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

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_606B3CD78234
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment.
Périodique
Nature communications
Auteur⸱e⸱s
Darrous L., Hemani G., Davey Smith G., Kutalik Z.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Statut éditorial
Publié
Date de publication
15/02/2024
Peer-reviewed
Oui
Volume
15
Numéro
1
Pages
1420
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
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.
Mots-clé
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
Oui
Création de la notice
20/02/2024 8:16
Dernière modification de la notice
09/08/2024 15:00
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