Dataset Information

Single-marker and multi-marker mixed models for polygenic score analysis in family-based data.

ABSTRACT: Genome-wide association studies have proven successful but they remain underpowered for detecting variants of weaker effect. Alternative methods propose to test for association by using an aggregate score that combines the effects of the most associated variants. The set of variants that are to be aggregated may come from either of two modeling approaches: single-marker or multi-marker. The goal of this paper is to evaluate this alternative strategy by using sets of single-nucleotide polymorphisms identified by the two modeling approaches in the simulated pedigree data set provided for the Genetic Analysis Workshop 18. We focused on quantitative traits association analysis of diastolic blood pressure and of Q1, which served to control the statistical significance of our results. We carried out all analyses with knowledge of the underlying simulation model. We found that the probability to replicate association with the aggregate score depends on the single-nucleotide polymorphism set size and, for smaller sets (?100), on the modeling approach. Nonetheless, assessing the statistical significance of these results in this data set was challenging, likely because of linkage because we are analyzing pedigree data, and also because the genotypes were the same across the replicates. Further methods need to be developed to facilitate the application of this alternative strategy in pedigree data.

SUBMITTER: Bohossian N

PROVIDER: S-EPMC4143662 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Single-marker and multi-marker mixed models for polygenic score analysis in family-based data.

Bohossian Nora N Saad Mohamad M Legarra Andrés A Martinez Maria M

BMC proceedings 20140617 Suppl 1

Genome-wide association studies have proven successful but they remain underpowered for detecting variants of weaker effect. Alternative methods propose to test for association by using an aggregate score that combines the effects of the most associated variants. The set of variants that are to be aggregated may come from either of two modeling approaches: single-marker or multi-marker. The goal of this paper is to evaluate this alternative strategy by using sets of single-nucleotide polymorphis ...[more]

PMID: 25519337

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Project description:Objectives: The aim of the present study was to construct a polygenic risk score (PRS) for poor survival among patients with stomach adenocarcinoma (STAD) based on expression of malignant cell markers. Methods: Integrated analyses of bulk and single-cell RNA sequencing (scRNA-seq) of STAD and normal stomach tissues were conducted to identify malignant and non-malignant markers. Analyses of the scRNA-seq profile from early STAD were used to explore intratumoral heterogeneity (ITH) of the malignant cell subpopulations. Dimension reduction, cell clustering, pseudotime, and gene set enrichment analyses were performed. The marker genes of each malignant tissue and cell clusters were screened to create a PRS using Cox regression analyses. Combined with the PRS and routine clinicopathological characteristics, a nomogram tool was generated to predict prognosis of patients with STAD. The prognostic power of the PRS was validated in two independent external datasets. Results: The malignant and non-malignant cells were identified according to 50 malignant and non-malignant cell markers. The malignant cells were divided into nine clusters with different marker genes and biological characteristics. Pseudotime analysis showed the potential differentiation trajectory of these nine malignant cell clusters and identified genes that affect cell differentiation. Ten malignant cell markers were selected to generate a PRS: RGS1, AADAC, NPC2, COL10A1, PRKCSH, RAMP1, PRR15L, TUBA1A, CXCR6, and UPP1. The PRS was associated with both overall and progression-free survival (PFS) and proved to be a prognostic factor independent of routine clinicopathological characteristics. PRS could successfully divide patients with STAD in three datasets into high- or low-risk groups. In addition, we combined PRS and the tumor clinicopathological characteristics into a nomogram tool to help predict the survival of patients with STAD. Conclusion: We revealed limited but significant intratumoral heterogeneity in STAD and proposed a malignant cell subset marker-based PRS through integrated analysis of bulk sequencing and scRNA-seq data.

Project description:Background Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk. Results We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGSHL) and a biologically informed PGS for CIO (PGSCIO). The PGSCIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGSCIO demonstrated superior performance (P = 5.54 × 10− 5) relative to PGSHL (P = 2.93 × 10− 3). PGSCIO was also associated with CIO in our test cohort (P = 0.04), while the PGSHL did not show a significant association with CIO (P = 0.52). Conclusion This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.

Dataset Information

Single-marker and multi-marker mixed models for polygenic score analysis in family-based data.

Publications

Single-marker and multi-marker mixed models for polygenic score analysis in family-based data.

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