Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure

Visconti, Alessia; Duffy, David L.; Liu, Fan; Zhu, Gu; Wu, Wenting; Chen, Yan; Hysi, Pirro G.; Zeng, Changqing; Sanna, Marianna; Iles, Mark M.; Kanetsky, Peter A.; Demenais, Florence; Hamer, Merel A.; Uitterlinden, André G.; Ikram, M. Arfan; Nijsten, Tamar; Martin, Nicholas G.; Kayser, Manfred; Spector, Timothy D.; Han, Jiali; Bataille, Véronique; Falchi, Mario

doi:10.1038/s41467-018-04086-y

Cited by 92 publications

(90 citation statements)

References 54 publications

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“…Many of these genes have a strong biological rationale for involvement in breast carcinogenesis and are in or near genomic regions associated with other cancer types or potential cancer risk factors. For example, the ZNF276 intronic variant rs12925026 is associated at genome-wide significance with nonmelanoma skin cancer (29). ZNF276 overlaps FANCA in a tail-to-tail manner (30).…”

Section: Discussionmentioning

confidence: 99%

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Kar¹,

Considine²,

Tyrer³

et al. 2020

Preprint

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Familial, genome-wide association (GWAS), and sequencing studies and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWAS) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through novel application of a pleiotropy-guided conditional/conjunction false discovery rate approach for the first time in the setting of a TWAS. This identified 14 new candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 new candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were > 1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. Overlaying candidate causal risk variants identified by GWAS fine mapping onto expression prediction models for genes at known loci suggested that the association for 55% of these genes was driven by the underlying GWAS signal. SignificanceThe 22 new genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

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Section: Discussionmentioning

confidence: 99%

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Kar¹,

Considine²,

Tyrer³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Although a phenotypic relationship between eyebrow and scalp hair color clearly exists, such a correlation is not perfect, suggesting the existence of overlapping and unique genetic components for both traits. Although previous genome-wide association studies (GWASs) on human eye (Kayser et al, 2008;Liu et al, 2010;Sulem et al, 2007Sulem et al, , 2008, scalp hair (Han et al, 2008;Hysi et al, 2018;Sulem et al, 2007), and skin color (Han et al, 2008;Liu et al, 2015;Sulem et al, 2007;Visconti et al, 2018) have identified multiple DNA variants, no GWAS for eyebrow color has been reported as of yet.…”

Section: Genome-wide Association Studies Identify Multiple Genetic Lomentioning

confidence: 99%

Genome-Wide Association Studies Identify Multiple Genetic Loci Influencing Eyebrow Color Variation in Europeans

Peng

Zhu

Hysi

et al. 2019

Journal of Investigative Dermatology

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“…GWAS for melanoma risk, nevus count, and multiple pigmentation traits have identified numerous associated genetic loci (Stokowski et al 2007;Sulem et al 2007;Brown et al 2008;Gudbjartsson et al 2008;Han et al 2008;Sulem et al 2008;Bishop et al 2009;Falchi et al 2009;Nan et al 2009;Duffy et al 2010;Eriksson et al 2010;Amos et al 2011;Barrett et al 2011;Macgregor et al 2011;Nan et al 2011;Candille et al 2012;Zhang et al 2013;Law et al 2015;Liu et al 2015;Hysi et al 2018;Visconti et al 2018), with melanoma GWAS alone identifying 20 regions associated with risk. Trait-associated variation explaining many of these loci could reasonably be expected to be reflected in the biology of the melanocyte, the pigment producing cell in human skin and the cellular origin of melanoma.…”

Section: Introductionmentioning

confidence: 99%

Cell-type specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Zhang¹,

Choi²,

Kovacs³

et al. 2017

Preprint

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7 These authors contributed equally to this work 8 These authors co-supervised this work 9,10 A complete list of consortium authors appears at the end of this paper Corresponding authors: bpavan@mail.nih.gov, kevin.brown3@nih.gov RUNNING TITLE: Cell-type specific melanocyte eQTL dataset KEY WORDS: eQTL, Melanocyte, Melanoma, cell-type specific peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/231423 doi: bioRxiv preprint first posted online 2 ABSTRACT Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogenous tissues as opposed to specific cell types. To better understand the cell-type specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTLs and 4,997 eGenes (FDR<0.05), which are higher numbers than any GTEx tissue type with a similar sample size.Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissues, including skin. Over a third of melanocyte eGenes including key genes in melanin synthesis pathways were not observed in two types of GTEx skin tissues or melanoma samples. The melanocyte dataset also identified cell-type specific trans-eQTL of a pigmentation-associated SNP for four genes, likely through its cis-regulation of IRF4, encoding a transcription factor implicated in human pigmentation phenotypes. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as melanoma-associate variants identified through genome-wide association studies (GWAS). Co-localization of melanoma GWAS variants and eQTLs from melanocyte and skin eQTL datasets identified candidate melanoma susceptibility genes for most of the known GWAS loci including unique genes identified by the melanocyte dataset.Further, a transcriptome-wide association study using published melanoma GWAS data uncovered four new loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant Pvalues. Our data highlights the utility of lineage-specific eQTL resources for annotating GWAS findings and present a robust database for genomic research of melanoma risk and melanocyte biology.

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Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure

Cited by 92 publications

References 54 publications

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

Genome-Wide Association Studies Identify Multiple Genetic Loci Influencing Eyebrow Color Variation in Europeans

Cell-type specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

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