Life course plasma metabolomic signatures of genetic liability to Alzheimer's disease.

Mechanisms through which most known Alzheimer's disease (AD) loci operate to increase AD risk remain unclear. Although Apolipoprotein E (APOE) is known to regulate lipid homeostasis, the effects of broader AD genetic liability on non-lipid metabolites remain unknown, and the earliest ages at which metabolic perturbations occur and how these change over time are yet to be elucidated. We examined the effects of AD genetic liability on the plasma metabolome across the life course. Using a reverse Mendelian randomization framework in two population-based cohorts [Avon Longitudinal Study of Parents and Children (ALSPAC, n = 5648) and UK Biobank (n ≤ 118,466)], we estimated the effects of genetic liability to AD on 229 plasma metabolites, at seven different life stages, spanning 8 to 73 years. We also compared the specific effects of APOE ε4 and APOE ε2 carriage on metabolites. In ALSPAC, AD genetic liability demonstrated the strongest positive associations with cholesterol-related traits, with similar magnitudes of association observed across all age groups including in childhood. In UK Biobank, the effect of AD liability on several lipid traits decreased with age. Fatty acid metabolites demonstrated positive associations with AD liability in both cohorts, though with smaller magnitudes than lipid traits. Sensitivity analyses indicated that observed effects are largely driven by the strongest AD instrument, APOE, with many contrasting effects observed on lipids and fatty acids for both ε4 and ε2 carriage. Our findings indicate pronounced effects of the ε4 and ε2 genetic variants on both pro- and anti-atherogenic lipid traits and sphingomyelins, which begin in childhood and either persist into later life or appear to change dynamically.

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity.

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10-4; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10-4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No.