Genome‐wide association studies: quality control and population‐based measures

Ziegler, Andreas

doi:10.1002/gepi.20472

Cited by 39 publications

(41 citation statements)

References 40 publications

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“…17 Genotyping was conducted on the Affymetrix Genome-Wide Human SNP 6.0 Array; quality control on sample and SNP level was performed according to standardized criteria. 18 Genotyping was performed in individuals of European descent only. A detailed description of genotyping methods and quality control is provided in the Supplemental Material .…”

Section: Methodsmentioning

confidence: 99%

A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Wild¹,

Zeller²,

Schillert³

et al. 2011

Circ Cardiovasc Genet

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Background eQTL analyses are important to improve the understanding of genetic association results. Here, we performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results In a genome-wide association analysis of 2,078 CAD cases and 2,953 controls, we identified 950 single nucleotide polymorphisms (SNPs) that were associated with CAD at P<10-3. Subsequent in silico and wet-lab replication stages and a final meta-analysis of 21,428 CAD cases and 38,361 controls revealed a novel association signal at chromosome 10q23.31 within the LIPA (Lysosomal Acid Lipase A) gene (P=3.7×10-8; OR 1.1; 95% CI: 1.07-1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1,494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10-96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10-3). Conclusions The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which itself was related to endothelial dysfunction, a precursor of CAD.

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Section: Methodsmentioning

confidence: 99%

A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Wild¹,

Zeller²,

Schillert³

et al. 2011

Circ Cardiovasc Genet

Self Cite

128

100

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“…SNPs with differing genotypic distributions between datasets were excluded from imputation using the Fisher's exact test approached described earlier [58]. Both primary and replication datasets were imputed to a HapMap reference of over 2.5 million SNPs.…”

Section: Methodsmentioning

confidence: 99%

Dementia Revealed: Novel Chromosome 6 Locus for Late-Onset Alzheimer Disease Provides Genetic Evidence for Folate-Pathway Abnormalities

et al. 2010

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Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold () were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, ). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (; Bonferroni-corrected P = 0.022). Subsequent genotyping of SNPs in high linkage disequilibrium () with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P = 0.016; rs2073067, P = 0.03; rs2072064, P = 0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P = 0.002 ( in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P = 0.005; rs803422, P = 0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development.

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“…4 5 The reasons for inaccurate data results are experimental systematic errors, incomplete genotyping algorithms, etc. SNPs are usually filtered based on the following parameters: 6 (1) MAF. Genotyping algorithms tend to perform poorly for SNPs with low MAF.…”

Section: Introductionmentioning

confidence: 99%

A Novel Single Nucleotide Polymorphisms Quality Control Method in Genome-Wide Association Studies

Sun¹,

Li²,

Liu³

et al. 2014

Jnl of Comp & Theo Nano

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The quality of single nucleotide polymorphisms (SNPs) is of paramount importance for genome-wide association studies (GWAS) to reduce potential false findings. The SNP genotyping data are not always accurate because of various reasons such as experimental systematic errors. SNP quality control methods commonly use filter-by-extreme filters based on quality control variables of HardyWeinberg equilibrium (HWE), missing frequency (MiF) and minor allele frequency (MAF), to remove outliers. These filters neglect the fact that variables may contribute differently for different SNP clusters, and their implementation requires arbitrary thresholds. For this problem, a novel filtering method based on weighted fuzzy kernel clustering algorithm (WFKCA) is described to identify outlier SNPs.

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Genome‐wide association studies: quality control and population‐based measures

Cited by 39 publications

References 40 publications

A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Dementia Revealed: Novel Chromosome 6 Locus for Late-Onset Alzheimer Disease Provides Genetic Evidence for Folate-Pathway Abnormalities

A Novel Single Nucleotide Polymorphisms Quality Control Method in Genome-Wide Association Studies

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