Performance Metrics for Selecting Single Nucleotide Polymorphisms in Late-onset Alzheimer's Disease.
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.
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.|Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan.|Research Center for Genes, Environment and Human Health, College of Public Health, National Taiwan University, Taipei, Taiwan.
Yen-Ching
YC
Chen
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Chi-Jung
CJ
Hsiao
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Chien-Cheng
CC
Jung
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Hui-Han
HH
Hu
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.|Department of Geriatrics and Gerontology, National Taiwan University, Taipei, Taiwan.
Jen-Hau
JH
Chen
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.|Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan.|Research Center for Genes, Environment and Human Health, College of Public Health, National Taiwan University, Taipei, Taiwan.
Wen-Chung
WC
Lee
Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Jeng-Min
JM
Chiou
Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
Ta-Fu
TF
Chen
Department of Neurology, En Chu Kong Hospital, Taipei, Taiwan.
Yu
Y
Sun
Department of Laboratory Medicine, En Chu Kong Hospital, Taipei, Taiwan.
Li-Li
LL
Wen
Center of Neurological Medicine, Cardinal Tien Hospital, Taipei, Taiwan.|School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
Ping-Keung
PK
Yip
Department of Laboratory Medicine, Cardinal Tien Hospital, Taipei, Taiwan.
Yi-Min
YM
Chu
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Chien-Jen
CJ
Chen
Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Hwai-I
HI
Yang
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D053302:Apolipoprotein C-I / Q000235:genetics*; D043422:Carboxypeptidases A / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013624:Taiwan
C505803:APOC1 protein, human; D053302:Apolipoprotein C-I; D004268:DNA-Binding Proteins; C529598:zinc finger protein 521, human; D043422:Carboxypeptidases A