Reassessing the validity of using weighted linear models to implement multi-generational GWAS-by-subtraction: a response to Evans et al

TL;DR

This paper responds to criticisms of a method for estimating genetic effects of paternal smoking using GWAS by subtraction.

Contribution

The paper addresses and evaluates the theoretical and practical limitations raised by Evans et al. regarding the GWAS-by-subtraction approach.

Findings

The authors acknowledge limitations in their original method's theoretical and practical validity.

They explore the criticisms and provide a detailed response to the concerns raised.

The paper aims to clarify and refine the approach based on the feedback received.

Abstract

Evans and colleagues for providing a critique on our article “Deriving GWAS summary estimates for paternal smoking in UK biobank: a GWAS by subtraction”. They highlight important limitations in our approach, which we overlooked. They argue that our approach works neither in theory nor in practice– that there are both flaws in the method and in our execution of the method. Here we explore these issues and address what we consider to be the most important criticisms.

The online version contains supplementary material available at 10.1186/s13104-025-07327-8.

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