Design of the study.

<p>DIAGRAM, DIAbetes Genetics Replication And Meta-analysis.</p

Genetically predicted or measured levels of the branched-chain amino acids and risk of type 2 diabetes.

<p>(A) Comparison of (i) the association of a difference of 1 SD in the levels of BCAAs at baseline with incident type 2 diabetes in prospective observational studies (bars with blue circles) and (ii) the association of a genetically predicted difference of 1 SD in BCAA levels with type 2 diabetes in genetic Mendelian randomisation studies (bars with red squares for analyses of independent genetic variants and bars with orange diamonds for analyses of correlated genetic variants). (B) Regional association plots for the association of variants at the <i>PPM1K</i> locus with valine (top; representative of the three BCAAs) and type 2 diabetes (bottom). Associations were characterised by a peak of signal upstream of the <i>PPM1K</i> gene, with the lead rs1440581 polymorphism and other polymorphisms in high linkage disequilibrium, as well as a peripheral signal overlaying the gene, with variants in lower linkage disequilibrium with the lead polymorphism. (C) Scatter plot of the association of the isoleucine-raising alleles included in the isoleucine genetic score with amino acid levels and with type 2 diabetes risk. (D) The association of the quartiles of isoleucine level at baseline with incident type 2 diabetes in the EPIC-Norfolk case-cohort study, the Framingham Offspring Study, and the Malmö Diet and Cancer Study (1,025 cases of incident type 2 diabetes and 1,182 controls). Error bars represent the 95% confidence intervals around the central estimates. BCAA, branched-chain amino acid; OR, odds ratio; RR, relative risk; SD, standard deviation; T2D, type 2 diabetes.</p

Association of branched-chain amino acid genetic scores with metabolites in the Fenland study.

<p>Associations of the BCAA scores with the BCAAs are highlighted in dark red. Error bars represent the 95% confidence interval around the central estimate.BCAA, branched-chain amino acid; SD, standard deviation.</p

Manhattan plot of the association of genetic variants with the levels of branched-chain amino acids.

<p>Manhattan plot of the association of genetic variants with the levels of branched-chain amino acids.</p

BCAA pathway associations.

<p>BCAA pathway associations.</p