Genetic analyses identify brain structures related to cognitive impairment associated with elevated blood pressure

Abstract

Background and aims: Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive impairment remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function.

Methods and results: Data on BP were integrated with 3935 brain magnetic resonance imaging-derived phenotypes (IDPs) and cognitive function defined by fluid intelligence score. Observational analyses were performed in the UK Biobank and a prospective validation cohort. Mendelian randomisation (MR) analyses used genetic data derived from the UK Biobank, International Consortium for Blood Pressure, and COGENT consortium. Mendelian randomisation analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [-0.044 standard deviation (SD); 95% confidence interval (CI) -0.066, -0.021] with the MR estimate strengthening (-0.087 SD; 95% CI -0.132, -0.042), when further adjusted for diastolic BP. Mendelian randomisation analysis found 242, 168, and 68 IDPs showing significant (false discovery rate P < 0.05) association with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomisation analysis identified relationships between cognitive function and the nine of the systolic BP-associated IDPs, including the anterior thalamic radiation, anterior corona radiata, or external capsule.

Conclusion: Complementary MR and observational analyses identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance.

Keywords: Blood pressure; Brain; Cognitive function; Genome-wide association study; Hypertension; Mendelian randomisation.

Structured Graphical Abstract

BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; ICPB, International Consortium for Blood Pressure; PP, pulse pressure; SBP, systolic blood pressure.

Figure 1

Observational and genetic effects of BP on brain IDPs. Characteristics table of UK Biobank subjects with BP and/or cognitive function test available at the imaging visit (A). Comparison of Mendelian randomisation (using IVW method) and observational estimates concerning 242, 168, and 68 brain IDPs significantly affected by genetically instrumented SBP, DBP, and PP, respectively (B). Heatmap (C) presents observational effects of BP indices on all 33 brain volumetric IDPs that were significantly affected by either BP index (IDPs depicted in blue are related to the hippocampus, while IDPs depicted in green are related to the amygdala nuclei; GM, grey matter; LH/RH, left/right hemisphere; UK Biobank field IDs are depicted on the right). Scatter plots present genetic causal estimates corresponding to the effect of SBP and DBP on all 3935 brain IDPs considered in univariable (D) and multivariable (E) Mendelian randomisation analyses. IVW, inverse variance–weighted; SD, standard deviation; SBP/DBP, systolic/diastolic blood pressure; PP, pulse pressure; MR, Mendelian randomisation; IDP, imaging-derived phenotype.

Figure 2

Observational and genetic association of BP with cognitive function. Univariable and multivariable Mendelian randomisation analysis testing the total and direct effects of BP indices on cognitive function, respectively (A). Standardised causal estimates were calculated assuming SD of 18.58, 10.08, and 13.62 mmHg for systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP), respectively. Instrumental variables for Mendelian randomisation analysis were derived from the meta-analysis of the UK Biobank and ICBP consortium. At the same time, a genome-wide association study by Lee and colleagues was used as a source of genetic summary statistics concerning cognitive function. Observational association between various BP indices and cognitive function was tested at baseline visit in the UK Biobank (B) in the overall cohort (C) and according to quintiles of age (D). IVW, inverse variance–weighted; SD, standard deviation; SBP/DBP, systolic/diastolic blood pressure; PP, pulse pressure; MR, Mendelian randomisation; mv, multivariable.

Figure 3

Observational association of brain IDPs with SBP and cognitive function. The circular bar blot presents absolute standardised estimates of the association of 155 imaging-derived phenotypes (IDPs) with SBP (outer bars) and cognitive function (inner bars). Presented IDPs demonstrated significant genetic and observational association with SBP and significant observational association with cognitive function (nominal P < 0.05; 150 IDPs with FDR-adjusted P < 0.05) in the opposite direction compared with the association with SBP. Shaded circles demonstrate a standardised observational estimate of 0.05 (SBP) or 0.025 (cognitive function). Tracts and structures from either hemisphere and appearing more than three times (diffusion-weighted IDPs) or one time (structural IDPs) among 155 IDPs are depicted. (B) Heatmap shows the association’s strength between the cerebral regions identified by diffusion-weighted magnetic resonance imaging with TBSS analyses and the link with SBP. (C) Heatmap shows the association’s strength between the cerebral regions identified by diffusion-weighted magnetic resonance imaging with PROBTRACK analyses and the connection with SBP.

Figure 4

Relation between observational and genetic estimates linking brain IDPs to SBP or to cognitive function. Observational, standardised coefficients concerning 242 brain IDPs, genetically affected by SBP (FDR P < 0.05 for the IVW method and nominal P < 0.05 for the weighted median, MR–Egger, and robust IVW methods using instrumental variables from the ICBP + UK Biobank meta-analysis and nominal P < 0.05 for IVW method using instrumental variables from the separate ICBP or UK Biobank analysis), corresponding to their association with cognitive function or SBP at the imaging visit in the UK Biobank are depicted on a scatter plot (A). After the exclusion of 38 potential outlier points (Beta_{cognitive function} > 0 and Beta_SBP < 0), the correlation coefficient was r = −0.37, yet retaining statistical significance (P = 5.6 × 10⁻⁸). Mendelian randomisation estimates linking nine IDPs, affecting cognitive function in MR analysis at FDR P < 0.05, to SBP or cognitive function are presented on panel (B) (MD, mean diffusivity; ISOVF, isotropic or free water volume fraction; LH, left hemisphere; UK Biobank field IDs are depicted on the right).

Figure 5

Summary of associations between brain IDPs, SBP, and cognitive function identified using observational and genetic approaches. Circular plot presents an association summary for 242 brain imaging-derived phenotypes (IDPs) significantly (FDR P < 0.05 for the IVW method and nominal P < 0.05 for the weighted median, MR–Egger, and robust IVW methods using instrumental variables from the ICBP + UK Biobank meta-analysis and nominal P < 0.05 for IVW method using instrumental variables from the separate ICBP or UK Biobank analysis) affected by SBP. Red/dark blue squares correspond to a significant (at least nominal P < 0.05), positive/negative association with SBP using MR or observational analysis (two outer circles) and cognitive function using MR (at least 1 instrumental variable available) or observational analysis in the UK Biobank (two inner rings). Grey squares correspond to brain IDPs with no instrumental variables available for MR analysis linking them to cognitive function. Brain IDPs labelled in red are associated with SBP below the Bonferroni-defined significance threshold (P < 0.05/3935) using a weighted median MR approach. IDP, imaging-derived phenotype; RH/LH, right/left hemisphere; WM, white matter; MD, mean diffusivity; ISOVF, isotropic or free water volume fraction; FA, fractional anisotropy; ICVF, intra-cellular volume fraction.

Figure 6

Comparison of results obtained in the prospective cohort and case–control study and the UK Biobank. One hundred seventy brain IDPs, out of 242 genetically affected by SBP in the MR analyses of the UK Biobank and ICBP cohorts, were extracted and tested for association with SBP and Montreal Cognitive Assessment score (only those 127 IDPs with FDR P < 0.05 for association with cognitive function in the UK Biobank) in 116 subjects from the prospective cohort and case–control study. Standardised, observational estimates were compared with the ones obtained in the UK Biobank. IDPs associated at nominal P < 0.05/FDR P < 0.1 with SBP (A) or Montreal Cognitive Assessment score (B) in the prospective cohort and case–control study are depicted in red/blue. Top (based on P values) brain IDPs associated with SBP or Montreal Cognitive Assessment score in the prospective cohort and case–control study are named (MD, mean diffusivity; HTN, hypertension; FA, fractional anisotropy; MoCA, Montreal Cognitive Assessment; SD, standard deviation; SBP/DBP, systolic/diastolic blood pressure; PP, pulse pressure; UK Biobank field IDs are depicted on the right).