Dataset Information

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.

SUBMITTER: Qiao J

PROVIDER: S-EPMC9503281 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Qiao Jiahao J Shao Zhonghe Z Wu Yuxuan Y Zeng Ping P Wang Ting T

Journal of translational medicine 20220923 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 36138484

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Project description:To investigate the polygenicity of complex traits in populations of East Asian (EAS) and European (EUR) descents, we leveraged genome-wide data from Biobank Japan, UK Biobank, and FinnGen cohorts. Specifically, we analyzed up to 215 outcomes related to 18 health domains, assessing their polygenic architecture via descriptive statistics, such as the proportion of susceptibility SNPs per trait (πc). While we did not observe EAS-EUR differences in the overall distribution of polygenicity parameters across the phenotypes investigated, there were ancestry-specific patterns in the polygenicity differences between health domains. In EAS, pairwise comparisons across health domains showed enrichment for πc differences related to hematological and metabolic traits (hematological fold-enrichment = 4.45, p = 2.15 × 10-7; metabolic fold-enrichment = 4.05, p = 4.01 × 10-6). For both categories, the proportion of susceptibility SNPs was lower than that observed for several other health domains (EAS-hematological median πc = 0.15%, EAS-metabolic median πc = 0.18%) with the strongest πc difference with respect to respiratory traits (EAS-respiratory median πc = 0.50%; hematological-p = 2.26 × 10-3; metabolic-p = 3.48 × 10-3). In EUR, pairwise comparisons showed multiple πc differences related to the endocrine category (fold-enrichment = 5.83, p = 4.76 × 10-6), where these traits showed a low proportion of susceptibility SNPs (EUR-endocrine median πc = 0.01%) with the strongest difference with respect to psychiatric phenotypes (EUR-psychiatric median πc = 0.50%; p = 1.19 × 10-4). Simulating sample sizes of 1,000,000 and 5,000,000 individuals, we also showed that ancestry-specific polygenicity patterns translate into differences across health domains in the genetic variance explained by susceptibility SNPs projected to be genome-wide significant (e.g., EAS hematological-neoplasm p = 2.18 × 10-4; EUR endocrine-gastrointestinal p = 6.80 × 10-4). These findings highlight that traits related to the same health domains may present ancestry-specific variability in their polygenicity.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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