{"title":"Estimating the <i>cis</i> -heritability of gene expression using single cell expression profiles controls false positive rate of eGene detection.","authors":"Ziqi Xu, Arya Massarat, Laurie Rumker, Melissa Gymrek, Soumya Raychaudhuri, Wei Zhou, Tiffany Amariuta","doi":"10.1101/2025.02.24.639892","DOIUrl":null,"url":null,"abstract":"<p><p>For gene expression traits, <i>cis</i> -genetic heritability can quantify the strength of genetic regulation in particular cell types, elucidating the cell-type-specificity of disease variants and genes. To estimate gene expression heritability, standard models require a single gene expression value per individual, forcing data from single cell RNA-sequencing (scRNA-seq) experiments to be \"pseudobulked\". Here, we show that applying standard heritability models to pseudobulk data overestimates gene expression heritability and produces inflated false positive rates for detecting <i>cis</i> -heritable genes. Therefore, we introduce a new method called scGeneHE ( s ingle c ell Gene expression H eritability E stimation), a Poisson mixed-effects model that quantifies the <i>cis</i> -genetic component of gene expression using individual cellular profiles. In simulations, scGeneHE has a consistently well-calibrated false positive rate for eGene detection and unbiasedly estimates <i>cis</i> -heritability at many parameter settings. We applied scGeneHE to scRNA-seq data from 969 individuals, 11 immune cell types, and 822,552 cells from the OneK1K cohort to infer cell-type-specificity of genetic regulation at risk genes for immune-mediated diseases and trace the fluctuation of <i>cis</i> -heritability across cellular populations of varying resolution. In summary, we developed a new statistical method that resolves the analytical challenge of estimating gene expression <i>cis</i> -heritability from native scRNA-seq data.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888288/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv : the preprint server for biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2025.02.24.639892","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
For gene expression traits, cis -genetic heritability can quantify the strength of genetic regulation in particular cell types, elucidating the cell-type-specificity of disease variants and genes. To estimate gene expression heritability, standard models require a single gene expression value per individual, forcing data from single cell RNA-sequencing (scRNA-seq) experiments to be "pseudobulked". Here, we show that applying standard heritability models to pseudobulk data overestimates gene expression heritability and produces inflated false positive rates for detecting cis -heritable genes. Therefore, we introduce a new method called scGeneHE ( s ingle c ell Gene expression H eritability E stimation), a Poisson mixed-effects model that quantifies the cis -genetic component of gene expression using individual cellular profiles. In simulations, scGeneHE has a consistently well-calibrated false positive rate for eGene detection and unbiasedly estimates cis -heritability at many parameter settings. We applied scGeneHE to scRNA-seq data from 969 individuals, 11 immune cell types, and 822,552 cells from the OneK1K cohort to infer cell-type-specificity of genetic regulation at risk genes for immune-mediated diseases and trace the fluctuation of cis -heritability across cellular populations of varying resolution. In summary, we developed a new statistical method that resolves the analytical challenge of estimating gene expression cis -heritability from native scRNA-seq data.