Dataset Information

Detecting Weak Signals by Combining Small P-Values in Genetic Association Studies.

ABSTRACT: We approach the problem of combining top-ranking association statistics or P-values from a new perspective which leads to a remarkably simple and powerful method. Statistical methods, such as the rank truncated product (RTP), have been developed for combining top-ranking associations, and this general strategy proved to be useful in applications for detecting combined effects of multiple disease components. To increase power, these methods aggregate signals across top ranking single nucleotide polymorphisms (SNPs), while adjusting for their total number assessed in a study. Analytic expressions for combined top statistics or P-values tend to be unwieldy, which complicates interpretation and practical implementation and hinders further developments. Here, we propose the augmented rank truncation (ART) method that retains main characteristics of the RTP but is substantially simpler to implement. ART leads to an efficient form of the adaptive algorithm, an approach where the number of top ranking SNPs is varied to optimize power. We illustrate our methods by strengthening previously reported associations of ?-opioid receptor variants with sensitivity to pain.

SUBMITTER: Vsevolozhskaya OA

PROVIDER: S-EPMC6879667 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Detecting Weak Signals by Combining Small P-Values in Genetic Association Studies.

Vsevolozhskaya Olga A OA Hu Fengjiao F Zaykin Dmitri V DV

Frontiers in genetics 20191120

We approach the problem of combining top-ranking association statistics or P-values from a new perspective which leads to a remarkably simple and powerful method. Statistical methods, such as the rank truncated product (RTP), have been developed for combining top-ranking associations, and this general strategy proved to be useful in applications for detecting combined effects of multiple disease components. To increase power, these methods aggregate signals across top ranking single nucleotide p ...[more]

PMID: 31824555

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Project description:BACKGROUND:There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype. METHODS:We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype. RESULTS:We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10- 3 in the original GWAS or were within LD (r2 > 0.8, Europeans) to the genotyped SNPs. We identified 215, 320, and 172 disease-associated genes for LUAD, LUSC, and SCLC, respectively. Only five genes (CHRNA5, IDH3A, PSMA4, RP11-650 L12.2, and TBC1D2B) overlapped all subtypes. Furthermore, we observed only two pathways from the Kyoto Encyclopedia of Genes and Genomes shared by all subtypes. At the regulatory level, only three eQTL target genes and two enhancer target genes overlapped between all subtypes. CONCLUSIONS:Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype.

Dataset Information

Detecting Weak Signals by Combining Small P-Values in Genetic Association Studies.

Publications

Detecting Weak Signals by Combining Small P-Values in Genetic Association Studies.

Similar Datasets

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