Genetic evidence has supported a protective effect of cerebral angiotensin converting enzyme (ACE) against Alzheimer’s disease (AD). However, it is unclear whether this is mediated through blood pressure and extends to other neurodegenerative diseases. We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk. We further investigated whether any effect of ACE expression is mediated through changes in blood pressure, and whether effects extend to Parkinson’s disease, small vessel disease or cognitive function. There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure, nor that ACE expression affected risk of other neurodegenerative traits. Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes.

Abstract Interleukin 6 (IL-6) is a circulating cytokine that is implicated in a range of inflammatory diseases. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines, and growth factors. The findings from this study support feedback effects of IL-6R signalling on reducing levels of a range of circulating cytokines and identify compensatory mechanisms that may be modulating its inflammatory effects. These results provide novel insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.

Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is being pursued in early stage clinical trials as pharmacological target to treat a range of metabolic diseases. In animal models, increased FGF21 signalling has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer’s disease risk and lifespan. However, studies investigating the effect of FGF21 signalling on these clinical outcomes in humans have been inconclusive. In this study, a genetic variant associated with higher circulating FGF21 levels was leveraged to investigate its clinical effects in humans. Higher genetically proxied circulating FGF21 levels were associated favourably with lipid levels, blood pressure traits, waist-to-hip ratio, chronic inflammation, cardiovascular outcomes, Alzheimer’s disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling and inform the design of further clinical trials.

Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis. Its circulating levels are acutely increased by the type 2 diabetes medication metformin, resulting in reduced appetite and weight loss. We identified a genetic variant at the GDF15 gene to proxy a small, lifelong increase in circulating GDF15 levels, and leveraged it in colocalization and Mendelian randomization analyses to investigate the effects of chronically elevated GDF15 levels on body mass index (BMI) and type 2 diabetes liability. The results provide human genetic evidence supporting that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI lowering effects of an acute increase in GDF15 levels observed after metformin use. These findings have direct implications for informing pharmacological strategies aimed at targeting GDF15 levels for weight loss.

Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD) but the direct renal effects of IL-6 inhibition are not established. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods. There was no evidence for an association of genetically proxied inhibition of IL-6 signalling (scaled per unit decrease in natural log transformed C-reactive protein) with log eGFR (0.002, 95% confidence interval -0.004 – 0.008), BUN (0.088, 95% confidence interval -0.003 – 0.019) and CKD (odds ratio 1.018, 95% confidence interval 0.899 – 1.153). These findings suggest that inhibition of IL-6 signalling is unlikely to have a direct effect on renal function.