Mendelian randomization analysis with survival outcomes

Mendelian randomization (MR) is an established approach for assessing the causal effects of heritable exposures on outcomes. Outcomes of interest often include binary clinical endpoints, but may also include censored survival times. We explore the implications of both the Cox proportional hazard model and the additive hazard model in the context of MR, with a specific emphasis on two‐stage methods. We show that naive application of standard MR approaches to censored survival times may induce significant bias. Through simulations and analysis of data from the Women's Health Initiative, we provide practical advice on modeling survival outcomes in MRs.     

Mendelian randomization suggests a potential causal effect of eosinophil count on influenza vaccination responsiveness

Currently, the clinical factors affecting immune responses to influenza vaccines have not been systematically explored. The mechanism of low responsiveness to influenza vaccination (LRIV) is complicated and not thoroughly elucidated. Thus, we integrate our in-house genome-wide association studies (GWAS) analysis result of LRIV (N = 111, Ncase [Low Responders] = 34, Ncontrol [Responders] = 77) with the GWAS summary of 10 blood-based biomarkers (sample size ranging from 62 076−108 794) deposited in BioBank Japan (BBJ) to comprehensively explore the shared genetics between LRIV and blood-based biomarkers to investigate the causal relationships between blood-based biomarkers and LRIV by Mendelian randomization (MR). The applications of four MR approaches (inverse-variance-weighted [IVW], weighted median, weighted mode, and generalized summary-data-based MR [GSMR]) suggested that the genetically instrumented LRIV was associated with decreased eosinophil count (β = −5.517 to −4.422, p = 0.004−0.039). Finally, we conclude that the low level of eosinophil count is a suggestive risk factor for LRIV.     

Inactivation of DRG1, encoding a translation factor GTPase,causes a recessive neurodevelopmental disorder

PurposeDevelopmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants.MethodsWe collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles.ResultsWe identified private germline DRG1 variants, including 3 stop-gained p.Gly54¹, p.Arg140¹, p.Lys263¹, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality.ConclusionOur work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1’s importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.     

基于两样本孟德尔随机化研究血脂水平和子宫内膜异位症之间的关系

目的 采用两样本孟德尔随机化研究,探索血脂水平和子宫内膜异位症之间的因果关系。方法 利用大样本全基因组关联研究(GWAS)汇总数据,选择与各类血脂水平密切相关的遗传位点为工具变量,采用逆方差加权法进行两样本孟德尔随机化分析,以OR值评价各类血脂水平与子宫内膜异位症间的因果关系。结果 除了极小极低密度脂蛋白(VLDL)胆固醇外,其余与VLDL有关的血脂水平升高会增加子宫内膜异位症的发病风险(OR>1)。高密度脂蛋白(HDL)中与胆固醇有关的血脂类型、小低密度脂蛋白(LDL)中总胆固醇水平升高可减少子宫内膜异位症的发病风险(OR<1)。所有与甘油三酯相关的血脂类型、小LDL中胆固醇酯与总脂质比率的升高均可增加子宫内膜异位症的发病风险(OR>1)。结论 多种类型的血脂水平会影响子宫内膜异位症的发生,HDL中与胆固醇或甘油三酯相关的血脂水平可作筛查子宫内膜异位症的生物指标。     

Type 2 Diabetes,Fasting Glucose,Hemoglobin A1c Levels and Risk of Primary Open-Angle Glaucoma: A Mendelian Randomization Study

PurposeTo evaluate the potential causal associations between type 2 diabetes and fasting glucose and HbA1c levels and the risk of primary open-angle glaucoma (POAG) in European and East Asian populations.MethodsWe selected genetic variants (P < 5 × 10⁻⁸) for type 2 diabetes (898,130 Europeans; 433,540 East Asians), fasting glucose, and HbA1c (196,991 Europeans; 36,584 East Asians) from three meta-analyses of genome-wide association studies (GWAS). The GWAS for POAG provided summary statistics (192,702 Europeans; 46,523 East Asians). Mendelian randomization (MR) analysis was accomplished using the inverse variance–weighted method, weighted-median method, MR Egger method, and MR-Pleiotropy RESidual Sum and Outlier test.ResultsGenetically predicted type 2 diabetes was potentially positively associated with POAG in the European ancestry (body mass index [BMI]–unadjusted: odds ratio [OR] = 1.07, 95% confidence interval [CI], 1.01–1.14, P = 0.028; BMI-adjusted: OR = 1.07, 95% CI, 1.01–1.15, P = 0.035), but not in the East Asian ancestry (BMI-unadjusted: OR = 1.01, 95% CI, 0.95–1.06, P = 0.866; BMI-adjusted: OR = 1.00, 95% CI, 0.94–1.05, P = 0.882). There was no evidence to support a causal association of fasting glucose (European: OR = 1.19, P = 0.157; East Asian: OR = 0.94, P = 0.715) and HbA1c (European: OR = 1.27, P = 0.178; East Asian: OR = 0.85, P = 0.508) levels with POAG.ConclusionsThe causal effect of type 2 diabetes on the risk of POAG is different in European and East Asian populations. The point estimates of fasting glucose and Hb1Ac with POAG are large but not statistically significant, which prompts the question of statistical power.     

Assessing the Association between Important Dietary Habits and Osteoporosis: A Genetic Correlation and Two-Sample Mendelian Randomization Study

Objective: Osteoporosis (OP) is the most common bone disease. The genetic and metabolic factors play important roles in OP development. However, the genetic basis of OP is still elusive. The study aimed to explore the relationships between OP and dietary habits. Methods: This study used large-scale genome-wide association study (GWAS) summary statistics from the UK Biobank to explore potential associations between OP and 143 dietary habits. The GWAS summary data of OP included 9434 self-reported OP cases and 444,941 controls, and the GWAS summary data of the dietary habits included 455,146 participants of European ancestry. Linkage disequilibrium score regression (LDSC) was used to detect the genetic correlations between OP and each of the 143 dietary habits, followed by Mendelian randomization (MR) analysis to further assess the causal relationship between OP and candidate dietary habits identified by LDSC. Results: The LDSC analysis identified seven candidate dietary habits that showed genetic associations with OP including cereal type such as biscuit cereal (coefficient = −0.1693, p value = 0.0183), servings of raw vegetables per day (coefficient = 0.0837, p value = 0.0379), and spirits measured per month (coefficient = 0.115, p value = 0.0353). MR analysis found that OP and PC17 (butter) (odds ratio [OR] = 0.974, 95% confidence interval [CI] = (0.973, 0.976), p value = 0.000970), PC35 (decaffeinated coffee) (OR = 0.985, 95% CI = (0.983, 0.987), p value = 0.00126), PC36 (overall processed meat intake) (OR = 1.035, 95% CI = (1.033, 1.037), p value = 0.000976), PC39 (spirits measured per month) (OR = 1.014, 95% CI = (1.011, 1.015), p value = 0.00153), and servings of raw vegetables per day (OR = 0.978, 95% CI = (0.977, 0.979), p value = 0.000563) were clearly causal. Conclusions: Our findings provide new clues for understanding the genetic mechanisms of OP, which focus on the possible role of dietary habits in OP pathogenesis.     

完全随机型神经网络在1,6-二磷酸果糖制备条件优化上的应用

采用改进模拟退火法作为人工神经网络的学习算法,提出了适用于连续型输入变量、整体优化的完全随机型神经网络,并在1,6-二磷酸果糖制备条件优化中得到了成功应用,单位体积产率显著提高,为工业化生产提供了有利条件。     

IL-12RB1基因突变致孟德尔遗传易感分枝杆菌病2例临床特点及基因分析

目的　研究白细胞介素12受体B1基因（IL-12RB1）突变所致孟德尔遗传易感分枝杆菌病的基因资料及临床特点,提高对该病的认识。方法　检测2016—2018年中国医学科学院北京协和医院就诊的2例播散性卡介苗感染患儿基因并分析结果,同时总结患儿的临床资料。结果　2例患儿分别为11月龄和13月龄男性儿童,均于出生后接种卡介苗,接种后3个月出现同侧腋下淋巴结肿大,病原学检查提示抗酸杆菌生长。均否认结核病接触史。基因检测分析结果显示2例患儿均为IL-12RB1复合杂合基因突变,分别为c.1561C＞T,p.R521X;c.632G＞C,p.R211P;c.339-340 del CT,p.L113Lfs*15和c.1791+2T＞G。其中c.339-340 del CT,p.L113Lfs*15未见报道,是新突变。结论　对于接种卡介苗后出现感染性播散的患儿,应进行原发性免疫缺陷基因检测,相关基因突变的识别,可为早期治疗及遗传咨询提供依据。     

91种炎症蛋白与5种心血管疾病之间的因果关系：双样本孟德尔随机化研究

摘要 目的：通过采用孟德尔随机化(MR)方法和反向孟德尔随机化方法评估91种炎症蛋白与5种心血管疾病（动脉夹层、动脉瘤、冠心病、非风湿性瓣膜病和风湿性瓣膜病）之间的因果关系。 方法：使用来自欧洲人群的全基因组关联研究（GWAS）数据,利用孟德尔随机化（MR）方法和反向孟德尔随机化方法对 91 种炎症蛋白与5种心血管疾病之间的双向因果关系进行评估分析。MR分析方法包括inverse variance weighted (IVW)、Weighted median、MR-Egger、Simple Mode和Weighted mode。敏感性分析包括 Cochran''s Q 检验、MR-Egger 截距检验、MR-PRESSO 方法和 leave-one-out 方法。 结果：共有16种炎症蛋白可能与心血管疾病风险存在相关性,包括CCL20、CD5、CCL28、IL20RA、LAP-TGF-β1、TSLP、CST5、LIF、EIF4EBP1、CCL4、IL22RA1、IL-10、IL-17C、MCP-2/CCL8、NRTN和MCP-3/CCL7。此外,心血管疾病的进展可能会导致总共 10 种炎症蛋白水平的变化,包括 CCL11、IL-8、TNF-β、FGF19、IL10RA、FGF-21、IL10RB、β-NGF、CD5 和 MCP-1/CCL2。 结论：本研究结果表明,多种炎症蛋白与5种心血管疾病之间存在双向因果关系,证明了进一步研究各种炎症蛋白与上述心血管疾病之间的相关性存在更深入的研究空间。