The Relationship Between Common Variant Schizophrenia Liability and Number of Offspring in the UK Biobank
The Relationship Between Common Variant Schizophrenia Liability and Number of Offspring in the UK Biobank
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DOI：
10.1176/appi.ajp.2018.18020140
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发表时间：
2019-08-01
影响因子：
17.7
通讯作者：
ODonovan, Michael C.
中科院分区：
文献类型：
--
作者：
Escott-Price, Valentina;Pardinas, Antonio F.;ODonovan, Michael C.
目的：精神分裂症与生殖成功率显著降低有关，但常见的等位基因在很大程度上导致了这种疾病的发生。对此有几种可能的解释，其中一种假设是，携带风险等位基因但未受影响的个体具有某种生殖优势，抵消了受影响个体的负选择效应。作者试图验证这一假设，将风险等位基因对生育能力的影响与可能表达精神分裂症的影响分离开来。方法：将英国生物银行研究中139679名未患精神分裂症的参与者携带的精神分裂症风险等位基因负担（多基因风险评分（PRS））与这些个体的后代数量进行比较。结果：在没有明显精神障碍的研究对象中，较高的精神分裂症倾向与生育更多孩子呈弱但显著相关（B=0.006, 95% CI=0.002, 0.010）。这种关系依赖于性别，在女性中，子女数量与责任呈正相关（B=0.011, 95% CI=0.006, 0.016），而在男性中，较高的责任与无子女相关（优势比=0.96,95% CI=0.94, 0.98）。在未受影响的个体中，与精神分裂症本身相关的儿童数量的负面影响是与PRS相关的积极影响的两倍到15倍。结论：这些发现表明，责任和繁殖力之间的复杂关系与性选择是一致的。尽管总体上与倾向性弱正相关的模式可能有助于精神分裂症风险等位基因的持续存在，但这些结果表明，在一般人群中，精神分裂症患者的负选择作用大于未受影响个体的遗传负荷所赋予的任何优势。
Objective: Schizophrenia is associated with a marked reduction in reproductive success, yet alleles that are common contribute substantially to the liability of the disorder. Among several possible explanations for this, it has been postulated that individuals who carry risk alleles but are unaffected are at some reproductive advantage, offsetting the effects of negative selection among those who are affected. The authors sought to test this hypothesis, isolating the effects of risk alleles on fecundity from the effects that are contingent on expressing schizophrenia.Methods: The burden of schizophrenia risk alleles, as indexed by a polygenic risk score (PRS), carried by 139,679 participants in the UK Biobank study who did not have schizophrenia was compared with the number of offspring of these individuals.Results: Higher schizophrenia liability in study subjects without manifest disorder was weakly but significantly associated with having more children (B=0.006, 95% CI=0.002, 0.010). The relationship was dependent on sex, with a positive correlation between number of children and liability among females (B=0.011, 95% CI=0.006, 0.016), whereas among males, higher liability was associated with being childless (odds ratio=0.96, 95% CI=0.94, 0.98). The negative effect on number of children associated with schizophrenia itself was twofold to 15-fold greater than the positive effect associated with PRS in unaffected individuals.Conclusions: These findings suggest that a complex relationship between liability and fecundity is consistent with sexual selection. Although the overall pattern of a weak positive correlation with liability may contribute to the persistence of schizophrenia risk alleles, these results indicate that the negative selection acting on individuals affected by schizophrenia in the general population is larger than any advantage conferred by genetic loading in unaffected individuals.