Performance Metrics for Selecting Single Nucleotide Polymorphisms in Late-onset Alzheimer's Disease.

Yen-Ching Chen,Jen-Hau Chen,Yu Sun,Jeng-Min Chiou,Chien-Cheng Jung,Ping-Keung Yip,Wen-Chung Lee,Yi-Min Chu,Chi-Jung Hsiao,Hui-Han Hu,Hwai-I Yang,Li-Li Wen,Chien-Jen Chen,Ta-Fu Chen

doi:10.1038/srep36155

Abstract

Previous genome-wide association studies using P-values to select single nucleotide polymorphisms (SNPs) have suffered from high false-positive and false-negative results. This case-control study recruited 713 late-onset Alzheimer’s disease (LOAD) cases and controls aged ≥65 from three teaching hospitals in northern Taiwan from 2007 to 2010. Performance metrics were used to select SNPs in stage 1, which were then genotyped to another dataset (stage 2). Four SNPs (CPXM2 rs2362967, APOC1 rs4420638, ZNF521 rs7230380, and rs12965520) were identified for LOAD by both traditional P-values (without correcting for multiple tests) and performance metrics. After correction for multiple tests, no SNPs were identified by traditional P-values. Simultaneous testing of APOE e4 and APOC1 rs4420638 (the SNP with the best performance in the performance metrics) significantly improved the low sensitivity of APOE e4 from 0.50 to 0.78. A point-based genetic model including these 2 SNPs and important covariates was constructed. Compared with elders with low-risks score (0–6), elders belonging to moderate-risk (score = 7–11) and high-risk (score = 12–18) groups showed a significantly increased risk of LOAD (adjusted odds ratio = 7.80 and 46.93, respectively; Ptrend < 0.0001). Performance metrics allow for identification of markers with moderate effect and are useful for creating genetic tests with clinical and public health implications.

Highlights

Dementia is an important health issue in the elderly
The quantile-quantile (QQ) plot for the observed chi-square P-values of 500,941 single nucleotide polymorphisms (SNPs) revealed no deviation from the expected values, i.e., there was no significant association with the Alzheimer’s disease (AD) outcome as demonstrated by the diagonal line (Figure S1)
These SNPs were located at four genes, including apolipoprotein C-I (APOC1) for rs4420638, carboxypeptidase-2 (CPXM2) for rs2362967, coiled-coil domain containing 81 (CCDC81) for rs10501617, and zinc finger protein[521] (ZNF521) for rs7230380 and rs12965520

Summary

Introduction

Dementia is an important health issue in the elderly (aged ≥6 5 years). Alzheimer’s disease (AD) is the most common subtype of dementia and cannot currently be cured, prevented, or even slowed[1]. Studies applying traditional P-values to identify genetic markers for various research outcomes have suffered from high false-positive and false-negative results[25,26]. These studies are unable to identify SNPs with moderate effects. Clinical validity (i.e., sensitivity, specificity) has been proposed to be a more practical measure for selecting SNPs in GWASs30 and is important for evaluating and translating genetic tests for public health and clinical implications (Centers for Disease Control and Prevention, USA) (http://www.cdc.gov/genomics/gtesting/ ACCE/). A point-based genetic model including these two SNPs and important covariates was constructed to differentiate elders with low, moderate, and high risk of LOAD

Methods

Results

Conclusion