Selection of genetic instruments in Mendelian randomisation studies of sleep traits

Valentina Paz; Hassan S Dashti; Stephen Burgess; Victoria Garfield

doi:10.1016/j.sleep.2023.10.036

Selection of genetic instruments in Mendelian randomisation studies of sleep traits

Sleep Med. 2023 Dec:112:342-351. doi: 10.1016/j.sleep.2023.10.036. Epub 2023 Nov 2.

Authors

Valentina Paz¹, Hassan S Dashti², Stephen Burgess³, Victoria Garfield⁴

Affiliations

¹ Instituto de Psicología Clínica, Facultad de Psicología, Universidad de la República, Tristán Narvaja, 1674, Montevideo, 11200, Uruguay; MRC Unit for Lifelong Health & Ageing, Institute of Cardiovascular Science, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK. Electronic address: vpaz@psico.edu.uy.
² Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA, 02114, USA; Broad Institute, 415 Main Street, Cambridge, MA, 02142, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Edwards 4-410C, Boston, MA, 02114, USA.
³ MRC Biostatistics Unit, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK; Department of Public Health and Primary Care, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
⁴ MRC Unit for Lifelong Health & Ageing, Institute of Cardiovascular Science, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK.

Abstract

This review explores the criteria used for the selection of genetic instruments of sleep traits in the context of Mendelian randomisation studies. This work was motivated by the fact that instrument selection is the most important decision when designing a Mendelian randomisation study. As far as we are aware, no review has sought to address this to date, even though the number of these studies is growing rapidly. The review is divided into the following sections which are essential for genetic instrument selection: 1) Single-gene region vs polygenic analysis; 2) Polygenic analysis: biologically-vs statistically-driven approaches; 3) P-value; 4) Linkage disequilibrium clumping; 5) Sample overlap; 6) Type of exposure; 7) Total (R²) and average strength (F-statistic) metrics; 8) Number of single-nucleotide polymorphisms; 9) Minor allele frequency and palindromic variants; 10) Confounding. Our main aim is to discuss how instrumental choice impacts analysis and compare the strategies that Mendelian randomisation studies of sleep traits have used. We hope that our review will enable more researchers to take a more considered approach when selecting genetic instruments for sleep exposures.

Keywords: Genetic epidemiology; Review; Sleep genetic variants.

Publication types

Review

MeSH terms

Genome-Wide Association Study
Humans
Mendelian Randomization Analysis*
Phenotype
Polymorphism, Single Nucleotide / genetics
Sleep* / genetics

Grants and funding

100114/WT_/Wellcome Trust/United Kingdom