Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization.

BACKGROUND: Caffeine is one of the most utilized drugs in the world, yet its clinical effects are not fully understood. Circulating caffeine levels are influenced by the interplay between consumption behaviour and metabolism. This study aimed to investigate the effects of circulating caffeine levels by considering genetically predicted variation in caffeine metabolism. METHODS: Leveraging genetic variants related to caffeine metabolism that affect its circulating levels, we investigated the clinical effects of plasma caffeine in a phenome-wide association study (PheWAS). We validated novel findings using a two-sample Mendelian randomization framework and explored the potential mechanisms underlying these effects in proteome-wide and metabolome-wide Mendelian randomization. RESULTS: Higher levels of genetically predicted circulating caffeine among caffeine consumers were associated with a lower risk of obesity (odds ratio (OR) per standard deviation increase in caffeine = 0.97, 95% confidence interval (CI) CI: 0.95-0.98, p = 2.47 × 10-4), osteoarthrosis (OR = 0.97, 95% CI: 0.96-0.98, P=1.10 × 10-8) and osteoarthritis (OR: 0.97, 95% CI: 0.96 to 0.98, P = 1.09 × 10-6). Approximately one third of the protective effect of plasma caffeine on osteoarthritis risk was estimated to be mediated through lower bodyweight. Proteomic and metabolomic perturbations indicated lower chronic inflammation, improved lipid profiles, and altered protein and glycogen metabolism as potential biological mechanisms underlying these effects. CONCLUSIONS: We report novel evidence suggesting that long-term increases in circulating caffeine may reduce bodyweight and the risk of osteoarthrosis and osteoarthritis. We confirm prior genetic evidence of a protective effect of plasma caffeine on risk of overweight and obesity. Further clinical study is warranted to understand the translational relevance of these findings before clinical practice or lifestyle interventions related to caffeine consumption are introduced.

Cerebrospinal and Brain Proteins Implicated in Neuropsychiatric and Risk Factor Traits: Evidence from Mendelian Randomization.

Neuropsychiatric disorders present a global health challenge, necessitating an understanding of their molecular mechanisms for therapeutic development. Using Mendelian randomization (MR) analysis, this study explored associations between genetically predicted levels of 173 proteins in cerebrospinal fluid (CSF) and 25 in the brain with 14 neuropsychiatric disorders and risk factors. Follow-up analyses assessed consistency across plasma protein levels and gene expression in various brain regions. Proteins were instrumented using tissue-specific genetic variants, and colocalization analysis confirmed unbiased gene variants. Consistent MR and colocalization evidence revealed that lower cortical expression of low-density lipoprotein receptor-related protein 8, coupled higher abundance in the CSF and plasma, associated with lower fluid intelligence scores and decreased bipolar disorder risk. Additionally, elevated apolipoprotein-E2 and hepatocyte growth factor-like protein in the CSF and brain were related to reduced leisure screen time and lower odds of physical activity, respectively. Furthermore, elevated CSF soluble tyrosine-protein kinase receptor 1 level increased liability to attention deficit hyperactivity disorder and schizophrenia alongside lower fluid intelligence scores. This research provides genetic evidence supporting novel tissue-specific proteomic targets for neuropsychiatric disorders and their risk factors. Further exploration is necessary to understand the underlying biological mechanisms and assess their potential for therapeutic intervention.

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.

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.

A drug target for erectile dysfunction to help improve fertility, sexual activity, and wellbeing: mendelian randomisation study.

OBJECTIVE: To investigate the association of genetically proxied (using a surrogate biomarker) inhibition of phosphodiesterase 5 (PDE5), an established drug target for erectile dysfunction, with fertility, sexual behaviour, and subjective wellbeing. DESIGN: Two sample cis-mendelian randomisation study. SETTING: Summary data on genetic associations obtained from the International Consortium for Blood Pressure and UK Biobank. PARTICIPANTS: Individuals of European ancestry from the International Consortium for Blood Pressure (n=757 601) for estimating PDE5 inhibition (using the surrogate biomarker of diastolic blood pressure reduction), and UK Biobank (n=211 840) for estimating the fertility, sexual behaviour, and subjective wellbeing outcomes in male participants. INTERVENTION: Genetically proxied PDE5 inhibition. MAIN OUTCOME MEASURES: Number of children fathered, number of sexual partners, probability of never having had sexual intercourse, and subjective wellbeing. RESULTS: Genetically proxied PDE5 inhibition was associated with male participants having 0.28 (95% confidence interval 0.16 to 0.39) more children (false discovery rate corrected P<0.001). This association was not identified in female participants. No evidence was found of an association between genetically proxied PDE5 inhibition and number of sexual partners, probability of never having had sexual intercourse, or self-reported wellbeing in male participants. CONCLUSIONS: The findings of this study provide genetic support for PDE5 inhibition potentially increasing the number of children fathered by male individuals. Absence of this association in female participants supports increased propensity for sustained and robust penile erections as a potential underlying mechanism. Further studies are required to confirm this, however, and these findings should not promote indiscriminate use of PDE5 inhibitors, which can also have harmful adverse effects.

Caffeine Intake, Plasma Caffeine Level, and Kidney Function: A Mendelian Randomization Study.

Caffeine is a psychoactive substance widely consumed worldwide, mainly via sources such as coffee and tea. The effects of caffeine on kidney function remain unclear. We leveraged the genetic variants in the CYP1A2 and AHR genes via the two-sample Mendelian randomization (MR) framework to estimate the association of genetically predicted plasma caffeine and caffeine intake on kidney traits. Genetic association summary statistics on plasma caffeine levels and caffeine intake were taken from genome-wide association study (GWAS) meta-analyses of 9876 and of >47,000 European ancestry individuals, respectively. Genetically predicted plasma caffeine levels were associated with a decrease in estimated glomerular filtration rate (eGFR) measured using either creatinine or cystatin C. In contrast, genetically predicted caffeine intake was associated with an increase in eGFR and a low risk of chronic kidney disease. The discrepancy is likely attributable to faster metabolizers of caffeine consuming more caffeine-containing beverages to achieve the same pharmacological effect. Further research is needed to distinguish whether the observed effects on kidney function are driven by the harmful effects of higher plasma caffeine levels or the protective effects of greater intake of caffeine-containing beverages, particularly given the widespread use of drinks containing caffeine and the increasing burden of kidney disease.

Appraising the causal relationship between plasma caffeine levels and neuropsychiatric disorders through Mendelian randomization.

BACKGROUND: Caffeine exposure modifies the turnover of monoamine neurotransmitters, which play a role in several neuropsychiatric disorders. We conducted a Mendelian randomization study to investigate whether higher plasma caffeine levels are causally associated with the risk of anorexia nervosa, bipolar disorder, major depressive disorder (MDD), and schizophrenia. METHODS: Summary-level data on the neuropsychiatric disorders were obtained from large-scale genome-wide association studies (GWASs) of European ancestry participants (n = 72,517 to 807,553) and meta-analyzed with the corresponding data from the FinnGen study (n = 356,077). Summary-level data on plasma caffeine were extracted from a GWAS meta-analysis of 9876 European ancestry individuals. The Mendelian randomization analyses estimated the Wald ratio for each genetic variant and meta-analyzed the variant-specific estimates using multiplicative random effects meta-analysis. RESULTS: After correcting for multiple testing, genetically predicted higher plasma caffeine levels were associated with higher odds of anorexia nervosa (odds ratio [OR] = 1.124; 95% confidence interval [CI] = 1.024-1.238, pFDR = 0.039) and a lower odds of bipolar disorder (OR = 0.905, 95% CI = 0.827-0.929, pFDR = 0.041) and MDD (OR = 0.965, 95% CI = 0.937-0.995, pFDR = 0.039). Instrumented plasma caffeine levels were not associated with schizophrenia (OR = 0.986, 95% CI = 0.929-1.047, pFDR = 0.646). CONCLUSIONS: These Mendelian randomization findings indicate that long-term higher plasma caffeine levels may lower the risk of bipolar disorder and MDD but increase the risk of anorexia nervosa. These results warrant further research to explore whether caffeine consumption, supplementation, or abstinence could render clinically relevant therapeutic or preventative psychiatric effects.

Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study.

INTRODUCTION: Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated. METHODS: We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline. RESULTS: In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20-1.84) and 1.38 (1.15-1.66) for incident dementia, and 2.87 (1.79-4.61) and 2.76 (1.73-4.40) for dementia-specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline. DISCUSSION: Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.

Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study.

BACKGROUND: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). METHODS: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites). RESULTS: We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10-4), higher urinary sodium excretion (p = 5.1 × 10-11), and lower urine albumin-creatinine ratio (p = 3.6 × 10-5). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94-0.98; p = 3.2 × 10-4). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10-07) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10-24) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction. CONCLUSION: This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.

Assessing racial bias in type 2 diabetes risk prediction algorithms.

Risk prediction models for type 2 diabetes can be useful for the early detection of individuals at high risk. However, models may also bias clinical decision-making processes, for instance by differential risk miscalibration across racial groups. We investigated whether the Prediabetes Risk Test (PRT) issued by the National Diabetes Prevention Program, and two prognostic models, the Framingham Offspring Risk Score, and the ARIC Model, demonstrate racial bias between non-Hispanic Whites and non-Hispanic Blacks. We used National Health and Nutrition Examination Survey (NHANES) data, sampled in six independent two-year batches between 1999 and 2010. A total of 9,987 adults without a prior diagnosis of diabetes and with fasting blood samples available were included. We calculated race- and year-specific average predicted risks of type 2 diabetes according to the risk models. We compared the predicted risks with observed ones extracted from the US Diabetes Surveillance System across racial groups (summary calibration). All investigated models were found to be miscalibrated with regard to race, consistently across the survey years. The Framingham Offspring Risk Score overestimated type 2 diabetes risk for non-Hispanic Whites and underestimated risk for non-Hispanic Blacks. The PRT and the ARIC models overestimated risk for both races, but more so for non-Hispanic Whites. These landmark models overestimated the risk of type 2 diabetes for non-Hispanic Whites more severely than for non-Hispanic Blacks. This may result in a larger proportion of non-Hispanic Whites being prioritized for preventive interventions, but it also increases the risk of overdiagnosis and overtreatment in this group. On the other hand, a larger proportion of non-Hispanic Blacks may be potentially underprioritized and undertreated.

Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study.

BACKGROUND: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. METHODS: Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. RESULTS: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64-0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60-0.92), stroke (0.69, 95% CI 0.50-0.95) and heart failure (0.77, 95% CI 0.58-1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. CONCLUSIONS: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling.

Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis.

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including ß-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. ARTICLE HIGHLIGHTS: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Sphingomyelins and ceramides: possible biomarkers for dementia?

PURPOSE OF REVIEW: Dementia is a public health challenge with no existing cure or early biomarkers. We review the evidence for blood-based measures of sphingomyelins and ceramides as potential novel biomarkers of dementia. RECENT FINDINGS: In recent years, lipids have been under investigation for their role in neurodegenerative diseases especially dementia and Alzheimer's disease. Increasing evidence from postmortem human brains suggests that alterations in the metabolism of sphingolipids could play a crucial part in dementia. Findings from epidemiological investigations of blood-based sphingomyelins and ceramides have been inconsistent. SUMMARY: This review focuses on blood-based measures of 10 specific ceramides and sphingomyelins (Cer C16:0, Cer C20:0, Cer C22:0, Cer C24:0, Cer C24:1 and SM C16:0, SM C20:0, SM C22:0, SM C24:0, SM C24:1) in relation to cognition and dementia. On the bais of 15 studies, there was no robust association between ceramide and sphingomyelin levels and prevalent or incident dementia. Cross-sectionally, Cer C16:0 and Cer C24:1 tends to be higher in dementia cases vs. controls.

Comparison of DNA methylation clocks in Black South African men.

Aims: DNA methylation clocks are widely used to estimate biological age, although limited data are available on non-European ethnicities. This manuscript characterizes the behavior of five DNA methylation clocks in 120 older Black South African men. Methods: The age estimation accuracy of the Horvath, Hannum and skin and blood clocks and the relative age-related mortality risk and predicted time to death portrayed by the PhenoAge and GrimAge biomarkers are investigated, respectively. Results: The results confirm the tendency of DNA methylation clocks to underestimate the biological age of older individuals. GrimAge more accurately characterizes biological decline in this African cohort compared with PhenoAge owing to the unique inclusion of smoking-related damage in the GrimAge estimate. Conclusions: Each clock provides a different fraction of information regarding the aging body. It is essential to continue studying under-represented population groups to ensure methylation-derived indicators are robust and useful in all populations.

Leveraging the urban-rural divide for epigenetic research.

Urbanization coincides with a complex change in environmental exposure and a rapid increase in noncommunicable diseases (NCDs). Epigenetics, including DNA methylation (DNAm), is thought to mediate part of the association between genetic/environmental exposure and NCDs. The urban-rural divide provides a unique opportunity to investigate the effect of the combined presence of multiple forms of environmental exposure on DNAm and the related increase in disease risk. This review evaluates the ability of three epidemiological study designs (migration, income-comparative and urban-rural designs) to investigate the role of DNAm in the association between urbanization and the rise in NCD prevalence. We also discuss the ability of each study design to address the gaps in the current literature, including the complex methylation-mediated risk attributable to the cluster of forms of exposure characterizing urban and rural living, while providing a platform for developing countries to leverage their demographic discrepancies in future research ventures.