Document Type

Article

Publication Date

5-4-2023

Keywords

JMG, Chromosome Mapping, Quantitative Trait Loci, Genotype, Phenotype

JAX Source

Genetics. 2023;224(1).

ISSN

1943-2631

PMID

36932658

DOI

https://doi.org/10.1093/genetics/iyad045

Grant

This work was support by NIH grants R01 GM070683 (GAC) and F32 GM134599 (GRK).

Abstract

Mediation analysis is used in genetic mapping studies to identify candidate gene mediators of quantitative trait loci (QTL). We consider genetic mediation analysis of triplets-sets of three variables consisting of a target trait, the genotype at a QTL for the target trait, and a candidate mediator that is the abundance of a transcript or protein whose coding gene co-locates with the QTL. We show that, in the presence of measurement error, mediation analysis can infer partial mediation even in the absence of a causal relationship between the candidate mediator and the target. We describe a measurement error model and a corresponding latent variable model with estimable parameters that are combinations of the causal effects and measurement errors across all three variables. The relative magnitudes of the latent variable correlations determine whether or not mediation analysis will tend to infer the correct causal relationship in large samples. We examine case studies that illustrate the common failure modes of genetic mediation analysis and demonstrate how to evaluate the effects of measurement error. While genetic mediation analysis is a powerful tool for identifying candidate genes, we recommend caution when interpreting mediation analysis findings.

Comments

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Download

Share

COinS