New basal cell carcinoma susceptibility loci

Stacey, Simon; Helgason, Hannes; Gudjonsson, Sigurjon A.; Þorleifsson, Guðmar; Zink, Florian; Sigurðsson, Ásgeir; Kehr, Birte; Guðmundsson, Jūlı́us; Sulem, Patrick; Sigurgeirsson, Bárður; Benediktsdóttir, Kristrún R.; Thorisdottir, Kristin; Ragnarsson, Rafn; Fuentelsaz, Victoria; Corredera, Cristina; Gilaberte, Yolanda; Grasa, Matilde; Planelles, Dolores; Sanmartín, O.; Rudnai, Péter; Gurzău, Eugen; Koppová, Kvetoslava; Nexø, Bjørn A.; Tjønneland, Anne; Overvad, Kim; Jonasson, Jón G.; Tryggvadóttír, Laufey; Johannsdottir, Hrefna; Kristinsdottir, Anna M.; Stefánsson, Hreinn; Másson, Gísli; Magnússon, Ólafur Þ.; Halldórsson, Bjarni V.; Kong, Augustine; Rafnar, Thorunn; Þorsteinsdóttir, Unnur; Vogel, Ulla; Kumar, Rajiv; Nagore, Eduardo; Mayordomo, J. I.; Guðbjartsson, Daníel F.; Ólafsson, Jón; Stefánsson, Kāri

doi:10.1038/ncomms7825

Cited by 62 publications

(60 citation statements)

References 68 publications

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“…SNPs close to CDKN1A, for example, have been associated with electrocardiographic measures (35) and colorectal cancer (36). While the CDKN2A/CDKN2B and CDKN2B-AS1 locus has been found in GWAS of Type 2 Diabetes (37), fasting glucose (38), intracranial aneurysm (39), myocardial infraction (40), coronary heart disease (41) and various cancers, including basal cell carcinoma (42), breast (43) and prostate (44) cancer, and glioma (45). Interestingly, the same allele in CDKN2B that decrease risk of POAG, was found associated with increased risk of glioma.…”

Section: à5mentioning

confidence: 99%

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

et al. 2017

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Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

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Section: à5mentioning

confidence: 99%

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

et al. 2017

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“…Zfh2 is part of a large family of zinc finger homeodomain proteins present in most metazoans (Fig. 3 B and (46)), with the two clearest human orthologs of Zfh2 being ZFHX3 (also known as ATBF1, ATBT, ZNF927) (47-54) and ZFHX4 (55-57). Human ZFHX3 and ZFHX4 also encode large ~400 kDa proteins containing 23 zinc fingers and 4 homeodomains (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…ZFHX3 is involved in neural and epithelial development (47-50), implicated by GWAS in atrial fibrillation (51) and has roles in multiple types of cancer (52-54). Similarly, ZFHX4 is involved in epithelial and glial cancers (55, 56), and neuronal development (57). However, neither Zfh2 nor its human orthologs ZFHX3 and ZFHX4 had previously been shown to regulate immune gene transcription or gas sensing.…”

Section: Resultsmentioning

confidence: 99%

Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen

Helenius

Haake

Kwon

et al. 2016

The Journal of Immunology

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Hypercapnia, elevated partial pressure of carbon dioxide (PCO2) in blood and tissue, develops in many patients with chronic severe obstructive pulmonary disease and other advanced lung disorders. Patients with advanced disease frequently develop bacterial lung infections, and hypercapnia is a risk factor for mortality in such individuals. We previously demonstrated that hypercapnia suppresses induction of NF-κB-regulated innate immune response genes required for host defense in human, mouse and Drosophila cells, and increases mortality from bacterial infections in both mice and Drosophila. However, the molecular mediator(s) of hypercapnic immune suppression are undefined. Here, we report a genome-wide RNAi screen in Drosophila S2* cells stimulated with bacterial peptidoglycan (PGN). The screen identified 16 genes with human orthologs whose knockdown reduced hypercapnic suppression of the gene encoding the antimicrobial peptide (AMPs) Diptericin (Dipt), but did not increase Dipt mRNA levels in air. In vivo tests of one of the strongest screen hits, Zfh2 (mammalian orthologs ZFHX3/ATBF1 and ZFHX4), demonstrate that reducing zfh2 function using a mutation or RNAi improves survival of flies exposed to elevated CO2 and infected with S. aureus. Tissue-specific knockdown of zfh2 in the fat body, the major immune and metabolic organ of the fly, mitigates hypercapnia-induced reductions in Dipt and other AMPs and improves resistance of CO2-exposed flies to infection. Zfh2 mutations also partially rescue hypercapnia-induced delays in egg hatching, suggesting that Zfh2's role in mediating responses to hypercapnia extends beyond the immune system. Together, these results identify Zfh2 as the first in vivo mediator of hypercapnic immune suppression.

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“…GWASs have also shown associations with basal cell and melanoma skin cancer risk (Barrett et al, 2011; Bishop et al, 2009; Brown et al, 2008; Falchi et al, 2009; Gudbjartsson et al, 2008; Law et al, 2015; Macgregor et al, 2011; Stacey et al, 2008, 2009, 2011, 2015). In the case of melanoma these include genes involved in melanocyte development and telomere maintenance.…”

Section: Gwas Highlights In Dermatologymentioning

confidence: 99%

The Molecular Revolution in Cutaneous Biology: The Era of Genome-Wide Association Studies and Statistical, Big Data, and Computational Topics

Anbunathan

Bowcock

2017

Journal of Investigative Dermatology

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The investigation of biological systems involving all organs of the body including the skin is in an era of big data. This requires heavy-duty computational tools, and novel statistical methods. Microarrays have allowed the interrogation of thousands of common genetic markers in thousands of individuals from the same population (termed genome wide association studies or GWAS) to reveal common variation associated with disease or phenotype. These markers are usually single nucleotide polymorphisms (SNPs) that are relatively common in the population. In the case of dermatological diseases such as alopecia areata, vitiligo, psoriasis and atopic dermatitis, common variants have been identified that are associated with disease, and these provide insights into biological pathways and reveal possible novel drug targets. Other skin phenotypes such as acne, color and skin cancers are also being investigated with GWAS. Analyses of such large GWAS datasets require a consideration of a number of statistical issues including the testing of multiple markers, population substructure, and ultimately a requirement for replication. There are also issues regarding the missing heritability of disease that cannot be entirely explained with current GWAS approaches. Next generation sequencing technologies such as exome and genome sequencing of similar patient cohorts will reveal additional variants contributing to disease susceptibility. However, the data generated with these approaches will be orders of magnitude greater than that those generated with arrays, with concomitant challenges in the identification of disease causing variants.

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New basal cell carcinoma susceptibility loci

Cited by 62 publications

References 68 publications

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen

The Molecular Revolution in Cutaneous Biology: The Era of Genome-Wide Association Studies and Statistical, Big Data, and Computational Topics

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