PDE11A associations with asthma: Results of a genome-wide association scan

DeWan, Andrew T.; Triche, Elizabeth W.; Xu, Xuming; Hsu, Ling‐I; Zhao, Connie; Belanger, Kathleen; Hellenbrand, Karen; Willis‐Owen, Saffron A.G.; Moffatt, Miriam F.; Cookson, William; Himes, Blanca E.; Weiss, Scott T.; Gauderman, W. James; Baurley, James W.; Gilliland, Frank D.; Wilk, Jemma B.; O’Connor, George T.; Strachan, David P.; Hoh, Josephine; Bracken, Michael B.

doi:10.1016/j.jaci.2010.06.051

Cited by 48 publications

(35 citation statements)

References 17 publications

(8 reference statements)

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“…Recent genome-wide association studies (GWASs) have identified loci that harbor susceptibility genes for many respiratory diseases, including asthma and related phenotypes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Many of the most significant GWAS hits are at loci with unknown function that had not been previously considered biologically plausible candidates for disease pathogenesis.…”

Section: Clinical Relevancementioning

confidence: 99%

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Luo

Obeidat

Narzo

et al. 2016

Am J Respir Cell Mol Biol

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Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. For the small airways (n = 105), we discovered 660 eQTLs at a 10% false discovery rate (FDR), among which 315 eQTLs were not previously reported in a large-scale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from Encyclopedia of DNA Elements (ENCODE) showing that the eQTLs reside in regulatory elements (57.5 and 67.6% of cis-and trans-eQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2-fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL-4 signaling (FDR, 5.2 3 10 24 ). The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS-associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway-related conditions.

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Section: Clinical Relevancementioning

confidence: 99%

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Luo

Obeidat

Narzo

et al. 2016

Am J Respir Cell Mol Biol

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“…A subset of PRAM samples was previously genotyped on the Affymetrix Genome-Wide Human SNP Array 5.0 (Santa Clara, Calif., USA) [7] . DNA samples were subjected to whole genome amplification using the QIAGEN REPLI-g Mini kit (Valencia, Calif., USA), and then loaded to the microarray chip after demonstrating successful amplification and correct NspI and StyI digestion fragment size.…”

Section: Pram Gwasmentioning

confidence: 99%

“…Recently, we conducted an exploratory genome-wide association study (GWAS) for asthma using a small cohort of children (n = 66 cases and n = 42 controls) from the Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study that identified variants in PDE11A associated with asthma [7] . Although the evidence from this GWAS was limited due to its small sample size, we used data from this study as well as prior reports in the literature to generate a ranked list of the most likely candidate genes for replication.…”

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confidence: 99%

Attempted Replication of 50 Reported Asthma Risk Genes Identifies a SNP in RAD50 as Associated with Childhood Atopic Asthma

Murk

Walsh²,

Hsu³

et al. 2011

Hum Hered

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Objectives: Asthma is a childhood disease that is strongly influenced by genetic factors. We sought to replicate an association between single nucleotide polymorphisms (SNPs) of the top-ranked candidate genes and childhood atopic asthma in Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study subjects. Methods: Using data from a systematic literature search and an exploratory genome-wide association study conducted in a subset of the PRAM cohort, we followed a strict procedure to generate a ranked list of candidate genes. SNPs in the top 50 genes were genotyped in the full PRAM cohort (n = 103 cases with doc- tor-diagnosed atopic asthma at age 6, and n = 499 controls). Results: The literature search identified 251 prior risk genes from 469 publications. RAD50 (rs2706347) and PTPRE (rs10830196) revealed crude associations with asthma at a Bonferroni-corrected level of significance (p < 0.0011). IL4R (rs1801275), CCL5 (rs2280788), and TBXA2R (rs4523) revealed nominal significance (p < 0.05). When adjusted for race and gender, only rs2706347 in RAD50 remained significantly associated with asthma. SNPs in frequently replicated asthma risk genes, including TNF, IL13, ADAM33, TGFB1, and MS4A2, revealed no association. Conclusion:RAD50 may be a promising candidate asthma risk gene. Lack of evidence of highly reported polymorphisms in the present study highlights the genetic heterogeneity of asthma and emphasizes the need for robust replication of candidate genes.

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“…Similarly, PDE11A, which encodes a related phosphodiesterase, has also been linked with asthma. 26 We recently conducted a case-control study of pediatric asthma, 27 identifying a novel asthma locus on 1q31 containing DENND1B, which is expressed by natural killer (NK) cells and dendritic cells. Homolog proteins of DENND1B are thought to interact with the TNFa receptor.…”

mentioning

confidence: 99%

The Impact of Genomics on Pediatric Research and Medicine

Connolly

Hákonarson²

2012

Pediatrics

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In this review, we discuss some of the most recent developments in genomics research and their relevance to the field of pediatrics. In particular, we examine 3 major approaches that are being used to identify genetic correlates of disease: genome-wide association studies, copy number variation studies, and next-generation sequencing.In the past few years, these approaches have yielded major insights into the causes and pathophysiology of a wide range of diseases but are also constrained by certain limitations. This review provides an overview of the genomic landscape in complex pediatric disorders and sets the stage for translating new discoveries into clinical practice, the future of genomic medicine. 1150CONNOLLY and HAKONARSONIn this review, we provide a narrative of recent developments in genomics, with the aim of generating a broad overview of the field as a whole. We focus on the 3 main approaches (genome-wide association studies (GWAS), copy number variation analysis, and next-generation sequencing [NGS]) that have been instrumentalinpropellingthefieldforward. GENOME-WIDE ASSOCIATION STUDIESGWAS use single nucleotide polymorphisms (SNPs) to identify and compare allele frequencies in target populations, typically by using either case-control or family-based designs. The former is the most common because it is conducive to large-scale recruitment and is not constrained by limits on the numbers of controls. The latter has advantages in terms of controlling for population stratification and the types of analysis that are possible. GWAS use microarrays to tag up to several million SNPs at once, which gives broad coverage of genic and nongenic regions. The approach is hypothesis-independent, and all SNPs carry equal weight during statistical analyses. When a significant difference in SNP frequency is observed between cases and controls, we infer a difference in the underlying genomic locus, which may affect gene expression or regulation. Because of the large number of comparisons being made, most GWAS require large numbers of patients and controls to achieve requisite statistical power, and sample sizes in excess of several thousand are the norm. A major advantage of the approach is its applicability to complex disease, where numerous loci may be implicated as causal factors.GWAS are constrained by the fact that they can only examine SNPs found in relative abundance in the population of interest; generally SNPs with a population frequency of ∼5% or greater. A major assumption, therefore, is that the variants under investigation are common. By extension, a second assumption is that the phenotype of interest is caused by the cumulative result of many small-effect variants. These assumptions constitute the so-called common disease, common variant model, 1 which has successfully identified variants in many complex disorders, some of which are reviewed here. For diseases caused by rare variants, including many Mendelian syndromes, GWAS are underpowered, and sequencing approaches are required, either of lin...

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PDE11A associations with asthma: Results of a genome-wide association scan

Cited by 48 publications

References 17 publications

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Attempted Replication of 50 Reported Asthma Risk Genes Identifies a SNP in RAD50 as Associated with Childhood Atopic Asthma

The Impact of Genomics on Pediatric Research and Medicine

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