Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Lancet Psychiatry. 2021 Dec;8(12):1062-1070. doi: 10.1016/S2215-0366(21)00286-8. Epub 2021 Nov 1.
Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia.
We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides.
Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]).
Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia.
National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.
虽然有研究表明，精神分裂症患者体内的ω-3 和 ω-6 脂肪酸浓度较低，但脂肪酸补充有益影响的证据很少。因此，在这项研究中，我们旨在确定 ω-3 和 ω-6 脂肪酸浓度是否与精神分裂症有因果关系。
我们进行了一项两样本孟德尔随机化研究，使用了公开的可识别的汇总水平数据。使用基于全基因组关联研究（GWAS）的脂肪酸浓度和精神分裂症的逆方差加权两样本孟德尔随机化方法评估暴露-结局关系。GWAS 结果可用于欧洲（脂肪酸）和欧洲和亚洲（精神分裂症）血统样本。总体年龄和性别信息无法从汇总水平 GWAS 结果中计算得出。加权中位数、加权模式和孟德尔随机化 Egger 回归方法被用作敏感性分析。为了解决潜在机制，还使用 FADS 基因簇和 ELOVL2 基因座内的单个工具进行了进一步分析。通过将单核苷酸多态性（SNP）-精神分裂症效应估计值除以 SNP-脂肪酸效应估计值，计算 FADS 基因簇和 ELOVL2 基因对精神分裂症的因果效应，标准误差是使用德尔塔方法扩展的第一个术语计算的比值估计值。多变量孟德尔随机化用于估计ω-3 脂肪酸对精神分裂症的直接影响，独立于 ω-6 脂肪酸、脂蛋白（即 HDL 和 LDL）和甘油三酯。
孟德尔随机化分析表明，长链 ω-3 和长链 ω-6 脂肪酸浓度与较低的精神分裂症风险相关（例如，二十二碳六烯酸的逆方差加权比值比 [OR] 0.83 [95%CI 0.75-0.92]）。相比之下，有微弱的证据表明短链 ω-3 和短链 ω-6 脂肪酸与精神分裂症风险增加有关（例如，α-亚麻酸的逆方差加权 OR 1.07 [95%CI 0.98-1.18]）。敏感性分析和 FADS 单 SNP 分析的结果一致，表明长链 ω-3 和长链 ω-6 脂肪酸浓度与较低的精神分裂症风险相关（例如，二十二碳六烯酸的 OR 0.74 [95%CI 0.58-0.96]），而短链 ω-3 和短链 ω-6 脂肪酸浓度与精神分裂症风险增加相关（例如，α-亚麻酸的 OR 1.08 [95%CI 1.02-1.15]）。相比之下，ELOVL2 单 SNP 分析的估计值不太精确，并且每种脂肪酸测量值都与风险增加和保护作用兼容。多变量孟德尔随机化表明，二十二碳六烯酸对精神分裂症的保护作用在考虑其他脂质后仍然存在，尽管证据稍弱（多变量逆方差加权 OR 0.84 [95%CI 0.71-1.01]）。
我们的结果与长链 ω-3 和长链 ω-6 脂肪酸对精神分裂症的保护作用一致，表明精神分裂症患者可能难以将短链多不饱和脂肪酸转化为长链多不饱和脂肪酸。需要进一步的研究来确定长链多不饱和脂肪酸补充或饮食富集是否有助于预防精神分裂症的发生。
英国国家卫生研究院生物医学研究中心，位于布里斯托大学医院和韦斯顿国民保健信托基金会以及布里斯托大学。
