biostudies-literatureUnknown26(1)Nishino J<h4>Background</h4>An alternative approach to investigate associations between genetic variants and disease is to examine deviations from the Hardy-Weinberg equilibrium (HWE) in genotype frequencies within a case population, instead of case-control association analysis. The HWE analysis requires disease cases and demonstrates a notable ability in mapping recessive variants. Allelic heterogeneity is a common phenomenon in diseases. While gene-based case-control association analysis successfully incorporates this heterogeneity, there are no such approaches for HWE analysis. Therefore, we proposed a gene-based HWE test (gene-HWT) by aggregating single-nucleotide polymorphism (SNP)-level HWE test statistics in a gene to address allelic heterogeneity.<h4>Results</h4>This method used only genotype count data and publicly available linkage disequilibrium information and has a very low computational cost. Extensive simulations demonstrated that gene-HWT effectively controls the type I error at a low significance level and outperforms SNP-level HWE test in power when there are multiple causal variants within a gene. Using gene-HWT, we analyzed genotype count data from a genome-wide association study of six cancer types in Japanese individuals and suggest DGKE and ANO3 as potential germline factors in colorectal cancer. Furthermore, FSTL4 was suggested through a combined analysis across the six cancer types, with particularly notable associations observed in colorectal and prostate cancers.<h4>Conclusions</h4>These findings indicate the potential of gene-HWT to elucidate the genetic basis of complex diseases, including cancer.BMC genomics124https://www.ebi.ac.uk/biostudies/studies/S-EPMC11809088biostudies-literatureGene-based Hardy-Weinberg equilibrium test using genotype count data: application to six types of cancers.PMC11809088Nishino JKato MMiya FfalseGene-based Hardy-Weinberg equilibrium test using genotype count data: application to six types of cancers.<h4>Background</h4>An alternative approach to investigate associations between genetic variants and disease is to examine deviations from the Hardy-Weinberg equilibrium (HWE) in genotype frequencies within a case population, instead of case-control association analysis. The HWE analysis requires disease cases and demonstrates a notable ability in mapping recessive variants. Allelic heterogeneity is a common phenomenon in diseases. While gene-based case-control association analysis successfully incorporates this heterogeneity, there are no such approaches for HWE analysis. Therefore, we proposed a gene-based HWE test (gene-HWT) by aggregating single-nucleotide polymorphism (SNP)-level HWE test statistics in a gene to address allelic heterogeneity.<h4>Results</h4>This method used only genotype count data and publicly available linkage disequilibrium information and has a very low computational cost. Extensive simulations demonstrated that gene-HWT effectively controls the type I error at a low significance level and outperforms SNP-level HWE test in power when there are multiple causal variants within a gene. Using gene-HWT, we analyzed genotype count data from a genome-wide association study of six cancer types in Japanese individuals and suggest DGKE and ANO3 as potential germline factors in colorectal cancer. Furthermore, FSTL4 was suggested through a combined analysis across the six cancer types, with particularly notable associations observed in colorectal and prostate cancers.<h4>Conclusions</h4>These findings indicate the potential of gene-HWT to elucidate the genetic basis of complex diseases, including cancer.2025-01-01T00:00:00Z2025 Feb2025-04-04T02:27:31.673Z2025-04-04T02:27:31.673ZS-EPMC118090883993036410.1186/s12864-025-11321-6