Interpreting Mendelian-randomization estimates of the effects of categorical exposures such as disease status and educational attainment
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Abstract
Background: Mendelian randomization has been previously used to estimate the effects of binary and ordinal categorical exposures—e.g. Type 2 diabetes or educational attainment defined by qualification—on outcomes. Binary and categorical phenotypes can be modelled in terms of liability—an underlying latent continuous variable with liability thresholds separating individuals into categories. Genetic variants influence an individual’s categorical exposure via their effects on liability, thus Mendelian-randomization analyses with categorical exposures will capture effects of liability that act independently of exposure category. Methods and results: We discuss how groups in which the categorical exposure is invariant can be used to detect liability effects acting independently of exposure category. For example, associations between an adult educational-attainment polygenic score (PGS) and body mass index measured before the minimum school leaving age (e.g. age 10 years), cannot indicate the effects of years in full-time education on this outcome. Using UK Biobank data, we show that a higher educational-attainment PGS is strongly associated with lower smoking initiation and higher odds of glasses use at age 15 years. These associations were replicated in sibling models. An orthogonal approach using the raising of the school leaving age (ROSLA) policy change found that individuals who chose to remain in education to age 16 years before the reform likely had higher liability to educational attainment than those who were compelled to remain in education to age 16 years after the reform, and had higher income, lower pack-years of smoking, higher odds of glasses use and lower deprivation in adulthood. These results suggest that liability to educational attainment is associated with health and social outcomes independently of years in full-time education. Conclusions: Mendelian-randomization studies with non-continuous exposures should be interpreted in terms of liability, which may affect the outcome via changes in exposure category and/or independently.
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In two sample MR studies with exposure samples containing only a small number of participants who have experienced the exposure, the causal effect estimate reflects the effects of the genetic liability to the exposure rather than the exposure itself.
“For example, when two sample MR studies are carried out in exposure samples that contain only a small number of participants who have experienced the exposure in question, it would be misleading to interpret the effects as being those of the exposure itself. Instead, the causal effect estimate should be interpreted as reflecting the effects of the genetic liability to the exposure.115 116”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [116]
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- Authors
- Howe, L. J., Tudball, M., Davey Smith, G., & Davies, N. M.
- Affiliations
- University of Bristol (GB)
- Medical Research Council Integrative Epidemiology Unit, University of Bristol , Bristol, UK
- Norwegian University of Science and Technology (NO)
- Corresponding author
- Howe, Laurence J
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-09-27
- Volume
- 51
- Issue
- 3
- Pages
- 948-957
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- PMC
- PMC9189950
- OpenAlex
- W3203077784
- Cited by
- 48
- References
- 63
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 12 · 2023: 8 · 2022: 5 · 2021: 4
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- International Journal of Epidemiology (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- Explore Bristol Research (submittedVersion, cc-by)
- Funders
- UK Biobank resource under Application (8786)
- The Medical Research Council (MRC) and the University of Bristol
- MRC Integrative Epidemiology Unit (MC_UU_00011/1)
- Economics and Social Research Council (ESRC) Future Research Leaders grant (ES/N000757/1)
- Norwegian Research Council (295989)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Sociology and Political Science › Intergenerational and Educational Inequality Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- Mendelian randomization, liability model, educational attainment, polygenic risk score, school leaving age, smoking initiation, body mass index
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Educational Status, Humans, Random Allocation, Multifactorial Inheritance, Genome-Wide Association Study, Mendelian Randomization Analysis
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