Drug target Mendelian randomization describes the use of genetic variants as instrumental variables for studying the effects of pharmacological agents. The paradigm can be used to inform on all aspects of drug development and has become increasingly popular over the last decade, particularly given the time- and cost-efficiency with which it can be performed even before commencing clinical studies.

In this review, we describe the recent emergence of drug target Mendelian randomization, its common pitfalls, how best to address them, as well as potential future directions. Throughout, we offer advice based on our experiences on how to approach these types of studies, which we hope will be useful for both practitioners and those translating the findings from such work.

Drug target Mendelian randomization is nuanced and requires a combination of biological, statistical, genetic, epidemiological, clinical, and pharmaceutical expertise to be utilized to its full potential. Unfortunately, these skillsets are relatively infrequently combined in any given study.

The mucosal barrier's immune-brain interactions, pivotal for neural development and function, are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome (IBS). Prior studies linking immune inflammation with IBS have been inconsistent. To further elucidate this relationship, we conducted a Mendelian randomization (MR) analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS. Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets.

To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS. We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies.

We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS. By utilizing genetic data from public databases, we examined the causal associations between 731 immune cell markers, encompassing median fluorescence intensity, relative cell abundance, absolute cell count, and morphological parameters, with IBS susceptibility. Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy.

Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes. However, our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes (P < 0.05). Nine immune phenotypes demonstrated a protective effect against IBS [inverse variance weighting (IVW) < 0.05, odd ratio (OR) < 1], while 21 others were associated with an increased risk of IBS onset (IVW ≥ 0.05, OR ≥ 1).

Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS, providing valuable insights into the pathophysiology of the condition. These results pave the way for the development of more precise biomarkers and targeted therapies for IBS. Furthermore, this research enriches our comprehension of immune cell roles in IBS pathogenesis, offering a foundation for more effective, personalized treatment approaches. These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.

To evaluate the potential causal effect of glycemic traits on lung cancer and investigate the impact of antihyperglycemic agent-target genes on lung cancer risk.

Genetic variants associated with glycemic traits, antihyperglycemic agent-target genes, and lung cancer were extracted from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), expression quantitative trait loci (eQTLs), protein quantitative trait loci (pQTLs), and the International Lung Cancer Consortium (ILCCO), respectively. Mendelian randomization (MR) analyses were performed to examine the associations of glycemic traits and antihyperglycemic agent-target genes with lung cancer. Mediation analysis was conducted to explore whether overweight operated as a mediator between antihyperglycemic agents and lung cancer outcomes.

Genetically determined glycated hemoglobin A1c levels were associated with squamous cell lung cancer (OR = 1.78; 95 % CI, 1.08-2.92; p = 0.023). The PRKAB1 gene (the target of metformin) was associated with a lower risk of developing lung adenocarcinoma (OR = 0.85; 95 % CI, 0.76-0.96; p = 0.006). Further mediation analyses did not support overweight as a mediator between PRKAB1 activation and lung adenocarcinoma.

Our analyses suggest an association of genetically determined abnormal glycemic traits with squamous cell lung cancer. The potential association between PRKAB1 activation and a reduced risk of developing lung adenocarcinoma appears to be independent of the anti-obesity effects of metformin, suggesting that PRKAB1 activation may have a direct protective effect on lung adenocarcinoma development.

Previous studies on the associations between serum urate levels and neurodegenerative outcomes have yielded inconclusive results, and the causality remains unclear. This study aimed to investigate whether urate levels are associated with the risks of Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), and neurodegenerative deaths.

This prospective study included 382,182 participants (45.7% men) from the UK Biobank cohort. Cox proportional hazards models were used to assess the associations between urate levels and risk of neurodegenerative outcomes. In the Mendelian randomization (MR) analysis, urate-related single-nucleotide polymorphisms were identified through a genome-wide association study. Both linear and non-linear MR approaches were utilized to investigate the potential causal associations.

During a median follow-up period of 12 years, we documented 5,400 ADRD cases, 2,553 PD cases, and 1,531 neurodegenerative deaths. Observational data revealed that a higher urate level was associated with a decreased risk of ADRD (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.90, 0.96), PD (HR: 0.87, 95% CI: 0.82, 0.91), and neurodegenerative death (HR: 0.88, 95% CI: 0.83, 0.94). Negative linear associations between urate levels and neurodegenerative events were observed (all P-values for overall < 0.001 and all P-values for non-linearity > 0.05). However, MR analyses yielded no evidence of either linear or non-linear associations between genetically predicted urate levels and the risk of the aforementioned neurodegenerative events.

Although the prospective cohort study demonstrated that elevated urate levels were associated with a reduced risk of neurodegenerative outcomes, MR analyses found no evidence of causality.

The Mendelian randomization (MR) paradigm allows for causal inferences to be drawn using genetic data. In recent years, the expansion of well-powered publicly available genetic association data related to phenotypes such as brain tissue gene expression, brain imaging, and neurologic diseases offers exciting opportunities for the application of MR in the field of neurology. In this review, we discuss the basic principles of MR, its myriad applications to research in neurology, and potential pitfalls of injudicious applications. Throughout, we provide examples where MR-informed findings have shed light on long-standing epidemiologic controversies, provided insights into the pathophysiology of neurologic conditions, prioritized drug targets, and informed drug repurposing opportunities. With the ever-expanding availability of genome-wide association data, we project MR to become a key driver of progress in the field of neurology. It is therefore paramount that academics and clinicians within the field are familiar with the approach.

Increasing number of studies reported the positive effect of metformin on the prevention and treatment of cancers. However, the genetic causal effect of metformin utilization on the risk of common cancers was not completely demonstrated.

Two-sample Mendelian Randomization (two-sample MR) analysis was conducted to uncover the genetically predicted causal association between metformin use and 26 kinds of cancers. Besides, two-step Mendelian Randomization (two-step MR) assessment was applied to clarify the mediators which mediated the causal effect of metformin on certain cancer. We utilized five robust analytical methods, in which the inverse variance weighting (IVW) method served as the major one. Sensitivity, pleiotropy, and heterogeneity were assessed. The genetic statistics of exposure, outcomes, and mediators were downloaded from publicly available datasets, including the Open Genome-Wide Association Study (GWAS), FinnGen consortium (FinnGen), and UK Biobank (UKB).

Among 26 kinds of common cancers, HER-positive breast cancer was presented with a significant causal relationship with metformin use [Beta: - 4.0982; OR: 0.0166 (95% CI: 0.0008, 0.3376); P value: 0.0077], which indicated metformin could prevent people from HER-positive breast cancer. Other cancers only showed modest associations with metformin use. Potential mediators were included in two-step MR, among which total testosterone levels (mediating effect: 24.52%) displayed significant mediating roles. Leave-one-out, MR-Egger, and MR-PRESSO analyses produced consistent outcomes.

Metformin use exhibited a genetically protective effect on HER-positive breast cancer, which was partially mediated by total testosterone levels.

Lung cancer is a malignant tumor with a high incidence, it is vital to identify modifiable and avoidable risk factors for primary prevention, which can significantly lower the risk of cancer by preventing exposure to hazards and altering risky behavior. Some observational studies suggest that an increase in docosahexaenoic acid (DHA) consumption can reduce lung cancer risk. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To evaluate the link between DHA and lung cancer, we have undertaken this analysis to examine the causal association between DHA and the risk of lung cancer using a two-sample Mendelian randomization (MR) framework.

We performed a two-sample MR analysis to evaluate the causal effect of plasma DHA levels on lung cancer risk. For the exposure data, we extracted genetic variants as instrumental variables (IVs) that are strongly associated with DHA from a large-scale genome-wide association study (GWAS). We obtained the corresponding effect estimates for IVs on the risk of lung cancer with 11,348 cases and 15,861 controls. Finally, we applied Mendelian randomization analysis to obtain preliminary MR results and performed sensitivity analyses to verify the robustness of our results.

According to the primary MR estimates and further sensitivity analyses, a higher serum DHA level was associated with a higher risk of lung cancer [OR = 1.159, 95% CI (1.04-1.30), P = 0.01]. For lung adenocarcinoma, the results also showed a close correlation between the DHA level and lung adenocarcinoma [OR = 1.277, 95% CI (1.09-1.50), P = 0.003], but it was not statistically significant for squamous cell carcinoma [OR = 1.071, 95% CI (0.89-1.29), P = 0.467].

Our study revealed that plasma DHA is positively associated with the risk of lung cancer overall, especially for lung adenocarcinoma. This study provides new information to develop dietary guidelines for primary lung cancer prevention.

Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer's disease and potential causal mechanisms in the brain linking the two.

Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer's disease or Alzheimer's disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer's disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer's disease was further estimated.

Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA1c, was associated with 4% lower odds of Alzheimer's disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10-4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer's disease (OR 0.88, p=4.73×10-4) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer's disease risk (OR 0.95, p=4.64×10-4) and favourable cognitive function.

Metformin use may cause reduced Alzheimer's disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.

We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.

We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.

We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.

Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.

There has been no study systematically assessing the causal effects of putative modifiable risk factors on lung cancer. In this study, we aimed to construct a modifiable risk factors atlas of lung cancer by using the two-sample Mendelian randomization framework.

We included 46 modifiable risk factors identified in previous studies. Traits with p-value smaller than 0.05 were considered as suggestive risk factors. While the Bonferroni corrected p-value for significant risk factors was set to be 8.33 × 10-4 .

In this two-sample Mendelian randomization analysis, we found that higher socioeconomic status was significantly correlated with lower risk of lung cancer, including years of schooling, college or university degree, and household income. While cigarettes smoked per day, time spent watching TV, polyunsaturated fatty acids, docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid in blood were significantly associated with higher risk of lung cancer. Suggestive risk factors for lung cancer were found to be serum vitamin A1, copper in blood, docosahexaenoic acid in blood, and body fat percentage.

This study provided the first Mendelian randomization assessment of the causality between previously reported risk factors and lung cancer risk. Several modifiable targets, concerning socioeconomic status, lifestyle, dietary, and obesity, should be taken into consideration for the development of primary prevention strategies for lung cancer.

Dyslipidaemia is a common chronic disease in China but is among the list of diseases treated by basic public health services. In this study, we aimed to use the European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) and visual analogue scale (VAS) to compare differences in health-related quality of life (HRQoL) between dyslipidaemic and non-dyslipidaemic individuals in rural China and to explore possible causes for the underlying differences.

This study examined 10,115 participants from 22 rural communities in Xinxiang County, Henan Province, China. The study participants were interviewed between March and June 2017. Generalised linear and Tobit regression models were used to analyse factors affecting participants' HRQoL.

Of 10,115 participants, 4355 had dyslipidaemia. The mean utility index was 0.953 (standard deviation = 0.119). Pain/discomfort (20.83%) and problems with mobility (15.91%) and self-care (3.75%) were frequently reported. Regression models revealed that patients with low utility index scores were older, ex-smokers, non-tea drinkers, and less active, consumed less fruit, lived in areas with a low socioeconomic status; and were less educated. Patients also had poorer sleep quality and mental health scores and suffered from chronic diseases. Cohen's D effect size for age, sleep quality, non-communicable diseases, and depression was ≥ 0.4.

The prevalence rate of dyslipidaemia was 43.05%, and it was correlated with a lower HRQoL. Age, sleep quality, non-communicable diseases, and depression may be significant predictors of the utility index and VAS scores. Patients were unaware of the risks of dyslipidaemia caused by an unhealthy lifestyle.