Background

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.

Methods

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.

Findings

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]).

Interpretation

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.

Funding

National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.

中文翻译：

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血浆脂肪酸浓度与精神分裂症之间的关联：双样本孟德尔随机研究

背景

尽管研究表明精神分裂症患者的 omega-3 和 omega-6 脂肪酸浓度较低，但补充脂肪酸有益效果的证据却很少。因此，在这项研究中，我们旨在确定 omega-3 和 omega-6 脂肪酸浓度是否与精神分裂症有因果关系。

方法

我们进行了一项双样本孟德尔随机化研究，使用的是公开可用的去标识化摘要级数据。使用脂肪酸浓度和精神分裂症的全基因组关联研究 (GWAS) 结果，使用逆方差加权双样本孟德尔随机化方法评估暴露-结果关系。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级 GWAS 结果中计算出来。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，使用FADS基因簇和ELOVL2中的单一仪器进行了进一步分析基因位点。FADS基因簇和ELOVL2基因对精神分裂症的因果影响是通过将单核苷酸多态性 (SNP)-精神分裂症效应估计值除以 SNP-脂肪酸效应估计值来计算的，标准误差是使用 delta 方法扩展的第一项得出的比率估计值. 多变量孟德尔随机化用于估计 omega-3 脂肪酸对精神分裂症的直接影响，独立于 omega-6 脂肪酸、脂蛋白（即 HDL 和 LDL）和甘油三酯。

发现

孟德尔随机化分析表明，长链 omega-3 和长链 omega-6 脂肪酸浓度与较低的精神分裂症风险相关（例如，逆方差加权比值比 [OR] 0·83 [95% CI 0·75 –0·92] 用于二十二碳六烯酸）。相比之下，短链 omega-3 和短链 omega-6 脂肪酸与精神分裂症风险增加相关的证据不足（例如，逆方差加权 OR 1·07 [95% CI 0·98–1 ·18] α-亚麻酸）。敏感性分析和FADS的效果是一致的单 SNP 分析表明，长链 omega-3 和长链 omega-6 脂肪酸浓度与较低的精神分裂症风险相关（例如，OR 0·74 [95% CI 0·58–0·96]二十二碳六烯酸），而短链 omega-3 和短链 omega-6 脂肪酸浓度与精神分裂症风险增加相关（例如，α- 的 OR 1·08 [95% CI 1·02–1·15]亚麻酸）。相比之下，来自ELOVL2的估计单 SNP 分析更加不精确，并且与每种脂肪酸措施的风险增加和保护作用相容。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调节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]）。

解释

我们的结果与长链 omega-3 和长链 omega-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剂或饮食丰富是否有助于预防精神分裂症的发作。

资金

布里斯托尔大学医院和韦斯顿 NHS 基金会信托基金和布里斯托尔大学国家健康研究所生物医学研究中心。