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SNPs, linkage disequilibrium, and chronic mountain sickness in Tibetan Chinese.

ABSTRACT: Chronic mountain sickness (CMS) is estimated at 1.2% in Tibetans living at the Qinghai-Tibetan Plateau. Eighteen single-nucleotide polymorphisms (SNPs) from nine nuclear genes that have an association with CMS in Tibetans have been analyzed by using pairwise linkage disequilibrium (LD). The SNPs included are the angiotensin-converting enzyme (rs4340), the angiotensinogen (rs699), and the angiotensin II type 1 receptor (AGTR1) (rs5186) from the renin-angiotensin system. A low-density lipoprotein apolipoprotein B (rs693) SNP was also included. From the hypoxia-inducible factor oxygen signaling pathway, the endothetal Per-Arnt-Sim domain protein 1 (EPAS1) and the egl nine homolog 1 (ENGL1) (rs480902) SNPs were included in the study. SNPs from the vascular endothelial growth factor (VEGF) signaling pathway included are the v-akt murine thymoma viral oncogene homolog 3 (rs4590656 and rs2291409), the endothelial cell nitric oxide synthase 3 (rs1007311 and rs1799983), and the (VEGFA) (rs699947, rs34357231, rs79469752, rs13207351, rs28357093, rs1570360, rs2010963, and rs3025039). An increase in LD occurred in 40 pairwise comparisons, whereas a decrease in LD was found in 55 pairwise comparisons between the controls and CMS patients. These changes were found to occur within and between signaling pathways, which suggests that there is an interaction between SNP alleles from different areas of the genome that affect CMS.

SUBMITTER: Buroker NE

PROVIDER: S-EPMC5529112 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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SNPs, linkage disequilibrium, and chronic mountain sickness in Tibetan Chinese.

Buroker Norman E NE Ning Xue-Han XH Zhou Zhao-Nian ZN Li Kui K Cen Wei-Jun WJ Wu Xiu-Feng XF Zhu Wei-Zhong WZ Scott C Ronald CR Chen Shi-Han SH

Hypoxia (Auckland, N.Z.) 20170714

Chronic mountain sickness (CMS) is estimated at 1.2% in Tibetans living at the Qinghai-Tibetan Plateau. Eighteen single-nucleotide polymorphisms (SNPs) from nine nuclear genes that have an association with CMS in Tibetans have been analyzed by using pairwise linkage disequilibrium (LD). The SNPs included are the angiotensin-converting enzyme (rs4340), the angiotensinogen (rs699), and the angiotensin II type 1 receptor (<i>AGTR1</i>) (rs5186) from the renin-angiotensin system. A low-density lipop ...[more]

PMID: 28770234

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Project description:Single nucleotide polymorphisms (SNPs) may be correlated due to linkage disequilibrium (LD). Association studies look for both direct and indirect associations with disease loci. In a Random Forest (RF) analysis, correlation between a true risk SNP and SNPs in LD may lead to diminished variable importance for the true risk SNP. One approach to address this problem is to select SNPs in linkage equilibrium (LE) for analysis. Here, we explore alternative methods for dealing with SNPs in LD: change the tree-building algorithm by building each tree in an RF only with SNPs in LE, modify the importance measure (IM), and use haplotypes instead of SNPs to build a RF.We evaluated the performance of our alternative methods by simulation of a spectrum of complex genetics models. When a haplotype rather than an individual SNP is the risk factor, we find that the original Random Forest method performed on SNPs provides good performance. When individual, genotyped SNPs are the risk factors, we find that the stronger the genetic effect, the stronger the effect LD has on the performance of the original RF. A revised importance measure used with the original RF is relatively robust to LD among SNPs; this revised importance measure used with the revised RF is sometimes inflated. Overall, we find that the revised importance measure used with the original RF is the best choice when the genetic model and the number of SNPs in LD with risk SNPs are unknown. For the haplotype-based method, under a multiplicative heterogeneity model, we observed a decrease in the performance of RF with increasing LD among the SNPs in the haplotype.Our results suggest that by strategically revising the Random Forest method tree-building or importance measure calculation, power can increase when LD exists between SNPs. We conclude that the revised Random Forest method performed on SNPs offers an advantage of not requiring genotype phase, making it a viable tool for use in the context of thousands of SNPs, such as candidate gene studies and follow-up of top candidates from genome wide association studies.

Project description:Background and Aims: This study was aim to investigate the relationship between the four intron SNPs (rs3087404, rs2029167, rs2029166 and rs7296239) of SMUG1 and the susceptibility of cervical squamous cell carcinoma. Methods: Four SMUG1 intron SNPs (rs3087404, rs2029167, rs2029166 and rs7296239) were genotyped by MA-PCR in 400 CSCCs, 400 CIN III and 1200 controls. qRT-PCR and Western blot were used to detect the SMUG1 mRNA and protein expression. Results: Interestingly, we found that the homozygous GG of rs3087404 had a significantly increased risk of CIN III [OR=1.78(1.27-2.51), P= 0.001] and CSCCs [OR=4.04(2.94-5.55), P=0.000]. The individuals with G allele or G carrier (AG +GG) at rs3087404 were at higher risk for CSCCs [OR=1.34 (1.04-1.71), P= 0.022]. Similarly, the homozygous GG of rs2029167 also had an increased risk of CIN III [OR=2.56 (1.91-3.43), P= 0.000] and CSCCs [OR=4.05(3.02-5.44), P=0.000]. The individuals with G allele or G carrier (AG +GG) at rs2029167 were at higher risk for CINIII [OR=1.41(1.10-1.80), P= 0.006] and CSCCs [OR=1.91 (1.48-2.47), P= 0.000]. In HR-HPV positive group, both the homozygous GG of rs3087404 and the homozygous GG of rs2029167 had an increased risk to CIN III and CSCC. Stratified analysis of the number of sexual partners and the age of first sexual intercourse found that the rs3087404 (A/G) had a particularly high level of enrichment in the CIN III or CSCCs groups. About the rs2029167 (A/G), we only found a particularly high level of enrichment grouping by the number of sexual partners in the CIN III and CSCCs groups. Meanwhile, we also found that there is a correlation between the SNPs of SMUG1 rs3087404 (A/G) and rs2029167 (A/G) with tumor cell differentiation and family heredity. But we didn't find that there was an association between the deferent genotypes of SMUG1 rs2029166 and rs7296239 with SMUG1 gene mRNA or protein expression. During the linkage disequilibrium analysis between rs3087404 (A/G) and rs2029167 (A/G), the genotype with AA-GG [OR=3.14(1.95-5.05)], AG-GG [OR=2.45(1.58-3.89)], GG-AA [OR=2.24(1.28-3.90)] and GG-AG [OR=2.58(1.54-4.32)] significantly increased the risk of CIN III. More notably, this risk is much greater in CSCCs: AA-GG [OR=7.13(4.03-12.61)], AG-GG [OR=7.22(4.21-12.38)], GG-AA [OR=8.60(4.73-15.63)], GG-AG [OR=9.64(5.43-17.13)]. Additionally, most GG (rs3087404) genotypes were linkage GG-AG (44/77, 80/140) in the CIN III and CSCCs, while most GG (rs2029167) genotypes were linkage genotype AG-GG (79/145, 112/184) in the CIN III and CSCCs, respectively. Conclusions: These findings suggested that there was association between the two genetic polymorphisms of SMUG1 rs3087404(A/G) and rs2029167(A/G) with the susceptibility of CIN III and CSCCs, and there was a linkage disequilibrium between the rs3087404 with the rs2029167 in CIN III and CSCCs. This particular linkage disequilibrium can be used as predictive biomarkers of CIN III and CSCC.

Project description:BackgroundRecent developments of high-density SNP chips across a number of species require accurate genetic maps. Despite rapid advances in genome sequence assembly and availability of a number of tools for creating genetic maps, the exact genome location for a number of SNPs from these SNP chips still remains unknown. We have developed a locus ordering procedure based on linkage disequilibrium (LODE) which provides estimation of the chromosomal positions of unaligned SNPs and scaffolds. It also provides an alternative means for verification of genetic maps. We exemplified LODE in cattle.ResultsThe utility of the LODE procedure was demonstrated using data from 1,943 bulls genotyped for 73,569 SNPs across three different SNP chips. First, the utility of the procedure was tested by analysing the masked positions of 1,500 randomly-chosen SNPs with known locations (50 from each chromosome), representing three classes of minor allele frequencies (MAF), namely >0.05, 0.01<MAF < or = 0.05 and 0.001<MAF < or = 0.01. The efficiency (percentage of masked SNPs that could be assigned a location) was 96.7%, 30.6% and 2.0%; with an accuracy (the percentage of SNPs assigned correctly) of 99.9%, 98.9% and 33.3% in the three classes of MAF, respectively. The average precision for placement of the SNPs was 914, 3,137 and 6,853 kb, respectively. Secondly, 4,688 of 5,314 SNPs unpositioned in the Btau4.0 assembly were positioned using the LODE procedure. Based on these results, the positions of 485 unordered scaffolds were determined. The procedure was also used to validate the genome positions of 53,068 SNPs placed on Btau4.0 bovine assembly, resulting in identification of problem areas in the assembly. Finally, the accuracy of the LODE procedure was independently validated by comparative mapping on the hg18 human assembly.ConclusionThe LODE procedure described in this study is an efficient and accurate method for positioning SNPs (MAF>0.05), for validating and checking the quality of a genome assembly, and offers a means for positioning of unordered scaffolds containing SNPs. The LODE procedure will be helpful in refining genome sequence assemblies, especially those being created from next-generation sequencing where high-throughput SNP discovery and genotyping platforms are integrated components of genome analysis.

Dataset Information

SNPs, linkage disequilibrium, and chronic mountain sickness in Tibetan Chinese.

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SNPs, linkage disequilibrium, and chronic mountain sickness in Tibetan Chinese.

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