The Impact of Improved Microarray Coverage and Larger Sample Sizes on Future Genome‐Wide Association Studies

Lindquist, Karla; Jorgenson, Eric; Hoffmann, Thomas J.; Witte, John S.

doi:10.1002/gepi.21724

Cited by 23 publications

(22 citation statements)

References 39 publications

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“…Significant positive correlations have been noted between the number of novel SNPs detected and the sample size of GWAS. 21 In our study, the 41 associations common to both meta-analysis and GWAS had effect sizes that were generally similar and mostly small. A notable outlier is the association of ALDH2 rs671 risk for esophageal cancer, which has been described by three meta-analyses and one GWAS since 2000.…”

Section: Discussionsupporting

confidence: 58%

“…It has been estimated that previous GWAS have detected less than 20% of all independent GWAS-detectable SNPs in chronic diseases, but future GWAS can potentially detect more SNPs through improved coverage and, especially, sample sizes. 21 Studies that use recently developed arrays such as MetaboChip, 34 ImmunoChip, 35 and iCOGS array 36 represent the latest reinvention of the candidate gene study. These chips can contain hundreds of thousands of SNPs that were chosen for replicating and fine-mapping loci identified from GWAS, as well as to cover the most promising candidate genes.…”

Section: Discussionmentioning

confidence: 99%

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A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes

et al. 2013

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Candidate gene and genome-wide association studies (GWAS) represent two complementary approaches to uncovering genetic contributions to common diseases. We systematically reviewed the contributions of these approaches to our knowledge of genetic associations with cancer risk by analyzing the data in the Cancer Genome-wide Association and Meta Analyses database (Cancer GAMAdb). The database catalogs studies published since January 1, 2000, by study and cancer type. In all, we found that meta-analyses and pooled analyses of candidate genes reported 349 statistically significant associations and GWAS reported 269, for a total of 577 unique associations. Only 41 (7.1%) associations were reported in both candidate gene meta-analyses and GWAS, usually with similar effect sizes. When considering only noteworthy associations (defined as those with false-positive report probabilities r0.2) and accounting for indirect overlap, we found 202 associations, with 27 of those appearing in both meta-analyses and GWAS. Our findings suggest that meta-analyses of well-conducted candidate gene studies may continue to add to our understanding of the genetic associations in the post-GWAS era.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes

et al. 2013

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“…Taken together, these imputation-based analyses can guide genetic studies, and complement recent reports 22,24 with several novel aspects that can improve performance:…”

Section: Discussionmentioning

confidence: 53%

“…It should be considered that increasing sample size can augment genome-wide power to assess rare variants more than increasing array density -even up to full genotyping of the complete 1000 Genomes Project variant set. 22,24 Thus, aids to imputation are increasingly valuable, because most studies are likely to be collecting increasing numbers of samples and using this inferential process rather than sequencing full genomes.…”

Section: Discussionmentioning

confidence: 99%

Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs

et al. 2014

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“…Our findings here demonstrate how improved coverage of genotyping arrays and imputation to more comprehensive reference panels can lead to novel findings, even for traits that have been investigated in depth in previous genetic association studies. 35 HLA-DQB1 and age-related macular degeneration E Jorgenson et al Table 3 The top classical HLA allele associations a with overall AMD and its subtypes The info metric from SNP2HLA is the estimated correlation of the imputed genotype to the true genotype.…”

Section: Discussionmentioning

confidence: 99%

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

et al. 2016

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Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR) = 1.21; P = 1.4 × 10 − 11 ) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR = 1.22; P = 3.9 × 10 − 10 ) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR = 1.28; P = 1.30 × 10 − 3 , DQB1*02: OR = 1.32; P = 9.00 × 10 − 4 ). These findings support a role of HLA class II alleles in the risk of AMD. European Journal of Human Genetics (2016) 24, 1049-1055; doi:10.1038/ejhg.2015.247; published online 6 January 2016 INTRODUCTION Age-related macular degeneration (AMD) is a complex, late-onset vision disorder, which is the leading cause of blindness among the elderly in developed countries. [1][2][3][4] Immune response and inflammation play a causal role in the pathogenesis and progression of AMD. [5][6][7][8][9][10][11] The human leukocyte antigen (HLA) region on chromosome 6p21.31 encodes gene products that regulate immune response. Drusen, a pathologic hallmark of AMD, contain HLA class II antigens, 12 and increased HLA class II immunoreactivity has been associated with drusen formation, 13 suggesting that HLA may influence the development of AMD. Although a few small candidate gene studies found that certain HLA class I and class II polymorphisms were associated with a predisposition to AMD, 14,15 the largest genome-wide association study (GWAS) meta-analysis conducted by the AMD Gene Consortium, which included more than 77 000 subjects, did not identify any HLA polymorphisms that were independently associated with the risk of AMD. 16 The AMD Consortium meta-analysis, although well powered to detect common variants of small effect, included a number of studies that utilized genotyping arrays, with array density ranging from 165 770 ...

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The Impact of Improved Microarray Coverage and Larger Sample Sizes on Future Genome‐Wide Association Studies

Cited by 23 publications

References 39 publications

A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes

A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes

Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

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