Genome-wide association studies of missing metabolite measures from two population-based studies

Suggestive genome-wide associations with inflammatory biomarkers in an admixed population, including a missense variant in the OR6K6 olfactory receptor gene associated with MCP-1

New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.

Meta-analysis of 49(cid:0)549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

This study illustrates that GWAS with high-scale imputation may still help to unravel the biological mechanism behind circulating lipid levels and identifies more new rare and low-frequency functional variants associated with circulating lipid levels.

Causal roles of phenotypic age and metabolic health on dementia: a Mendelian randomisation and structure learning study

Background Phenotypic age acceleration (PhenoAgeAccel), derived from PhenoAge, and MetaboHealth are composite exposures of biological ageing and metabolic health associated with dementia-related outcomes. Whether these associations are causal and reflect the exposures, constituent biomarkers, or both remains unclear. Methods This study included UK Biobank participants of White British genetic ancestry. MetaboHealth was derived from nuclear magnetic resonance (NMR) metabolomics and PhenoAgeAccel from clinical biomarkers and chronological age. Genome-wide association studies (GWAS) were conducted for MetaboHealth (n=272,568) and PhenoAgeAccel (n=274,077). Independent genome-wide significant variants were used as genetic instruments in two-sample Mendelian randomisation (MR) with FinnGen all-cause dementia summary statistics. Inverse-variance weighting was the primary MR method. Causal network analysis estimated relationships among constituent biomarkers and dementia. Findings GWAS identified 126 and 141 independent genome-wide significant variants for MetaboHealth and PhenoAgeAccel, of which 109 and 141 were retained as genetic instruments. MR found no evidence of a causal effect of genetically predicted MetaboHealth (per unit: OR 0.83, 95% CI 0.49-1.42; p=0.51) or PhenoAgeAccel (per year: OR 0.99, 95% CI 0.95-1.02; p=0.44) on all-cause dementia, with consistent findings across sensitivity analyses and robust MR methods. Lower lymphocyte percentage and higher NMR-derived glucose had direct relationships with dementia in the joint constituent-biomarker network. Interpretation MR provided no evidence that either composite exposure causally influenced dementia. The network prioritised lymphocyte percentage and NMR-derived glucose, supporting examination of composite exposures alongside their constituent biomarkers. Funding NIHR, UKRI, MRC, UK Dementia Research Institute, Innovate UK, and European Union. Full funding details are provided in the acknowledgements.

Elucidating the proteomic pathways linking childhood body mass index with type 2 diabetes: a Mendelian randomization and recall-by-genotype study

The authors' study identified putative actionable proteins that could reduce the elevated T2D risk attributable to childhood adiposity in Europeans, but their relevance in Asian populations requires further investigation.

Metabolomic signatures and causal effects of circulating metabolites on age-related cataract.

[Association between 473 gut microbiota and Alzheimer's disease: a Mendelian randomization mediation analysis of 233 circulating metabolites].

Negativibacillus massiliensis is likely associated with an increased risk of AD, and v-VLDL FC/TL may partially mediate this association, suggesting their potential as targets for AD prevention and treatment.