Genome-wide association studies: theoretical and practical concerns

Wang, William Y.S.; Barratt, Bryan J.; Clayton, David; Todd, John A.

doi:10.1038/nrg1522

Cited by 1,011 publications

(752 citation statements)

References 96 publications

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“…This value is in keeping with the genotypic ORs of the complex disease susceptibility genes that have been identified to date. 55 GPR78 was selected as a candidate gene for psychiatric illness by virtue of its genomic location in a region of confirmed linkage and its putative function. Expressed in the pituitary and the placenta, 16 GPR78 may play a role in the functioning of the HPA axis and during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

et al. 2006

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The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard v 2 statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (v 2 P = 0.044; LRT P = 0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR) = 1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR = 5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR = 5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P = 0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values < 0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P = 0.038 and 0.032) and in the full sample of affected female individuals (P = 0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.

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Section: Discussionmentioning

confidence: 99%

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

et al. 2006

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“…In GWAS, a large number of genetic markers are required spanning the whole genome, to achieve comprehensive coverage and adequate statistical power to detect unknown disease variants through linkage disequilibrium (LD). 45,46 In other words, the disease variants would not be detected if no markers in strong LD with them were genotyped.…”

Section: The Evolution Of Genetic Markers In Disease Gene Mappingmentioning

confidence: 99%

The discovery of human genetic variations and their use as disease markers: past, present and future

Loy

Salim

et al. 2010

J Hum Genet

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The field of human genetic variations has progressed rapidly over the past few years. It has added much information and deepened our knowledge and understanding of the diversity of genetic variations in the human genome. This significant progress has been driven mainly by the developments of microarray and next generation sequencing technologies. The array-based methods have been widely used for large-scale copy number variation (CNV) detection in the human genome. The arrival of next generation sequencing technologies, which enabled the completion of several whole genome resequencing studies, has also resulted in a massive discovery of genetic variations. These studies have identified several hundred thousand short indels and a total of thousands of CNVs and other structural variations in the human genome. The discovery of these 'newer' types of genetic variations, indels, CNVs and copy neutral variations (inversions and translocations) has also widened the scope of genetic markers in human genetic and disease gene mapping studies. The aim of this review article is to summarize the latest developments in the discovery of human genetic variations and address the issue of inadequate coverage of genetic variations in the current genome-wide association studies, which mainly focuses on common SNPs. Finally, we also discuss the future directions in the field and their impacts on next generation genome-wide association studies.

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“…Single-nucleotide polymorphisms (SNPs), the most abundant genetic markers in the human genome, have been widely used in genetic and genomic research such as studies of disease gene mapping [1-6], medical and clinical diagnostics [7-9], forensic tests [10-12], genome structure of linkage disequilibrium and recombination [13-18], chromosomal aberrations [19-24], and genetic diversity [25-27]. Modern high-throughput and high-resolution SNP array genotyping techniques, such as the Affymetrix GeneChip (Affymetrix Inc., Santa Clara, CA, USA) [28,29] and Illumina BeadChip (Illumina Inc., San Diego, CA, USA) [30-32], provide genotype and fluorescence intensity data on hundreds of thousands of SNPs for each study sample.…”

Section: Introductionmentioning

confidence: 99%

“…Modern high-throughput and high-resolution SNP array genotyping techniques, such as the Affymetrix GeneChip (Affymetrix Inc., Santa Clara, CA, USA) [28,29] and Illumina BeadChip (Illumina Inc., San Diego, CA, USA) [30-32], provide genotype and fluorescence intensity data on hundreds of thousands of SNPs for each study sample. Many genomic studies are using such SNP genotyping techniques to find marker-trait association via genome-wide association studies [4,6,33] and to identify disease-related chromosomal aberrations via allelic-imbalance analyses [34-39], loss-of-heterozygosity analyses [24,35,40-43], and copy-number analyses [23,24,41,44,45]. …”

Section: Introductionmentioning

confidence: 99%

SAQC: SNP Array Quality Control

et al. 2011

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BackgroundGenome-wide single-nucleotide polymorphism (SNP) arrays containing hundreds of thousands of SNPs from the human genome have proven useful for studying important human genome questions. Data quality of SNP arrays plays a key role in the accuracy and precision of downstream data analyses. However, good indices for assessing data quality of SNP arrays have not yet been developed.ResultsWe developed new quality indices to measure the quality of SNP arrays and/or DNA samples and investigated their statistical properties. The indices quantify a departure of estimated individual-level allele frequencies (AFs) from expected frequencies via standardized distances. The proposed quality indices followed lognormal distributions in several large genomic studies that we empirically evaluated. AF reference data and quality index reference data for different SNP array platforms were established based on samples from various reference populations. Furthermore, a confidence interval method based on the underlying empirical distributions of quality indices was developed to identify poor-quality SNP arrays and/or DNA samples. Analyses of authentic biological data and simulated data show that this new method is sensitive and specific for the detection of poor-quality SNP arrays and/or DNA samples.ConclusionsThis study introduces new quality indices, establishes references for AFs and quality indices, and develops a detection method for poor-quality SNP arrays and/or DNA samples. We have developed a new computer program that utilizes these methods called SNP Array Quality Control (SAQC). SAQC software is written in R and R-GUI and was developed as a user-friendly tool for the visualization and evaluation of data quality of genome-wide SNP arrays. The program is available online (http://www.stat.sinica.edu.tw/hsinchou/genetics/quality/SAQC.htm).

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Genome-wide association studies: theoretical and practical concerns

Cited by 1,011 publications

References 96 publications

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

The discovery of human genetic variations and their use as disease markers: past, present and future

SAQC: SNP Array Quality Control

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