Accurate detection of shared genetic architecture from GWAS summary statistics in the small-sample context

Abstract

Assessment of the genetic similarity between two phenotypes can provide insight into a common genetic aetiology and inform the use of pleiotropy-informed, cross-phenotype analytical methods to identify novel genetic associations. The genetic correlation is a well-known means of quantifying and testing for genetic similarity between traits, but its estimates are subject to comparatively large sampling error. This makes it unsuitable for use in a small-sample context. We discuss the use of a non-parametric test of genetic similarity first introduced by Li et al. for application to GWAS summary statistics. We establish that the null distribution of the test statistic is modelled better by an extreme value distribution than a transformation of the standard exponential distribution as originally recommended by Li and colleagues. We show with simulation studies and real data from GWAS of 18 phenotypes from the UK Biobank that the test is to be preferred for use with small sample sizes, particularly when genetic effects are few and large, outperforming the genetic correlation and another nonparametric statistical test of independence. We find the test suitable for the detection of genetic similarity in the rare disease context.

Competing Interest Statement

CW receives funding from GSK and MSD. These funders had no involvement in this work.

Footnotes

* https://doi.org/10.5281/zenodo.7150454