PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_606B3CD78234
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment.
Journal
Nature communications
Author(s)
Darrous L., Hemani G., Davey Smith G., Kutalik Z.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
15/02/2024
Peer-reviewed
Oui
Volume
15
Number
1
Pages
1420
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Mendelian Randomisation (MR) estimates causal effects between risk factors and complex outcomes using genetic instruments. Pleiotropy, heritable confounders, and heterogeneous causal effects violate MR assumptions and can lead to biases. To alleviate these, we propose an approach employing a Phenome-Wide association Clustering of the MR instruments (PWC-MR) and apply this method to revisit the surprisingly large apparent causal effect of body mass index (BMI) on educational attainment (EDU): [Formula: see text] = -0.19 [-0.22, -0.16]. First, we cluster 324 BMI-associated genetic instruments based on their association with 407 traits in the UK Biobank, which yields six distinct groups. Subsequent cluster-specific MR reveals heterogeneous causal effect estimates on EDU. A cluster enriched for socio-economic indicators yields the largest BMI-on-EDU causal effect estimate ([Formula: see text] = -0.49 [-0.56, -0.42]) whereas a cluster enriched for body-mass specific traits provides a more likely estimate ([Formula: see text] = -0.09 [-0.13, -0.05]). Follow-up analyses confirms these findings: within-sibling MR ([Formula: see text] = -0.05 [-0.09, -0.01]); MR for childhood BMI on EDU ([Formula: see text] = -0.03 [-0.06, -0.002]); step-wise multivariable MR ([Formula: see text] = -0.05 [-0.07, -0.02]) where socio-economic indicators are jointly modelled. Here we show how the in-depth examination of the BMI-EDU causal relationship demonstrates the utility of our PWC-MR approach in revealing distinct pleiotropic pathways and confounder mechanisms.
Keywords
Humans, Child, Genome-Wide Association Study/methods, Mendelian Randomization Analysis/methods, Obesity/epidemiology, Obesity/genetics, Risk Factors, Educational Status, Polymorphism, Single Nucleotide
Pubmed
Web of science
Open Access
Yes
Create date
20/02/2024 8:16
Last modification date
09/08/2024 15:00
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