Mendelian Randomization Applied to Neurology: Promises and Challenges

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.

Adiposity and Functional Outcome After Ischemic Stroke: A Mendelian Randomization Study

BACKGROUND AND OBJECTIVES: To investigate the causal relationships of abdominal adiposity (waist-to-hip ratio [WHR]) and overall adiposity (body mass index [BMI]) with functional outcome after ischemic stroke using Mendelian randomization. METHODS: Genetic instruments for WHR and BMI were obtained from the largest available genome-wide association studies meta-analysis of the Genetic Investigation of ANthropometric Traits consortium and the UK Biobank (N max = 806,834). Functional outcome after ischemic stroke was assessed using the modified Rankin Scale (mRS) score at 3-month after stroke onset, with mRS >2 (mRS 3-6) defined as an unfavorable functional outcome. Corresponding genetic estimates for an unfavorable functional outcome were extracted from the Genetics of Ischemic Stroke Functional Outcome network (N = 6,021). We applied a random-effects inverse variance weighted method as our main analysis. RESULTS: Genetically predicted higher WHR (per 0.09 ratio units) was associated with unfavorable functional outcome after ischemic stroke (mRS 3-6, OR = 1.48; 95% CI = 1.03-2.13; p = 0.033). The results remained directionally consistent in sensitivity analyses. Conversely, genetically predicted BMI (per 4.8 kg/m2) was not associated with unfavorable functional outcome after ischemic stroke (OR = 1.01; 95% CI = 0.75-1.36; p = 0.937). DISCUSSION: This study provides genetic evidence supporting the hypothesis that abdominal adiposity has a detrimental effect on functional recovery after ischemic stroke.

Cerebrospinal Fluid C1-Esterase Inhibitor and Tie-1 Levels Affect Cognitive Performance: Evidence from Proteome-Wide Mendelian Randomization.

OBJECTIVE: The association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance. METHODS AND ANALYSIS: Genetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals. We performed Mendelian randomization (MR) analyses to test the effect of randomly allocated variation in 154 genetically predicted CSF protein levels on cognitive performance. Findings were validated by performing colocalization analyses and considering cognition-related phenotypes. RESULTS: Genetically predicted C1-esterase inhibitor levels in the CSF were associated with a better cognitive performance (SD units of cognitive performance per 1 log-relative fluorescence unit (RFU): 0.23, 95% confidence interval: 0.12 to 0.35, p = 7.91 × 10-5), while tyrosine-protein kinase receptor Tie-1 (sTie-1) levels were associated with a worse cognitive performance (-0.43, -0.62 to -0.23, p = 2.08 × 10-5). These findings were supported by colocalization analyses and by concordant effects on distinct cognition-related and brain-volume measures. CONCLUSIONS: Human genetics supports a role for the C1-esterase inhibitor and sTie-1 in cognitive performance.

Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

BACKGROUND: High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke. METHODS: We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke). We first evaluated the associations of the CHA2DS2-VASc and stroke prognosis instrument II (SPI-II) scores with the risk of incident ischemic stroke and major hemorrhage (intracranial hemorrhage or major systemic hemorrhage). We then tested for heterogeneity of the relative and absolute treatment effect of DAPT relative to aspirin across low- and high-risk patient subgroups. RESULTS: A total of 4841 trial participants were included in this analysis, with 2400 participants assigned to treatment with short-term DAPT and 2430 participants to treatment with aspirin and placebo. The dichotomized SPI-II score, but not the CHA2DS2-VASc score (P=0.18), was associated with the risk of incident ischemic stroke. A high-risk SPI-II score (>3) was associated with greater risk of incident ischemic stroke (hazard ratio of incident ischemic stroke relative to low-risk SPI-II score of 1.84 [95% CI, 1.44-2.35]; P<0.001) and numerically greater risk of major hemorrhage though not meeting statistical significance (hazard ratio, 1.80 [95% CI, 0.90-3.57]; P=0.10). The relative risk reduction with DAPT was similar across SPI-II strata (Pinteraction=0.31). The absolute risk reduction for ischemic stroke with DAPT compared with aspirin was nearly 4-fold higher (2.80% versus 0.76%; number needed to treat, 31 versus 131) in the high-risk SPI-II stratum relative to the low-risk stratum. The absolute risk increase for major hemorrhage with DAPT compared with aspirin was 3-fold higher (0.84% versus 0.30%; number needed to harm, 119 versus 331) in the high-risk SPI-II stratum relative to the low-risk stratum. CONCLUSIONS: Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Causal Associations of Sleep Apnea with Alzheimer's Disease and Cardiovascular Disease: a Bidirectional Mendelian Randomization Analysis.

Background: Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer's disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization (MR). Methods: Using summary statistics from four recent, large genome-wide association studies of SA (n=523,366), AD (n=64,437), CAD (n=1,165,690), and stroke (n=1,308,460), we conducted bidirectional two-sample MR analyses. Our primary analytic method was fixed-effects inverse variance weighted MR; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results. Results: We identified a significant causal effect of SA on the risk of CAD (odds ratio (OR IVW ) =1.35 per log-odds increase in SA liability, 95% confidence interval (CI) =1.25-1.47) and stroke (OR IVW =1.13, 95% CI =1.01-1.25). These associations were somewhat attenuated after excluding single-nucleotide polymorphisms associated with body mass index (BMI) (OR IVW =1.26, 95% CI =1.15-1.39 for CAD risk; OR IVW =1.08, 95% CI =0.96-1.22 for stroke risk). SA was not causally associated with a higher risk of AD (OR IVW =1.14, 95% CI =0.91-1.43). We did not find causal effects of AD, CAD, or stroke on risk of SA. Conclusions: These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by BMI. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.

Genetically proxied lean mass and risk of Alzheimer's disease: mendelian randomisation study.

Objective: To examine whether genetically proxied lean mass is associated with risk of Alzheimer's disease. Design: Mendelian randomisation study. Setting: The UK Biobank study and genome wide association study meta-analyses of Alzheimer's disease and cognitive performance. Participants: Summary level genetic data from: 450 243 UK Biobank participants with impedance measures of lean mass and fat mass; an independent sample of 21 982 patients with Alzheimer's disease and 41 944 controls without Alzheimer's disease; a replication sample of 7329 patients with Alzheimer's disease and 252 879 controls; and 269 867 individuals taking part in a genome wide association study of cognitive performance. Main outcome measure: Effect of genetically proxied lean mass on the risk of Alzheimer's disease, and the related phenotype of cognitive performance. Results: An increase in genetically proxied appendicular lean mass of one standard deviation was associated with a 12% reduced risk of Alzheimer's disease (odds ratio 0.88, 95% confidence interval 0.82 to 0.95, P=0.001). This finding was replicated in an independent cohort of patients with Alzheimer's disease (0.91, 0.83 to 0.99, P=0.02) and was consistent in sensitivity analyses that are more robust to the inclusion of pleiotropic variants. Higher genetically proxied appendicular lean mass was also associated with increased cognitive performance (standard deviation increase in cognitive performance for each standard deviation increase in appendicular lean mass 0.09, 95% confidence interval 0.06 to 0.11, P=0.001), and adjusting for potential mediation through genetically proxied cognitive performance did not reduce the association between appendicular lean mass and risk of Alzheimer's disease. Similar results were found for the outcomes of Alzheimer's disease and cognitive performance when the risk factors of genetically proxied trunk lean mass and whole body lean mass were used, respectively, adjusted for genetically proxied fat mass. Conclusions: These findings suggest that lean mass might be a possible modifiable protective factor for Alzheimer's disease. The mechanisms underlying this finding, as well as the clinical and public health implications, warrant further investigation.

Genetic liability to migraine and functional outcome after ischemic stroke.

BACKGROUND AND PURPOSE: To evaluate the association of genetic liability to migraine with functional outcome after ischemic stroke using Mendelian randomization. METHODS: Genetic proxies for migraine were obtained from the largest genome-wide association study meta-analysis of 102,084 migraine cases and 771,257 controls. Genetic associations with functional outcome after ischemic stroke were obtained from the Genetics of Ischemic Stroke Functional Outcome network study (N = 6021). Poor functional outcome after ischemic stroke was defined as a score of 3-6 on the modified Rankin scale at 3 months (N = 2280). The inverse-variance weighted method was used to estimate the association of genetic liability to migraine with functional outcome, and we performed sensitivity analyses to assess the robustness of results. RESULTS: Genetic liability to migraine was associated with poor functional outcome after ischemic stroke (odds ratio of poor functional outcome per doubling in migraine odds 1.22, 95% confidence interval 1.02-1.45, p = 0.031). This association remained directionally consistent across sensitivity analyses. CONCLUSIONS: This study provides genetic support that migraine is associated with poor functional outcome after ischemic stroke. These findings warrant further follow-up and, if replicated, may have clinical implications for post-stroke recovery.

Leveraging genetic predictors of factor XI levels to anticipate results from clinical trials.

BACKGROUND: Factor XI (FXI) is a promising therapeutic target for the prevention of thrombotic disease without increasing bleeding risk. METHODS: We performed Mendelian randomization (MR) analyses to investigate the association of genetically predicted reductions in FXI levels with risk of venous thromboembolism, ischemic stroke, bleeding outcomes, and lifespan. RESULTS: Genetically predicted reductions in FXI levels were associated with lower risk of ischemic stroke (odds ratio per 1 standard deviation (SD) lower serum FXI 0.90, 95% confidence interval 0.87-0.93, p = 1.59 × 10-11 ), and venous thromboembolism (0.54, 0.49-0.59, p = 2.13 × 10-39 ) but did not associate with increased bleeding risk (p > 0.16). Genetically predicted reductions in serum FXI levels associated with longer lifespan (0.37 years per 1 SD lower serum FXI, 0.13-0.61, p = 0.003). CONCLUSIONS: These genetic data support FXI as a potentially efficacious and safe therapeutic target and anticipate positive results from ongoing phase 3 clinical trials.

Evaluating the association between genetically proxied ACE inhibition and dementias.

INTRODUCTION: Angiotensin-converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown. METHODS: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two-sample Mendelian randomization (MR) approach. RESULTS: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04-1.10], P = 5 × 10-07 ) and frontotemporal dementia (1.16 [1.04-1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses. DISCUSSION: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition. HIGHLIGHTS: This study evaluated genetically proxied angiotensin-converting enzyme (ACE) inhibition association with dementias. The results suggest an association between ACE inhibition and Alzheimer's disease. The results suggest an association between ACE inhibition and frontotemporal dementia. Those associations can be interpreted as potentially causal.

Mendelian randomization as a tool to inform drug development using human genetics.

Drug development is essential to the advancement of human health, however, the process is slow, costly, and at high risk of failure at all stages. A promising strategy for expediting and improving the probability of success in the drug development process is the use of naturally randomized human genetic variation for drug target identification and validation. These data can be harnessed using the Mendelian randomization (MR) analytic paradigm to proxy the lifelong consequences of genetic perturbations of drug targets. In this review, we discuss the myriad applications of the MR paradigm for human drug target identification and validation. We review the methodology and applications of MR, key limitations of MR, and potential future opportunities for research. Throughout the review, we refer to illustrative examples of MR analyses investigating the consequences of genetic inhibition of interleukin 6 signaling which, in some cases, have anticipated results from randomized controlled trials. As human genetic data become more widely available, we predict that MR will serve as a key pillar of support for drug development efforts.

Evaluation of Sleep Habits and Disturbances Among US Adults, 2017-2020.

Importance: Unhealthy sleep behaviors and sleep disturbances are associated with higher risk of multiple diseases and mortality. The current profiles of sleep habits and disturbances, particularly the differences between workdays and free days, are unknown in the contemporary US. Objective: To comprehensively evaluate sleep habits on workdays and free days and the prevalence of sleep disturbances among US adults. Design, Setting, and Participants: This study is a cross-sectional analysis of US nationally representative data from the National Health and Nutrition Examination Survey (2017-2020) among adults aged 20 years or older. Data analysis was performed from February to May 2022. Main Outcomes and Measures: The main outcomes were means and/or distributions of sleep habits, including sleep duration and sleep-wake timing on workdays and free days, sleep debt (ie, the difference between sleep duration on free days and mean weekly sleep duration), and social jet lag (ie, the difference between the midpoint between sleep and wake time on workdays and free days). Prevalence of trouble sleeping (ie, participants told a doctor or other health professional that they have trouble sleeping) and daytime sleepiness (ie, self-reported feeling of being overly sleepy during the day ≥5 times per month) were also determined. Results: A total of 9004 individuals (mean [SE] age, 48.3 [0.53] years; 4635 women [51.9%]; 3158 non-Hispanic White [62.8%]) were included in the current study. The mean sleep duration was 7.59 hours (95% CI, 7.54 to 7.64 hours) on workdays and 8.24 hours (95% CI, 8.17 to 8.31 hours) on free days (difference, 0.65 hour). The mean sleep and wake times were at 11:02 pm (95% CI, 10:57 pm to 11:17 pm) and 6:41 am (95% CI, 6:36 am to 6:45 am), respectively, on workdays and 11:25 pm (95% CI, 11:21 pm to 11:35 pm) and 7:41 am (95% CI, 7:37 am to 7:46 am), respectively, on free days (differences, 0.23 hour for sleep time and 1.00 hour for wake time). On workdays, 23.1% (95% CI, 21.3% to 24.9%) of adults slept less than 7 hours and 25.4% (95% CI, 24.1% to 26.6%) went to sleep at midnight or later; the corresponding percentages changed to 12.9% (95% CI, 11.6% to 14.1%) and 40.9% (95% CI, 38.4% to 43.5%), respectively, on free days. Furthermore, the mean sleep debt was 0.73 hours (95% CI, 0.68 to 0.77 hours), and mean social jet lag was 1.10 hours (95% CI, 1.05 to 1.15 hours); 30.5% (95% CI, 26.8% to 33.3%) of adults experienced 1 hour or more of sleep debt, and 46.5% (95% CI, 42.6% to 50.3%) experienced 1 hour or more of social jet lag. The prevalence of trouble sleeping was 29.8% (95% CI, 28.2% to 31.5%), and that of daytime sleepiness was 27.2% (95% CI, 25.0% to 29.5%). Conclusions and Relevance: In 2017 to 2020, US adults showed variability in sleep habits between workdays and free days, with longer sleep duration and later sleep-wake phases on free days, and high percentages of US adults experienced long-term sleep deprivation, chronic social jet lag, and frequent sleep disturbances. These findings provide evidence to further investigate potential approaches to optimize overall US sleep health.

Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study.

Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2-1.26, P = 1.37 × 10-61), BP (OR = 1.15, 95% CI = 1.07-1.23, P = 5.11 × 10-5), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07-1.27, P = 2.30 × 10-4), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16-1.54, P = 5.97 × 10-5), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18-1.3, P = 1.47 × 10-18). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB.

Assessing the Causal Role of Sleep Traits on Glycated Hemoglobin: A Mendelian Randomization Study.

OBJECTIVE: To examine the effects of sleep traits on glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS: This study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female). RESULTS: Across MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA1c (MVR 0.05 SD units [95% CI 0.04-0.06]; 1SMR 0.52 [0.42-0.63]; 2SMR 0.24 [0.11-0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect. CONCLUSIONS: Our results suggest that frequent insomnia symptoms cause higher HbA1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes.

Alcohol, coffee consumption, and smoking in relation to migraine: a bidirectional Mendelian randomization study.

ABSTRACT: We conducted a Mendelian randomization study to assess whether alcohol and coffee consumption and smoking are causally associated with risk of developing migraine. Independent single-nucleotide polymorphisms associated with the potential risk factors at P < 5 × 10-8 in large-scale genome-wide association studies were selected as instrumental variables. Summary-level data for the associations of the selected single-nucleotide polymorphisms with migraine were obtained from the FinnGen consortium comprising 6687 cases and 144,780 noncases and the UK Biobank study comprising 1072 cases and 360,122 noncases. Estimates derived from the FinnGen and UK Biobank cohorts were combined using fixed-effects meta-analysis. We found evidence for associations of genetically predicted alcohol consumption (odds ratio [OR] 0.54 per SD increase in log-transformed alcoholic drinks per week, 95% confidence interval [CI], 0.35-0.82; P = 0.004), coffee consumption (OR 0.56 per 50% increase in coffee consumption, 95% CI, 0.45-0.70; P < 0.001), and smoking initiation (OR 1.15 for one SD increase in the prevalence of smoking initiation, 95% CI, 1.01-1.31; P = 0.038). These associations persisted in sensitivity analyses, including mutual adjustment in multivariable Mendelian randomization analyses. In reverse Mendelian randomization analyses, genetic liability to migraine was inversely associated with alcohol consumption but was not associated with coffee consumption or smoking initiation. This study provides genetic evidence in support of a protective role of moderate coffee consumption and a detrimental role of cigarette smoking in the etiology of migraine. The inverse association between alcohol consumption and migraine risk may be attributable to reverse causality.

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (ß = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subfractions.

BACKGROUND AND OBJECTIVE: To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions. METHODS: We evaluated phenotypic associations between migraine and 19 lipoprotein subfraction measures in the Women's Genome Health Study (n = 22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium for migraine (ncase = 54,552, ncontrol = 297,970) and combined summary data for lipoprotein subfractions (n up to 47,713). RESULTS: There was a significant phenotypic association (odds ratio 1.27 [95% confidence interval 1.12-1.44]) and a significant genetic correlation at 0.18 (p = 0.001) between migraine and triglyceride-rich lipoproteins (TRLPs) concentration but not for low-density lipoprotein or high-density lipoprotein subfractions. Mendelian randomization (MR) estimates were largely null, implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis, revealing significant shared signals at 4 loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (p < 0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues. CONCLUSIONS: The study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may help identify potential targets for future migraine therapeutics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling.

AIMS/HYPOTHESIS: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. METHODS: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. RESULTS: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. CONCLUSIONS/INTERPRETATION: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. DATA AVAILABILITY: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP .

Genetic Evidence for Repurposing of GLP1R (Glucagon-Like Peptide-1 Receptor) Agonists to Prevent Heart Failure.

Background This study was designed to investigate the genetic evidence for repurposing of GLP1R (glucagon-like peptide-1 receptor) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results We applied 2-sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction as the secondary outcome. The associations were compared with those of general glycemic control on the same outcomes. Genetic associations were obtained from genome-wide association study summary statistics of type 2 diabetes mellitus (228 499 cases and 1 178 783 controls), glycated hemoglobin (n=344 182), HF (47,309 cases and 930 014 controls), and left ventricular ejection fraction (n=16 923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1 mmol/mol decrease in glycated hemoglobin 0.75; 95% CI, 0.64-0.87; P=1.69×10-4), and higher left ventricular ejection fraction (SD change in left ventricular ejection fraction per 1 mmol/mol decrease in glycated hemoglobin 0.22%; 95% CI, 0.03-0.42; P=0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions This genetic evidence supports the repurposing of GLP1R agonists for preventing HF.

Metabolic Traits and Stroke Risk in Individuals of African Ancestry: Mendelian Randomization Analysis.

BACKGROUND AND PURPOSE: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals. METHODS: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy. RESULTS: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07-1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04-1.21]; total cholesterol: 1.23 [1.06-1.43]; HDL-C, 0.93 [0.89-0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals. CONCLUSIONS: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.

Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder.

Importance: Morning diurnal preference is associated with reduced risk of major depressive disorder (MDD); however, causality in this association is uncertain. Objective: To examine the association of genetically proxied morning diurnal preference with depression risk using mendelian randomization. Design, Setting, and Participants: This 2-sample mendelian randomization study used summary-level genetic associations with diurnal preference and MDD. Up to 340 genetic loci associated with diurnal preference in a meta-analysis of the UK Biobank and 23andMe cohorts were considered as genetic proxies for diurnal preference. The effect size of these variants was scaled using genetic associations with accelerometer-based measurement of sleep midpoint. Genetic associations with MDD were obtained from a meta-analysis of genome-wide association studies data from the Psychiatric Genomics Consortium and UK Biobank. The inverse-variance weighted method was used to estimate the association of genetically proxied morning diurnal preference, corresponding to a 1-hour earlier sleep midpoint, with MDD risk. Exposures: Morning diurnal preference scaled to a 1-hour earlier, objectively measured sleep midpoint. Main Outcomes and Measures: Risk of MDD, including self-reported and clinically diagnosed cases, as ascertained in meta-analyses of genome-wide association studies. Results: A total of 697 828 individuals (all of European ancestry) were in the UK Biobank and 23andMe cohorts; 85 502 in the UK Biobank had measurements of the sleep midpoint. A further 170 756 individuals with MDD and 329 443 control participants (all of European ancestry) were in the Psychiatric Genomics Consortium and UK Biobank data. Genetically proxied earlier diurnal preference was associated with a 23% lower risk of depression (odds ratio [OR] per 1-hour earlier sleep midpoint, 0.77 [95% CI, 0.63-0.94]; P = .01). This association was similar when restricting analysis to individuals with MDD as stringently defined by the Psychiatric Genomics Consortium (OR, 0.73 [95% CI, 0.54-1.00]; P = .05) but not statistically significant when defined by hospital-based billing codes in the UK Biobank (OR, 0.64 [95% CI, 0.39-1.06]; P = .08). Sensitivity analyses examining potential bias due to pleiotropy or reverse causality showed similar findings (eg, intercept [SE], 0.00 [0.001]; P = .66 by Egger intercept test). Conclusions and Relevance: The results of this mendelian randomization study support a protective association of earlier diurnal preference with risk of MDD and provide estimates contextualized to an objective sleep timing measure. Further investigation in the form of randomized clinical trials may be warranted.