Detecting associated genes for complex traits shared across East Asian and European populations under the framework of composite null hypothesis testing

Abstract

Background: Detecting trans-ethnic common associated genetic loci can offer important insights into shared genetic components underlying complex diseases/traits across diverse continental populations. However, effective statistical methods for such a goal are currently lacking.

Methods: By leveraging summary statistics available from global-scale genome-wide association studies, we herein proposed a novel genetic overlap detection method called CONTO (COmposite Null hypothesis test for Trans-ethnic genetic Overlap) from the perspective of high-dimensional composite null hypothesis testing. Unlike previous studies which generally analyzed individual genetic variants, CONTO is a gene-centric method which focuses on a set of genetic variants located within a gene simultaneously and assesses their joint significance with the trait of interest. By borrowing the similar principle of joint significance test (JST), CONTO takes the maximum P value of multiple associations as the significance measurement.

Results: Compared to JST which is often overly conservative, CONTO is improved in two aspects, including the construction of three-component mixture null distribution and the adjustment of trans-ethnic genetic correlation. Consequently, CONTO corrects the conservativeness of JST with well-calibrated P values and is much more powerful validated by extensive simulation studies. We applied CONTO to discover common associated genes for 31 complex diseases/traits between the East Asian and European populations, and identified many shared trait-associated genes that had otherwise been missed by JST. We further revealed that population-common genes were generally more evolutionarily conserved than population-specific or null ones.

Conclusion: Overall, CONTO represents a powerful method for detecting common associated genes across diverse ancestral groups; our results provide important implications on the transferability of GWAS discoveries in one population to others.

Keywords: CONTO; Composite null hypothesis testing; Gene-centric association analysis; Genome-wide association study; Joint significance test; Summary statistics; Trans-ethnic genetic overlap.