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.

Evaluating significance of European-associated index SNPs in the East Asian population for 31 complex phenotypes

“…However, the design discrepancies are difficult to handle with only summary statistics, a comprehensive investigation regarding these discrepancies needs individual-level data, and is thus impeded by privacy concerns when sharing data [ 88 ]. To handle the potential discrepancy of LD in various populations, we previously conducted a gene-based replicability analysis in the EAS and EUR populations [ 89 ], where we aggregated multiple SNP-level association signs into a single gene-level association sign while taking LD into account.…”

How can childhood maltreatment affect post-traumatic stress disorder in adult: Results from a composite null hypothesis perspective of mediation analysis

“…Therefore, the two path association tests in our mediation analysis can be implemented by an equivalent manner of variance-component based score tests under the context of mixed models. It has been demonstrated that the variance component test is often more powerful compared to its counterpart such as multivariate Wald test (43,44,46,(73)(74)(75)(76).…”

“…To effectively detect the existence of mediation effect with highdimensional mediators, we first employ the variance componentbased score test in a linear mixed model via an inverse transformation to assess the association between childhood maltreatment and a group of DNA methylation CpG sites, and then test for the effect of DNA methylation on the disorder of focus while adjusting for the direct influence of childhood maltreatment within the framework of linear mixed-effects model (43)(44)(45)(46). We finally determine whether the mediation effect of DNA methylation exists by following the main idea proposed in Liu et al (41), which can lead to desirable type I error rate control and higher power compared to existing mediation effect test methods.…”