Fig. 5: Genetic variants that influence expression of candidate proteins also relate to brain volume loss in the BLSA and an independent cohort, the ENIGMA consortium.
a, A boxplot showing plasma levels of ITGB6 stratified by the rs8099840 genotype. b, A scatterplot showing the associations of plasma ITGB6 protein levels with rates of temporal gray matter (TEMGM) volume loss over time stratified by rs8099840 alleles. c, A boxplot of TLR5 plasma levels stratified by the rs75118229 genotype. d, A scatterplot showing the associations of plasma TLR5 protein levels with rates of total brain (TB) volume loss over time stratified by rs75118229 alleles. Adjusted differences in log2(protein levels) associated with a given SNP were derived from multiple linear regression models (n = 469) adjusted for covariates used in the pQTL discovery cohort, namely baseline age and sex. Adjusted differences in annual changes of standardized brain volumes associated with a given SNP were derived from linear mixed-effect models (n = 469) adjusted for similar covariates, along with intracranial volume and two-way interactions with time. Individual specific rates of brain volume loss (random effect of time) are displayed. Associations displayed in b and d reflect statistically significant relationships. *Statistically significant (uncorrected P < 0.05); **statistically significant (uncorrected P < 0.01). Box plots: median, 25–75th quartiles; whiskers: 1.5× the IQR. The pQTLs were obtained from deCODE Genetics and SNPs in the BLSA were used for analyses. e, A forest plot displaying the results of Mendelian randomization analyses that assessed the relationship between genetically determined plasma protein levels and changes in MRI-derived TB volumes. The results were derived from inverse variance-weighted or Wald’s ratio estimates. Plasma pQTLs were obtained from deCODE Genetics (n = 35,559). Longitudinal TB volume summary statistics were obtained from an ENIGMA consortium GWAS (n = 15,640). Data are presented as β coefficients and 95% CIs. Red triangles indicate statistically significant associations (uncorrected P < 0.05). Statistical significance was defined at two-sided P < 0.05 without adjustment for multiple comparisons. The exact P values are presented in the source data files of Supplementary Tables 29 and 30. Misc., miscellaneous; r.f.u., relative fluorescence units.
