Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; Psychiatric Imaging Group, Imperial College London, London, UK.
Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK; Psychiatric Imaging Group, Imperial College London, London, UK.
Lancet Psychiatry. 2023 Feb;10(2):98-107. doi: 10.1016/S2215-0366(22)00403-5. Epub 2023 Jan 8.
Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication. Therefore, we aimed to explore whether shared genetic causes contribute to these cardiac variations.
For this observational study, we used data from the UK Biobank and included White British or Irish individuals without diagnosed schizophrenia with variable polygenic risk scores for the condition. To test the association between polygenic risk score for schizophrenia and cardiac phenotype, we used principal component analysis and regression. Robust regression was then used to explore the association between the polygenic risk score for schizophrenia and individual cardiac phenotypes. We repeated analyses with fibro-inflammatory pathway-specific polygenic risk scores for schizophrenia. Last, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium score regression. The primary outcome was principal component regression.
Of 33 353 individuals recruited, 32 279 participants had complete cardiac MRI data and were included in the analysis, of whom 16 625 (51·5%) were female and 15 654 (48·5%) were male. 1074 participants were excluded on the basis of incomplete cardiac MRI data (for all phenotypes). A model regressing polygenic risk scores for schizophrenia onto the first five cardiac principal components of the principal components analysis was significant (F=5·09; p=0·00012). Principal component 1 captured a pattern of increased cardiac volumes, increased absolute peak diastolic strain rates, and reduced ejection fractions; polygenic risk scores for schizophrenia and principal component 1 were negatively associated (β=-0·01 [SE 0·003]; p=0·017). Similar to the principal component analysis results, for individual cardiac phenotypes, we observed negative associations between polygenic risk scores for schizophrenia and indexed right ventricular end-systolic volume (β=-0·14 [0·04]; p=0·0013, p=0·015), indexed right ventricular end-diastolic volume (β=-0·17 [0·08]); p=0·025; p=0·082), and absolute longitudinal peak diastolic strain rates (β=-0·01 [0·003]; p=0·0024, p=0·015), and a positive association between polygenic risk scores for schizophrenia and right ventricular ejection fraction (β=0·09 [0·03]; p=0·0041, p=0·015). Models examining the transforming growth factor-β (TGF-β)-specific and acute inflammation-specific polygenic risk scores for schizophrenia found significant associations with the first five principal components (F=2·62, p=0·022; F=2·54, p=0·026). Using linkage disequilibrium score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume and right ventricular ejection fraction (p=0·0090, p=0·0077).
High polygenic risk scores for schizophrenia are associated with decreased cardiac volumes, increased ejection fractions, and decreased absolute peak diastolic strain rates. TGF-β and inflammatory pathways might be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Reduced absolute peak diastolic strain rates indicate increased myocardial stiffness and diastolic dysfunction, which increases risk of cardiac disease. Thus, genetic risk for schizophrenia is associated with cardiac structural changes that can worsen cardiac outcomes. Further work is required to determine whether these associations are specific to schizophrenia or are also seen in other psychiatric conditions.
National Institute for Health Research, Maudsley Charity, Wellcome Trust, Medical Research Council, Academy of Medical Sciences, Edmond J Safra Foundation, British Heart Foundation.
心血管疾病是精神分裂症患者死亡的主要原因之一。多种因素起作用，包括抗精神病药物的生活方式和代谢影响。然而，在没有心血管疾病风险因素且考虑生活方式和药物的情况下，精神分裂症患者的心脏结构和功能也会发生变化。因此，我们旨在探讨是否存在共同的遗传原因导致这些心脏变化。
在这项观察性研究中，我们使用了英国生物库的数据，纳入了没有诊断为精神分裂症的白种英国或爱尔兰个体，他们的精神分裂症多基因风险评分不同。为了测试精神分裂症多基因风险评分与心脏表型之间的关联，我们使用主成分分析和回归进行了分析。然后使用稳健回归来探索精神分裂症多基因风险评分与个体心脏表型之间的关联。我们对精神分裂症的纤维化-炎症途径特异性多基因风险评分进行了重复分析。最后，我们使用连锁不平衡得分回归来研究精神分裂症和心脏表型之间常见变异的全基因组共享情况。主要结果是主成分回归。
在招募的 33353 人中，有 32279 名参与者完成了完整的心脏 MRI 数据，并纳入了分析，其中 16625 名（51.5%）为女性，15654 名（48.5%）为男性。1074 名参与者因心脏 MRI 数据不完整而被排除（所有表型）。一个将精神分裂症多基因风险评分回归到主成分分析的前五个心脏主成分的模型是显著的（F=5.09；p=0.00012）。主成分 1 捕获了心脏容积增加、绝对舒张末期应变率增加和射血分数降低的模式；精神分裂症多基因风险评分与主成分 1 呈负相关（β=-0.01 [0.003]；p=0.017）。与主成分分析结果相似，对于个体心脏表型，我们观察到精神分裂症多基因风险评分与索引右心室收缩末期容积（β=-0.14 [0.04]；p=0.0013，p=0.015）、索引右心室舒张末期容积（β=-0.17 [0.08]；p=0.025，p=0.082）和绝对纵向舒张末期应变率（β=-0.01 [0.003]；p=0.0024，p=0.015）呈负相关，与右心室射血分数（β=0.09 [0.03]；p=0.0041，p=0.015）呈正相关。检查转化生长因子-β（TGF-β）特异性和急性炎症特异性精神分裂症多基因风险评分的模型发现与前五个主成分呈显著相关（F=2.62，p=0.022；F=2.54，p=0.026）。使用连锁不平衡得分回归，我们观察到与右心室收缩末期容积和右心室射血分数的遗传重叠（p=0.0090，p=0.0077）。
高精神分裂症多基因风险评分与心脏容积减少、射血分数增加和绝对舒张末期应变率降低有关。TGF-β和炎症途径可能涉及其中，并且一些心脏表型存在遗传重叠的证据。绝对舒张末期应变率的降低表明心肌僵硬和舒张功能障碍增加，从而增加了心脏疾病的风险。因此，精神分裂症的遗传风险与可能恶化心脏结局的心脏结构变化有关。需要进一步的工作来确定这些关联是否是精神分裂症特有的，还是也存在于其他精神疾病中。
英国国家卫生研究院、Maudsley 慈善基金会、惠康信托基金、医学研究理事会、医学科学院、Edmond J Safra 基金会、英国心脏基金会。
