Strategies to investigate and mitigate collider bias in genetic and Mendelian randomisation studies of disease progression.

Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors that influence on disease susceptibility. Studies of disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as "index event") bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomisation (MR) analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and MR studies using both individual- and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-Hunter and Dudbridge et al.'s index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, while our second example investigates genetic associations with breast cancer mortality.

Effectiveness of mRNA COVID-19 Vaccines as First Booster Doses in England: An Observational Study in OpenSAFELY-TPP.

BACKGROUND: The UK delivered its first "booster" COVID-19 vaccine doses in September 2021, initially to individuals at high risk of severe disease, then to all adults. The BNT162b2 Pfizer-BioNTech vaccine was used initially, then also Moderna mRNA-1273. METHODS: With the approval of the National Health Service England, we used routine clinical data to estimate the effectiveness of boosting with BNT162b2 or mRNA-1273 compared with no boosting in eligible adults who had received two primary course vaccine doses. We matched each booster recipient with an unboosted control on factors relating to booster priority status and prior COVID-19 immunization. We adjusted for additional factors in Cox models, estimating hazard ratios up to 182 days (6 months) following booster dose. We estimated hazard ratios overall and within the following periods: 1-14, 15-42, 43-69, 70-97, 98-126, 127-152, and 155-182 days. Outcomes included a positive SARS-CoV-2 test, COVID-19 hospitalization, COVID-19 death, non-COVID-19 death, and fracture. RESULTS: We matched 8,198,643 booster recipients with unboosted controls. Adjusted hazard ratios over 6-month follow-up were: positive SARS-CoV-2 test 0.75 (0.74, 0.75); COVID-19 hospitalization 0.30 (0.29, 0.31); COVID-19 death 0.11 (0.10, 0.14); non-COVID-19 death 0.22 (0.21, 0.23); and fracture 0.77 (0.75, 0.78). Estimated effectiveness of booster vaccines against severe COVID-19-related outcomes peaked during the first 3 months following the booster dose. By 6 months, the cumulative incidence of positive SARS-CoV-2 test was higher in boosted than unboosted individuals. CONCLUSIONS: We estimate that COVID-19 booster vaccination, compared with no booster vaccination, provided substantial protection against COVID-19 hospitalization and COVID-19 death but only limited protection against positive SARS-CoV-2 test. Lower rates of fracture in boosted than unboosted individuals may suggest unmeasured confounding. Observational studies should report estimated vaccine effectiveness against nontarget and negative control outcomes.

Genome-Wide Association Study Identifies Genes for Hair Growth and Patterning are Associated With Pilonidal Disease.

BACKGROUND: Pilonidal sinus disease is a highly morbid condition characterized by the formation of chronic sinus tracts throughout the sacrococcygeal region. Despite its commonality and strong association with family history, no prior investigation of genetic risk factors for pilonidal sinus disease exists. OBJECTIVE: To identify genetic risk factors for pilonidal sinus disease. DESIGN: A genome-wide association study. SETTINGS: The United Kingdom Biobank, FinnGen Biobank, and Penn Medicine BioBank. PATIENTS: There were 772,072 participants. MAIN OUTCOME MEASURE: Genome-wide significant variants ( p < 5 × 10 -8 ) were mapped to genes using physical distance and gene expression in skin. Genetic correlation between pilonidal sinus disease and morphometric, androgen-driven, and hair phenotypes was estimated with linkage disequilibrium score regression. Finally, a genome-first approach to rare predicted deleterious variants in hair shaft genes TCHH , PADI3 , and TGM3 was conducted for association with pilonidal sinus disease via the Penn Medicine BioBank. RESULTS: A genome-wide association study comprising 2835 individuals with pilonidal sinus disease identified 5 genome-wide significant loci, prioritizing HDAC9, TBX15, WARS2, RP11-293M10.1 , PRKAR1B , TWIST1, GPATCH2L, NEK9 , and EIF2B2 , as putative causal genes; several of these genes have known roles in balding and hair patterning. There was a significant correlation between the genetic background of pilonidal sinus disease and the androgen-driven hair traits of male pattern baldness and young age at first facial hair. In a candidate analysis of genes associated with syndromic hair disorders, rare coding variants in TCHH , a monogenic cause of uncombable hair syndrome, were associated with increased prevalence of pilonidal sinus disease (OR 4.81 [95% CI, 2.06-11.2]). LIMITATIONS: This study is limited to European ancestry. However, because there is a higher incidence of pilonidal sinus disease in men of European ancestry, this analysis is focused on the at-risk population. CONCLUSIONS: Genetic analysis of pilonidal sinus disease identified shared genetic architecture with hair biology and androgen-driven traits. As the first study investigating the genetic basis of pilonidal sinus disease, this provides biological insight into the long-appreciated connection between the disease state, male sex, and hair. See Video abstract. UN ESTUDIO DE ASOCIACIN DEL GENOMA COMPLETO IDENTIFICA GENES DEL CRECIMIENTO Y EL PATRN DEL PELO ASOCIADOS A LA ENFERMEDAD PILONIDAL: ANTECEDENTES:La enfermedad del seno pilonidal es una condición muy mórbida caracterizada por la formación de tractos sinusales crónicos en toda la región sacrococcígea. A pesar de su frecuencia y su fuerte asociación con los antecedentes familiares, no se han investigado previamente los factores de riesgo genéticos de la enfermedad sinusal pilonidal.OBJETIVO:Identificar factores genéticos de riesgo para la enfermedad del seno pilonidal.DISEÑO:Estudio de asociación de genoma completo.CONJUNTOS:Biobanco del Reino Unido, Biobanco FinnGen y Biobanco PennMedicine.PACIENTES:772.072 participantes.MEDIDA DE RESULTADO PRINCIPAL:Las variantes significativas en todo el genoma (p < 5x10-8) se asignaron a genes utilizando la distancia física y la expresión génica en la piel. La correlación genética entre la enfermedad del seno pilonidal y los fenotipos morfométricos, androgénicos y de cabello se estimó con regresión de puntuación LD. Por último, se realizó una aproximación genómica a variantes deletéreas raras predichas en los genes del tallo piloso TCHH, PADI3 y TGM3 para su asociación con la enfermedad del seno pilonidal a través del Biobanco PennMedicine.RESULTADOS:El estudio de asociación de todo el genoma, que incluyó a 2.835 individuos con enfermedad del seno pilonidal, identificó 5 loci significativos en todo el genoma, dando prioridad a HDAC9, TBX15, WARS2, RP11-293M10.1, PRKAR1B, TWIST1, GPATCH2L, NEK9 y EIF2B2, como genes causales putativos; varios de estos genes tienen funciones conocidas en la calvicie y el patrón del cabello. Se observó una correlación significativa entre los antecedentes genéticos de la enfermedad del seno pilonidal y los de los rasgos calvicie de patrón masculino y edad temprana del primer vello facial impulsados por andrógenos. En un análisis de genes candidatos asociados a trastornos capilares sindrómicos, las variantes raras de codificación en TCHH, una causa monogénica del síndrome capilar incombustible, se asociaron a una mayor prevalencia de la enfermedad del seno pilonidal (OR 4,81 [IC del 5%, 2,06-11,2]).LIMITACIONES:Este estudio se limita a la ascendencia europea. Sin embargo, debido a que hay una mayor incidencia de la enfermedad sinusal pilonidal en los hombres de ascendencia europea, este análisis se centra en la población de riesgo.CONCLUSIÓN:El análisis genético de la enfermedad del seno pilonidal identificó una arquitectura genética compartida con la biología del cabello y los rasgos impulsados por andrógenos. Siendo el primer estudio que investiga las bases genéticas de la enfermedad del seno pilonidal, esto proporciona una visión biológica de la conexión, apreciada desde hace tiempo, entre el estado de la enfermedad, el sexo masculino y el cabello. (Traducción-Dr. Aurian Garcia Gonzalez ).

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

Harmonising electronic health records for reproducible research: challenges, solutions and recommendations from a UK-wide COVID-19 research collaboration.

BACKGROUND: The CVD-COVID-UK consortium was formed to understand the relationship between COVID-19 and cardiovascular diseases through analyses of harmonised electronic health records (EHRs) across the four UK nations. Beyond COVID-19, data harmonisation and common approaches enable analysis within and across independent Trusted Research Environments. Here we describe the reproducible harmonisation method developed using large-scale EHRs in Wales to accommodate the fast and efficient implementation of cross-nation analysis in England and Wales as part of the CVD-COVID-UK programme. We characterise current challenges and share lessons learnt. METHODS: Serving the scope and scalability of multiple study protocols, we used linked, anonymised individual-level EHR, demographic and administrative data held within the SAIL Databank for the population of Wales. The harmonisation method was implemented as a four-layer reproducible process, starting from raw data in the first layer. Then each of the layers two to four is framed by, but not limited to, the characterised challenges and lessons learnt. We achieved curated data as part of our second layer, followed by extracting phenotyped data in the third layer. We captured any project-specific requirements in the fourth layer. RESULTS: Using the implemented four-layer harmonisation method, we retrieved approximately 100 health-related variables for the 3.2 million individuals in Wales, which are harmonised with corresponding variables for > 56 million individuals in England. We processed 13 data sources into the first layer of our harmonisation method: five of these are updated daily or weekly, and the rest at various frequencies providing sufficient data flow updates for frequent capturing of up-to-date demographic, administrative and clinical information. CONCLUSIONS: We implemented an efficient, transparent, scalable, and reproducible harmonisation method that enables multi-nation collaborative research. With a current focus on COVID-19 and its relationship with cardiovascular outcomes, the harmonised data has supported a wide range of research activities across the UK.

Separating the direct effects of traits on atherosclerotic cardiovascular disease from those mediated by type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes and atherosclerotic CVD share many risk factors. This study aimed to systematically assess a broad range of continuous traits to separate their direct effects on coronary and peripheral artery disease from those mediated by type 2 diabetes. METHODS: Our main analysis was a two-step Mendelian randomisation for mediation to quantify the extent to which the associations observed between continuous traits and liability to atherosclerotic CVD were mediated by liability to type 2 diabetes. To support this analysis, we performed several univariate Mendelian randomisation analyses to examine the associations between our continuous traits, liability to type 2 diabetes and liability to atherosclerotic CVD. RESULTS: Eight traits were eligible for the two-step Mendelian randomisation with liability to coronary artery disease as the outcome and we found similar direct and total effects in most cases. Exceptions included fasting insulin and hip circumference where the proportion mediated by liability to type 2 diabetes was estimated as 56% and 52%, respectively. Six traits were eligible for the analysis with liability to peripheral artery disease as the outcome. Again, we found limited evidence to support mediation by liability to type 2 diabetes for all traits apart from fasting insulin (proportion mediated: 70%). CONCLUSIONS/INTERPRETATION: Most traits were found to affect liability to atherosclerotic CVD independently of their relationship with liability to type 2 diabetes. These traits are therefore important for understanding atherosclerotic CVD risk regardless of an individual's liability to type 2 diabetes.

Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer's disease risk in the general population: a Mendelian randomisation study.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease.

BACKGROUND: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk. METHODS: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies. RESULTS: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; P=0.003) and CAD (marginal inclusion probability, 0.92; P=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84-0.91]; P=9×10-10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; P=4×10-73), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; P<1×10-6). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; P=2.3×10-4), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; P=0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03-1.04]; P=1.0×10-33). CONCLUSIONS: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.

Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England.

BACKGROUND: Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination. METHODS AND FINDINGS: In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection. Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021. The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572). Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex. The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding. CONCLUSIONS: In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.

Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.

BACKGROUND: Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS: We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), ß-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS: In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.

Association Between Genetic Variation in Blood Pressure and Increased Lifetime Risk of Peripheral Artery Disease.

[Figure: see text].

Comparison of Antihypertensive Drug Classes for Dementia Prevention.

BACKGROUND: Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink. METHODS: We assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over. RESULTS: We analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that ß-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, ß-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives. CONCLUSIONS: We estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis.

Genetic Insights Into Perinatal Outcomes of Maternal Antihypertensive Therapy During Pregnancy.

Importance: Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended fetal harm. Yet, maternal prescriptive drug use for chronic conditions such as hypertension is common. Objective: To investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring using mendelian randomization (MR). Design, Setting, and Participants: This 2-sample MR study used individual-level single-nucleotide variation (SNV) outcome data from mother-father-offspring trios with complete genetic and phenotypic information from the Norwegian Mother, Father and Child Cohort Study (MoBa) and summary-level SNV exposure data from UK Biobank participants sourced from the Integrative Epidemiology Unit OpenGWAS project. Pregnant individuals were recruited across Norway during their routine ultrasonography examination at 18 weeks' gestation between June 1999 and December 2008, and mothers, fathers, and offspring were followed up after birth. Novel genetic instruments for maternal antihypertensive drug targets that act via systolic blood pressure (SBP) were derived from individual-level data analyzed in January 2018. Two-sample multivariable MR analysis of these maternal drug targets and offspring outcomes were performed between January 2023 and April 2024. Exposures: Maternal genetic variants associated with drug targets for treatments of hypertension, as specified in the National Health Service dictionary of medicines and devices. Main Outcomes and Measures: Offspring outcomes were Apgar score at 1 minute and 5 minutes, offspring developmental score at 6 months, birth length, birth weight z score, gestational age, head circumference, and congenital malformation. Maternal hypertensive disorders of pregnancy were a positive control. Results: The MoBa sample contained 29 849 family trios, with a mean (SD) maternal age of 30.2 (18.6) years and a mean (SD) paternal age of 32.8 (13.1) years; 51.1% of offspring were male. Seven independent SNVs were identified as influencing maternal SBP via the antihypertensive drug target instruments. For higher levels of maternal SBP acting through the CACNB2 calcium channel blocker target, the estimated change in gestational age was 3.99 days (95% CI, 0.02-7.96 days) per 10-mm Hg decrease in SBP. There was no evidence of differential risk for measured perinatal outcomes from maternal SBP acting through drug targets for multiple hypertensive subclasses, such as between the ADRB1 ß-adrenoceptor-blocking target and risk of congenital malformation (estimated odds ratio, 0.28 [95% CI, 0.02-4.71] per 10-mm Hg decrease in SBP). Maternal and paternal SBP acting through the EDNRA vasodilator antihypertensive target did not have a potential causal effect on birth weight z score, with respective ß estimates of 0.71 (95% CI, -0.09 to 1.51) and 0.72 (95% CI, -0.08 to 1.53) per 10-mm Hg decrease in SBP. Conclusions and Relevance: The findings provided little evidence to indicate that perturbation of maternal genetic variants for SBP that influence antihypertensive drug targets had potential causal relationships with measures of perinatal development and health within this study. These findings may be triangulated with existing literature to guide physicians and mothers in decisions about antihypertensive use during pregnancy.

Cohort study of cardiovascular safety of different COVID-19 vaccination doses among 46 million adults in England.

The first dose of COVID-19 vaccines led to an overall reduction in cardiovascular events, and in rare cases, cardiovascular complications. There is less information about the effect of second and booster doses on cardiovascular diseases. Using longitudinal health records from 45.7 million adults in England between December 2020 and January 2022, our study compared the incidence of thrombotic and cardiovascular complications up to 26 weeks after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA-1273). These findings support the wide uptake of future COVID-19 vaccination programs.

Major Depressive Disorder Impacts Peripheral Artery Disease Risk Through Intermediary Risk Factors.

BACKGROUND: Major depressive disorder (MDD) has been identified as a causal risk factor for multiple forms of cardiovascular disease. Although observational evidence has linked MDD to peripheral artery disease (PAD), causal evidence of this relationship is lacking. METHODS AND RESULTS: Inverse variance weighted 2-sample Mendelian randomization was used to test the association the between genetic liability for MDD and genetic liability for PAD. Genetic liability for MDD was associated with increased genetic liability for PAD (odds ratio [OR], 1.17 [95% CI, 1.06-1.29]; P=2.6×10-3). Genetic liability for MDD was also associated with increased genetically determined lifetime smoking (ß=0.11 [95% CI, 0.078-0.14]; P=1.2×10-12), decreased alcohol intake (ß=-0.078 [95% CI, -0.15 to 0]; P=0.043), and increased body mass index (ß=0.10 [95% CI, 0.02-0.19]; P=1.8×10-2), which in turn were associated with genetic liability for PAD (smoking: OR, 2.81 [95% CI, 2.28-3.47], P=9.8×10-22; alcohol: OR, 0.77 [95% CI, 0.66-0.88]; P=1.8×10-4; body mass index: OR, 1.61 [95% CI, 1.52-1.7]; P=1.3×10-57). Controlling for lifetime smoking index, alcohol intake, and body mass index with multivariable Mendelian randomization completely attenuated the association between genetic liability for MDD with genetic liability for PAD. CONCLUSIONS: This work provides evidence for a possible causal association between MDD and PAD that is dependent on intermediate risk factors, adding to the growing body of evidence suggesting that effective management and treatment of cardiovascular diseases may require a composite of physical and mental health interventions.

Incidence of diabetes after SARS-CoV-2 infection in England and the implications of COVID-19 vaccination: a retrospective cohort study of 16 million people.

BACKGROUND: Some studies have shown that the incidence of type 2 diabetes increases after a diagnosis of COVID-19, although the evidence is not conclusive. However, the effects of the COVID-19 vaccine on this association, or the effect on other diabetes subtypes, are not clear. We aimed to investigate the association between COVID-19 and incidence of type 2, type 1, gestational and non-specific diabetes, and the effect of COVID- 19 vaccination, up to 52 weeks after diagnosis. METHODS: In this retrospective cohort study, we investigated the diagnoses of incident diabetes following COVID-19 diagnosis in England in a pre-vaccination, vaccinated, and unvaccinated cohort using linked electronic health records. People alive and aged between 18 years and 110 years, registered with a general practitioner for at least 6 months before baseline, and with available data for sex, region, and area deprivation were included. Those with a previous COVID-19 diagnosis were excluded. We estimated adjusted hazard ratios (aHRs) comparing diabetes incidence after COVID-19 diagnosis with diabetes incidence before or in the absence of COVID-19 up to 102 weeks after diagnosis. Results were stratified by COVID-19 severity (categorised as hospitalised or non-hospitalised) and diabetes type. FINDINGS: 16 669 943 people were included in the pre-vaccination cohort (Jan 1, 2020-Dec 14, 2021), 12 279 669 in the vaccinated cohort, and 3 076 953 in the unvaccinated cohort (both June 1-Dec 14, 2021). In the pre-vaccination cohort, aHRs for the incidence of type 2 diabetes after COVID-19 (compared with before or in the absence of diagnosis) declined from 4·30 (95% CI 4·06-4·55) in weeks 1-4 to 1·24 (1·14-1.35) in weeks 53-102. aHRs were higher in unvaccinated people (8·76 [7·49-10·25]) than in vaccinated people (1·66 [1·50-1·84]) in weeks 1-4 and in patients hospitalised with COVID-19 (pre-vaccination cohort 28·3 [26·2-30·5]) in weeks 1-4 declining to 2·04 [1·72-2·42] in weeks 53-102) than in those who were not hospitalised (1·95 [1·78-2·13] in weeks 1-4 declining to 1·11 [1·01-1·22] in weeks 53-102). Type 2 diabetes persisted for 4 months after COVID-19 in around 60% of those diagnosed. Patterns were similar for type 1 diabetes, although excess incidence did not persist beyond 1 year after a COVID-19 diagnosis. INTERPRETATION: Elevated incidence of type 2 diabetes after COVID-19 is greater, and persists for longer, in people who were hospitalised with COVID-19 than in those who were not, and is markedly less apparent in people who have been vaccinated against COVID-19. Testing for type 2 diabetes after severe COVID-19 and the promotion of vaccination are important tools in addressing this public health problem. FUNDING: UK National Institute for Health and Care Research, UK Research and Innovation (UKRI) Medical Research Council, UKRI Engineering and Physical Sciences Research Council, Health Data Research UK, Diabetes UK, British Heart Foundation, and the Stroke Association.

COVID-19 and Mental Illnesses in Vaccinated and Unvaccinated People.

Importance: Associations have been found between COVID-19 and subsequent mental illness in both hospital- and population-based studies. However, evidence regarding which mental illnesses are associated with COVID-19 by vaccination status in these populations is limited. Objective: To determine which mental illnesses are associated with diagnosed COVID-19 by vaccination status in both hospitalized patients and the general population. Design, Setting, and Participants: This study was conducted in 3 cohorts, 1 before vaccine availability followed during the wild-type/Alpha variant eras (January 2020-June 2021) and 2 (vaccinated and unvaccinated) during the Delta variant era (June-December 2021). With National Health Service England approval, OpenSAFELY-TPP was used to access linked data from 24 million people registered with general practices in England using TPP SystmOne. People registered with a GP in England for at least 6 months and alive with known age between 18 and 110 years, sex, deprivation index information, and region at baseline were included. People were excluded if they had COVID-19 before baseline. Data were analyzed from July 2022 to June 2024. Exposure: Confirmed COVID-19 diagnosis recorded in primary care secondary care, testing data, or the death registry. Main Outcomes and Measures: Adjusted hazard ratios (aHRs) comparing the incidence of mental illnesses after diagnosis of COVID-19 with the incidence before or without COVID-19 for depression, serious mental illness, general anxiety, posttraumatic stress disorder, eating disorders, addiction, self-harm, and suicide. Results: The largest cohort, the pre-vaccine availability cohort, included 18 648 606 people (9 363 710 [50.2%] female and 9 284 896 [49.8%] male) with a median (IQR) age of 49 (34-64) years. The vaccinated cohort included 14 035 286 individuals (7 308 556 [52.1%] female and 6 726 730 [47.9%] male) with a median (IQR) age of 53 (38-67) years. The unvaccinated cohort included 3 242 215 individuals (1 363 401 [42.1%] female and 1 878 814 [57.9%] male) with a median (IQR) age of 35 (27-46) years. Incidence of most outcomes was elevated during weeks 1 through 4 after COVID-19 diagnosis, compared with before or without COVID-19, in each cohort. Incidence of mental illnesses was lower in the vaccinated cohort compared with the pre-vaccine availability and unvaccinated cohorts: aHRs for depression and serious mental illness during weeks 1 through 4 after COVID-19 were 1.93 (95% CI, 1.88-1.98) and 1.49 (95% CI, 1.41-1.57) in the pre-vaccine availability cohort and 1.79 (95% CI, 1.68-1.90) and 1.45 (95% CI, 1.27-1.65) in the unvaccinated cohort compared with 1.16 (95% CI, 1.12-1.20) and 0.91 (95% CI, 0.85-0.98) in the vaccinated cohort. Elevation in incidence was higher and persisted longer after hospitalization for COVID-19. Conclusions and Relevance: In this study, incidence of mental illnesses was elevated for up to a year following severe COVID-19 in unvaccinated people. These findings suggest that vaccination may mitigate the adverse effects of COVID-19 on mental health.

Impact of vaccination on the association of COVID-19 with cardiovascular diseases: An OpenSAFELY cohort study.

Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a 'pre-vaccination' cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and 'vaccinated' and 'unvaccinated' cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years.