Using Mendelian Randomization to Understand and Develop Treatments for Neurodegenerative Disease

Overview

Journal Brain Commun

Publisher Oxford University Press

Specialty Neurology

Date 2020 Sep 21

PMID 32954289

Citations 8

Authors

Catherine S Storm

Demis A Kia

Mona Almramhi

Nicholas W Wood

Affiliations

Soon will be listed here.

Abstract

Common neurodegenerative diseases are thought to arise from a combination of environmental and genetic exposures. Mendelian randomization is a powerful way to leverage existing genetic data to investigate causal relationships between risk factors and disease. In recent years, Mendelian randomization has gathered considerable traction in neurodegenerative disease research, providing valuable insights into the aetiology of these conditions. This review aims to evaluate the impact of Mendelian randomization studies on translational medicine for neurodegenerative diseases, highlighting the advances made and challenges faced. We will first describe the fundamental principles and limitations of Mendelian randomization and then discuss the lessons from Mendelian randomization studies of environmental risk factors for neurodegeneration. We will illustrate how Mendelian randomization projects have used novel resources to study molecular pathways of neurodegenerative disease and discuss the emerging role of Mendelian randomization in drug development. Finally, we will conclude with our view of the future of Mendelian randomization in these conditions, underscoring unanswered questions in this field.

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References

Emilsson V, Ilkov M, Lamb J, Finkel N, Gudmundsson E, Pitts R . Co-regulatory networks of human serum proteins link genetics to disease. Science. 2018; 361(6404):769-773. PMC: 6190714. DOI: 10.1126/science.aaq1327. View

. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019; 365(6460). PMC: 7241648. DOI: 10.1126/science.aav7188. View

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

Raghavan N, Vardarajan B, Mayeux R . Genomic variation in educational attainment modifies Alzheimer disease risk. Neurol Genet. 2019; 5(2):e310. PMC: 6395060. DOI: 10.1212/NXG.0000000000000310. View

. Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell. 2015; 162(3):516-26. PMC: 4524551. DOI: 10.1016/j.cell.2015.07.003. View

Hamilton R . Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 2000; 10(3):378-84. PMC: 8098522. DOI: 10.1111/j.1750-3639.2000.tb00269.x. View

Walker V, Kehoe P, Martin R, Davies N . Repurposing antihypertensive drugs for the prevention of Alzheimer's disease: a Mendelian randomization study. Int J Epidemiol. 2019; 49(4):1132-1140. PMC: 7751008. DOI: 10.1093/ije/dyz155. View

Noyce A, Kia D, Hemani G, Nicolas A, Price T, De Pablo-Fernandez E . Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study. PLoS Med. 2017; 14(6):e1002314. PMC: 5469450. DOI: 10.1371/journal.pmed.1002314. View

Gianfrancesco M, Stridh P, Rhead B, Shao X, Xu E, Graves J . Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017; 88(17):1623-1629. PMC: 5405763. DOI: 10.1212/WNL.0000000000003849. View

10.

Dobson R, Giovannoni G . Multiple sclerosis - a review. Eur J Neurol. 2018; 26(1):27-40. DOI: 10.1111/ene.13819. View

11.

Wang Y, Wang Y, Li J, Zhang Y, Yin H, Han B . Body Mass Index and Risk of Parkinson's Disease: A Dose-Response Meta-Analysis of Prospective Studies. PLoS One. 2015; 10(6):e0131778. PMC: 4488297. DOI: 10.1371/journal.pone.0131778. View

12.

Slob E, Burgess S . A comparison of robust Mendelian randomization methods using summary data. Genet Epidemiol. 2020; 44(4):313-329. PMC: 7317850. DOI: 10.1002/gepi.22295. View

13.

Ference B, Yoo W, Alesh I, Mahajan N, Mirowska K, Mewada A . Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012; 60(25):2631-9. DOI: 10.1016/j.jacc.2012.09.017. View

14.

Policicchio S, Ahmad A, Powell J, Proitsi P . Rheumatoid arthritis and risk for Alzheimer's disease: a systematic review and meta-analysis and a Mendelian Randomization study. Sci Rep. 2017; 7(1):12861. PMC: 5634412. DOI: 10.1038/s41598-017-13168-8. View

15.

Anttila V, Bulik-Sullivan B, Finucane H, Walters R, Bras J, Duncan L . Analysis of shared heritability in common disorders of the brain. Science. 2018; 360(6395). PMC: 6097237. DOI: 10.1126/science.aap8757. View

16.

Hanagasi H, Emre M . Treatment of behavioural symptoms and dementia in Parkinson's disease. Fundam Clin Pharmacol. 2005; 19(2):133-46. DOI: 10.1111/j.1472-8206.2005.00317.x. View

17.

Davies N, Holmes M, Davey Smith G . Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362:k601. PMC: 6041728. DOI: 10.1136/bmj.k601. View

18.

Pierce B, Burgess S . Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 2013; 178(7):1177-84. PMC: 3783091. DOI: 10.1093/aje/kwt084. View

19.

Sun B, Maranville J, Peters J, Stacey D, Staley J, Blackshaw J . Genomic atlas of the human plasma proteome. Nature. 2018; 558(7708):73-79. PMC: 6697541. DOI: 10.1038/s41586-018-0175-2. View

20.

Taylor K, Davey Smith G, Relton C, Gaunt T, Richardson T . Prioritizing putative influential genes in cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization. Genome Med. 2019; 11(1):6. PMC: 6354354. DOI: 10.1186/s13073-019-0613-2. View