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

Mateusz Siedlinski; Lorenzo Carnevale; Xiaoguang Xu; Daniela Carnevale; Evangelos Evangelou; Mark J Caulfield; Pasquale Maffia; Joanna Wardlaw; Nilesh J Samani; Maciej Tomaszewski; Giuseppe Lembo; Michael V Holmes; Tomasz J Guzik

doi:10.1093/eurheartj/ehad101

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

Eur Heart J. 2023 Jun 20;44(23):2114-2125. doi: 10.1093/eurheartj/ehad101.

Authors

Mateusz Siedlinski^{1

2

3}, Lorenzo Carnevale⁴, Xiaoguang Xu⁵, Daniela Carnevale^{4

6}, Evangelos Evangelou^{7

8

9}, Mark J Caulfield¹⁰, Pasquale Maffia^{11

12}, Joanna Wardlaw¹³, Nilesh J Samani^{14

15}, Maciej Tomaszewski^{5

16}, Giuseppe Lembo^{4

6}, Michael V Holmes^{17

18}, Tomasz J Guzik^{1

2

3}

Affiliations

¹ Department of Internal Medicine, Jagiellonian University Medical College, ul. Skarbowa 1, 31-121 Krakow, Poland.
² Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
³ Center for Medical Genomics OMICRON, Jagiellonian University Medical College, ul. Kopernika 7c, 31-034 Kraków, Poland.
⁴ Department of Angiocardioneurology and Translational Medicine, I.R.C.C.S. INM Neuromed, Via Atinense, 18, 86077 Pozzilli, Italy.
⁵ Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.
⁶ Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 291 - 00161 Roma, Italy.
⁷ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
⁸ Department of Hygiene and Epidemiology, University of Ioannina Medical School, University Campus, University of Ioannina, P.O. Box: 1186, 451 10, Ioannina, Greece.
⁹ Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, University Campus GR -451 15, Ioannina, Greece.
¹⁰ William Harvey Research Institute, NIHR Biomedical Research Centre at Barts, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
¹¹ School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
¹² Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
¹³ Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
¹⁴ Department of Cardiovascular Sciences, University of Leicester, University Road, Leicester LE1 7RH, UK.
¹⁵ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
¹⁶ Division of Medicine, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.
¹⁷ Bristol Medical School, Population Health Sciences, University of Bristol, Queens Road, Bristol BS8 1QU, UK.
¹⁸ Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Queens Road, Bristol BS8 1QU, UK.

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.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Blood Pressure
Brain
Cognitive Dysfunction* / genetics
Genome-Wide Association Study
Humans
Hypertension* / complications
Hypertension* / genetics
Mendelian Randomization Analysis / methods
Polymorphism, Single Nucleotide / genetics

Abstract

Publication types

MeSH terms

Grants and funding