Evaluation of the Metabochip Genotyping Array in African Americans and Implications for Fine Mapping of GWAS-Identified Loci: The PAGE Study
Steven BuyskeYing WuCara L. CartyIona ChengThemistocles L. AssimesLogan DumitrescuLucia A. HindorffSabrina L. MitchellJosé Luis AmbiteEric BoerwinklePetra BůžkováChris CarlsonBarbara CochranDavid DugganCharles B. EatonMegan D. FesinmeyerNora FranceschiniJeffrey HaesslerNancy S. JennyHyun Min KangCharles KooperbergYi LinLoı̈c Le MarchandTara C. MatiseJennifer G. RobinsonCarlos J. RodríguezFredrick R. SchumacherBenjamin F. VoightAlicia YoungTeri A. ManolioKaren L. MohlkeChristopher A. HaimanUlrike PetersDana C. CrawfordKari E. North
71
Citation
42
Reference
10
Related Paper
Citation Trend
Abstract:
The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.Keywords:
Genome-wide Association Study
SNP
SNP genotyping
1000 Genomes Project
Genetic Association
This chapter contains sections titled: Introduction Genotyping of single nucleotide polymorphisms Methods for interrogating SNPs Analysis formats How can SNP genotyping be made more economic? Miniaturization – Multiplexing Haplotyping DNA methylation analysis – analysis of methylation variable positions (MVPs) SNP genotyping and quantitation Emerging methods High-throughput SNP genotyping methods The next generation Conclusions Acknowledgements References
SNP genotyping
SNP
Tag SNP
SNP array
Molecular Inversion Probe
Cite
Citations (6)
SNP
Molecular Inversion Probe
SNP genotyping
Tag SNP
SNP array
Inheritance
dbSNP
Cite
Citations (20)
SNP
SNP genotyping
Tag SNP
Minor allele frequency
Molecular Inversion Probe
SNP array
Cite
Citations (43)
Humans exhibit genetic polymorphism in NAT2 resulting in rapid, intermediate and slow acetylator phenotypes. Over 65 NAT2 variants possessing one or more SNPs in the 870-bp NAT2 coding region have been reported. The seven most frequent SNPs are rs1801279 (191G>A), rs1041983 (282C>T), rs1801280 (341T>C), rs1799929 (481C>T), rs1799930 (590G>A), rs1208 (803A>G) and rs1799931 (857G>A). The majority of studies investigate the NAT2 genotype assay for three SNPs: 481C>T, 590G>A and 857G>A. A tag-SNP (rs1495741) recently identified in a genome-wide association study has also been proposed as a biomarker for the NAT2 phenotype.Sulfamethazine N-acetyltransferase catalytic activities were measured in cryopreserved human hepatocytes from a convenience sample of individuals in the USA with an ethnic frequency similar to the 2010 US population census. These activities were segregated by the tag-SNP rs1495741 and each of the seven SNPs described above. We assessed the accuracy of the tag-SNP and various two-, three-, four- and seven-SNP genotyping panels for their ability to accurately infer NAT2 phenotype.The accuracy of the various NAT2 SNP genotype panels to infer NAT2 phenotype were as follows: seven-SNP: 98.4%; tag-SNP: 77.7%; two-SNP: 96.1%; three-SNP: 92.2%; and four-SNP: 98.4%.A NAT2 four-SNP genotype panel of rs1801279 (191G>A), rs1801280 (341T>C), rs1799930 (590G>A) and rs1799931 (857G>A) infers NAT2 acetylator phenotype with high accuracy, and is recommended over the tag-, two-, three- and (for economy of scale) the seven-SNP genotyping panels, particularly in populations of non-European ancestry.
SNP genotyping
SNP
SNP array
Cite
Citations (113)
Sézary syndrome (SS) is a rare variant of primary cutaneous T-cell lymphoma. Little is known about the underlying pathogenesis of S. To address this issue, we used Affymetrix 10K SNP microarray to analyse 13 DNA samples isolated from 8 SS patients and qPCR with ABI TaqMan SNP genotyping assays for the validation of the SNP microarray results. In addition, we tested the impact of SNP loss of heterozygosity (LOH) identified in SS cases on the gene expression profiles of SS cases detected with Affymetrix GeneChip U133A. The results showed: (1) frequent SNP copy number change and LOH involving 1, 2p, 3, 4q, 5q, 6, 7p, 8, 9, 10, 11, 12q, 13, 14, 16q, 17, and 20, (2) reduced SNP copy number at FAT gene (4q35) in 75% of SS cases, and (3) the separation of all SS cases from normal control samples by SNP LOH gene clusters at chromosome regions of 9q31q34, 10p11q26, and 13q11q12. These findings provide some intriguing information for our current understanding of the molecular pathogenesis of this tumour and suggest the possibility of presence of functional SNP LOH in SS tumour cells.
SNP
SNP genotyping
SNP array
Pathogenesis
Molecular Inversion Probe
Cite
Citations (5)
SNP genotyping
SNP
TaqMan
Molecular Inversion Probe
SNP array
Cite
Citations (22)
SNP genotyping
SNP
Molecular Inversion Probe
Tag SNP
Cite
Citations (70)
Single nucleotide polymorphism (SNP) is high-density genetic marker that could be utilized to dissect genetic traits that influence susceptibility to common diseases and responsiveness to drugs. Requirement for massive SNP analysis has enhanced development of various SNP genotyping technologies. DNA chip is one of such methods, which detects SNPs in parallel on an array of surface bound oligonucleotides. Recent application of DNA chip for high-throughput SNP analysis as well as clinical diagnosis will be presented.
SNP genotyping
Molecular Inversion Probe
SNP
SNP array
Tag SNP
Cite
Citations (0)
Carcass weight (CW) is one of the most important economic traits in pigs, directly affecting the income of farmers. In this study, a genome wide association study was performed to detect significant single nucleotide polymorphisms (SNPs) affecting CW in pigs derived from a $F_2$ intercross between Landrace and Korean native pig (KNP). Using high-density porcine SNP chips, highly significant SNPs were identified on SSC12. Two candidate genes, LOC100523510 and LOC100621652, were subsequently selected within this region and further investigated. Within these candidate genes, five SNPs were identified and genotyped using the VeraCode GoldenGate assay. The results revealed that one SNP in the LOC100621652 gene and four SNPs in the LOC100523510 gene are highly associated with CW. These SNP markers can thus have significant applications for improving CW in KNP. However, the functions of these candidate genes are not fully understood and require further study.
SNP
Candidate gene
SNP genotyping
SNP array
Tag SNP
Genome-wide Association Study
Cite
Citations (2)