差距可能具有深远的意义。