Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases

Plagnol, Vincent; Howson, Joanna M.M.; Smyth, Deborah J.; Walker, Neil M.; Hafler, Jason P.; Wallace, Chris; Stevens, Helen; Jackson, Laura; Simmonds, Matthew J.; Bingley, Polly J.; Gough, Stephen; Todd, John A.

doi:10.1371/journal.pgen.1002216

Cited by 239 publications

(214 citation statements)

References 50 publications

(73 reference statements)

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“…This example shows that even for common polymorphisms, the EM approach can help to find likely associations that the naive approach can not. The SNP rs2476601 was found to be associated with T1D in several studies before the publication of [8] and was confirmed in a recent study in [29] that was published after the publication of [8]. All these studies support our results for the association of common polymorphisms with T1D.…”

Section: Resultssupporting

confidence: 89%

A unified approach for allele frequency estimation, SNP detection and association studies based on pooled sequencing data using EM algorithms

Chen

Sun

2013

BMC Genomics

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BackgroundGenome-wide association studies (GWAS) have identified many common polymorphisms associated with complex traits. However, these associated common variants explain only a small fraction of the phenotypic variances, leaving a substantial portion of genetic heritability unexplained. As a result, searches for "missing" heritability are drawing increasing attention, particularly for rare variant studies that often require a large sample size and, thus, extensive sequencing effort. Although the development of next generation sequencing (NGS) technologies has made it possible to sequence a large number of reads economically and efficiently, it is still often cost prohibitive to sequence thousands of individuals that are generally required for association studies. A more efficient and cost-effective design would involve pooling the genetic materials of multiple individuals together and then sequencing the pools, instead of the individuals. This pooled sequencing approach has improved the plausibility of association studies for rare variants, while, at the same time, posed a great challenge to the pooled sequencing data analysis, essentially because individual sample identity is lost, and NGS sequencing errors could be hard to distinguish from low frequency alleles.ResultsA unified approach for estimating minor allele frequency, SNP calling and association studies based on pooled sequencing data using an expectation maximization (EM) algorithm is developed in this paper. This approach makes it possible to study the effects of minor allele frequency, sequencing error rate, number of pools, number of individuals in each pool, and the sequencing depth on the estimation accuracy of minor allele frequencies. We show that the naive method of estimating minor allele frequencies by taking the fraction of observed minor alleles can be significantly biased, especially for rare variants. In contrast, our EM approach can give an unbiased estimate of the minor allele frequency under all scenarios studied in this paper. A SNP calling approach, EM-SNP, for pooled sequencing data based on the EM algorithm is then developed and compared with another recent SNP calling method, SNVer. We show that EM-SNP outperforms SNVer in terms of the fraction of db-SNPs among the called SNPs, as well as transition/transversion (Ti/Tv) ratio. Finally, the EM approach is used to study the association between variants and type I diabetes.ConclusionsThe EM-based approach for the analysis of pooled sequencing data can accurately estimate minor allele frequencies, call SNPs, and find associations between variants and complex traits. This approach is especially useful for studies involving rare variants.

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Section: Resultssupporting

confidence: 89%

A unified approach for allele frequency estimation, SNP detection and association studies based on pooled sequencing data using EM algorithms

Chen

Sun

2013

BMC Genomics

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“…Importantly, our study validated an association of chromosome 12q24.12. This locus was reported to be associated with CAD, 5 intracranial aneurysm, 14 ischemic stroke, 15 blood pressure, 16 kidney function, 17 type 1 diabetes, 18 serum urate 19 and lipid concentration, 20 and drinking behavior, 21 suggesting that this locus is an important genetic component of cardiovascular diseases and their risk factors. Because top associated SNP (rs3782886:A4G) is closely linked to two functional variants in this region (rs671:A4G in ALDH2 and rs11066001:C4T in BRAP), 22 we confirmed that the risk haplotype, which contains several functional variants, will affect the susceptibility of cardiovascular disease and its risk factors.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

et al. 2014

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Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A4G, P ¼ 2.60 Â 10 À9 , odds ratio (OR) ¼ 0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A4C, P ¼ 3.84 Â 10 À9 , OR ¼ 0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A4G: P ¼ 1.14 Â 10 À14 , OR ¼ 1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci. INTRODUCTIONMyocardial infarction (MI), the severest form of coronary artery disease (CAD), is characterized by the occlusion of the coronary artery, resulting in ischemic damage of the myocardium. The occlusion of the coronary artery is characterized by abrupt plaque rupture with thrombogenesis 1 following the atherosclerotic process, which has recently been regarded as a chronic inflammatory condition involving lipid accumulation, abnormal extracellular matrix metabolism, innate immunity with macrophages, and the adaptive immune response with T and B lymphocytes. 2 Despite recent dramatic advances in preventive and/or therapeutic strategies, MI is still one of the leading causes of death in Asian populations as well as European populations.The pathogenesis of MI is considered to be the cumulative effect of multiple genetic and environmental factors. For the genetic aspect, a

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“…This CNVR is significantly heritable (P ¼ 6.35E-12), linked (P ¼ 0.045), and is flanked by SNPs associated with immunerelated functions. 22,23 A second of these 10 is a 370-bp CNVR within the first exon of the UGT1A7 gene. This CNVR is highly linked to its own genomic location (P ¼ 5.44E-60), and B6.6 kb from rs2602381, which was previously associated with attention-deficit hyperactivity disorder.…”

Section: Study Groupmentioning

confidence: 99%

Utilizing extended pedigree information for discovery and confirmation of copy number variable regions among Mexican Americans

et al. 2012

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Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases

Cited by 239 publications

References 50 publications

A unified approach for allele frequency estimation, SNP detection and association studies based on pooled sequencing data using EM algorithms

A unified approach for allele frequency estimation, SNP detection and association studies based on pooled sequencing data using EM algorithms

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

Utilizing extended pedigree information for discovery and confirmation of copy number variable regions among Mexican Americans

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