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Polygenic susceptibility to breast cancer: current state-of-the-art

Maya Ghoussaini, Paul DP Pharoah
2009 Future Oncology  
Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Ghoussaini and Pharoah Page 22 Ghoussaini and  ...  Ghoussaini Summary of the eleven well-validated common low-penetrance variants associated with breast cancer to date.  ...  Ghoussaini and Pharoah Page 20 Future Oncol. Author manuscript; available in PMC 2016 July 04.  ... 
doi:10.2217/fon.09.29 pmid:19519208 pmcid:PMC4931895 fatcat:vhn5gtwhofbgtio3xzfjqysyxu

Inherited Genetic Susceptibility to Breast Cancer

Maya Ghoussaini, Paul D.P. Pharoah, Douglas F. Easton
2013 American Journal of Pathology  
Genome-wide association studies have identified 72 loci associated with breast cancer susceptibility. Seventeen of these are known to predispose to other cancers. High-penetrance susceptibility loci for breast cancer usually result from coding alterations, principally in genes involved in DNA repair, whereas almost all of the associations identified through genome-wide association studies are found in noncoding regions of the genome and are likely to involve regulation of genes in multiple
more » ... ays. However, the genes underlying most associations are not yet known. In this review, we summarize the findings from genome-wide association studies in breast cancer and describe the genes and mechanisms that are likely to be involved in the tumorigenesis process. We also discuss approaches to fine-scale mapping of susceptibility regions used to identify the likely causal variant(s) underlying the associations, a major challenge in genetic epidemiology. Finally, we discuss the potential impact of such findings on personalized medicine and future avenues for screening, prediction, and prevention programs. (Am J Pathol 2013, 183: 1038e1051; http://dx. Rare High-Penetrance Alleles Family-based linkage analysis and positional cloning were used to identify high-penetrance alleles in BRCA1 and BRCA2, two tumor-suppressor genes involved in DNA
doi:10.1016/j.ajpath.2013.07.003 pmid:23973388 fatcat:waabb6nkdzdmzlzncf4boelava

Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation [article]

Julie Jerber, Daniel D Seaton, Anna SE Cuomo, Natsuhiko Kumasaka, James Haldane, Juliette Steer, Minal Patel, Daniel Pearce, Malin Andersson, Marc Jan Bonder, Ed Mountjoy, Maya Ghoussaini (+6 others)
2020 bioRxiv   pre-print
Common genetic variants can have profound effects on cellular function, but studying these effects in primary human tissue samples and during development is challenging. Human induced pluripotent stem cell (iPSC) technology holds great promise for assessing these effects across different differentiation contexts. Here, we use an efficient pooling strategy to differentiate 215 iPS cell lines towards a midbrain neural fate, including dopaminergic neurons, and profile over 1 million cells sampled
more » ... cross three differentiation timepoints using single cell RNA sequencing. We find that the proportion of neuronal cells produced by each cell line is highly reproducible over different experimental batches, and identify robust molecular markers in pluripotent cells that predict line-to-line differences in cell fate. We identify expression quantitative trait loci (eQTL) that manifest at different stages of neuronal development, and in response to oxidative stress, by exposing cells to rotenone. We find over one thousand eQTL that colocalise with a known risk locus for a neurological trait, nearly half of which are not found in GTEx. Our study illustrates how coupling single cell transcriptomics with long-term iPSC differentiation can profile mechanistic effects of human trait-associated genetic variants in otherwise inaccessible cell states.
doi:10.1101/2020.05.21.103820 fatcat:ihpof3ycjjecrpokczxyzoukli

Implication of the Pro12Ala polymorphism of the PPAR-gamma 2gene in type 2 diabetes and obesity in the French population

Maya Ghoussaini, David Meyre, Stéphane Lobbens, Guillaume Charpentier, Karine Clément, Marie-Aline Charles, Maïté Tauber, Jacques Weill, Philippe Froguel
2005 BMC Medical Genetics  
David Meyre and Maya Ghoussaini performed the statistical analyses to evaluate the Pro12Ala effect.  ...  Philippe Froguel and David Meyre have directed the study and the redaction of the article that was written by Maya Ghoussaini.  ... 
doi:10.1186/1471-2350-6-11 pmid:15784141 pmcid:PMC1084346 fatcat:y6kkvcpaf5ecneoftzscsp67fy

A Functional Variant at a Prostate Cancer Predisposition Locus at 8q24 Is Associated with PVT1 Expression

Kerstin B. Meyer, Ana-Teresa Maia, Martin O'Reilly, Maya Ghoussaini, Radhika Prathalingam, Patricia Porter-Gill, Stefan Ambs, Ludmila Prokunina-Olsson, Jason Carroll, Bruce A. J. Ponder, Bruce E. Clurman
2011 PLoS Genetics  
Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of
more » ... I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancerspecific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream.
doi:10.1371/journal.pgen.1002165 pmid:21814516 pmcid:PMC3140991 fatcat:zzziyixom5dy5bje26lufjpp3u

Analysis of the SIM1 Contribution to Polygenic Obesity in the French Population

Maya Ghoussaini, Fanny Stutzmann, Cyril Couturier, Vincent Vatin, Emmanuelle Durand, Cécile Lecoeur, Franck Degraeve, Barbara Heude, Maithé Tauber, Serge Hercberg, Claire Levy-Marchal, Patrick Tounian (+7 others)
2010 Obesity  
SIM1 (single-minded 1) haploinsufficiency is responsible for obesity in both humans and mice, but the contribution of frequent DNA variation to polygenic obesity is unknown. Sequencing of all exons, exon/intron boundaries, 870 base pairs (bp) of the putative promoter, and 1,095 bp of the 3′UTR of SIM1 gene in 143 obese children and 24 control adults identified 13 common variants. After analysis of the linkage disequilibrium (LD) structure, association study of eight variants was performed in
more » ... 75 obese children and severely obese adults, in 1,395 control subjects, and in 578 obesity-selected pedigrees. A nominal evidence of association was found for the nonsynonymous variant P352T C/ A (rs3734354) (P = 0.01, OR = 0.81 (0.70-0.95)), the +2,004 TGA −/insT SNP (rs35180395) (P = 0.02, OR = 1.21 (1.02-1.43)), the +2,215A/G TGA SNP (rs9386126) (P = 0.002, OR = 0.81 (0.71-Correspondence: Philippe Froguel (
doi:10.1038/oby.2009.468 pmid:20075856 pmcid:PMC2953787 fatcat:jqdhgt2ip5ffxhnxtd4ddwqqbu

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance [article]

Mohd Anisul Karim, Jarrod Shilts, Jeremy Schwartzentruber, James Hayhurst, Annalisa Buniello, Elmutaz Shaikho Elhaj Mohammed, Jie Zheng, Michael V. Holmes, David Ochoa, Miguel Carmona, Joseph Maranville, Tom R. Gaunt (+6 others)
2021 medRxiv   pre-print
The virus SARS-CoV-2 can exploit biological vulnerabilities in susceptible hosts that predispose to development of severe COVID-19. Previous reports have identified several host proteins related to the interferon response (e.g. OAS1), interleukin-6 signalling (IL-6R), and the coagulation cascade (linked via ABO) that were associated with risk of COVID-19. In the present study, we performed proteome-wide genetic colocalisation tests leveraging publicly available protein and COVID-19 datasets, to
more » ... identify additional proteins that may contribute to COVID-19 risk. Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble FAS (colocalisation probability > 0.9, p = 1 x 10-4), implicating FAS-mediated apoptosis as a potential target for COVID-19 risk. We also undertook polygenic (pan) and cis-Mendelian randomisation analyses that showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal was associated with plasma concentrations of several proteins, with the strongest association observed with CD209 in several proteomic datasets. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.
doi:10.1101/2021.03.15.21253625 fatcat:c2dbiq3csvhtzj4a6346gjamay

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

Mohd Anisul, Jarrod Shilts, Jeremy Schwartzentruber, James Hayhurst, Annalisa Buniello, Elmutaz Shaikho, Jie Zheng, Michael Holmes, David Ochoa, Miguel Carmona, Joseph Maranville, Tom R Gaunt (+6 others)
2021 eLife  
The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19.Methods: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets.Results: Our analytic approach identified several known targets (e.g. ABO,
more » ... ), but also nominated new proteins such as soluble Fas (colocalisation probability > 0.9, p = 1 x 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19.Conclusions: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.Funding: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
doi:10.7554/elife.69719 pmid:34402426 pmcid:PMC8457835 fatcat:ul4fd4kbevc7zbipw5vucjdgwy

Genetic Study of the Melanin-Concentrating Hormone Receptor 2 in Childhood and Adulthood Severe Obesity

Maya Ghoussaini, Vincent Vatin, Cécile Lecoeur, Victor Abkevich, Adib Younus, Chantal Samson, Christophe Wachter, Barbara Heude, Maïté Tauber, Patrick Tounian, Serge Hercberg, Jacques Weill (+5 others)
2007 Journal of Clinical Endocrinology and Metabolism  
Genetic study of the melanin-concentrating hormone receptor 2 in childhood and adulthood severe obesity.: Absence of association of MCHR2 gene with human obesity.
doi:10.1210/jc.2006-2316 pmid:17698913 fatcat:rsfwyt5uknfq5fe2kd2yxu524u

Genome-wide association study identifies five new breast cancer susceptibility loci

Clare Turnbull, Shahana Ahmed, Jonathan Morrison, David Pernet, Anthony Renwick, Mel Maranian, Sheila Seal, Maya Ghoussaini, Sarah Hines, Catherine S Healey, Deborah Hughes, Margaret Warren-Perry (+14 others)
2010 Nature Genetics  
Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 × 10 −7 to P = 3.2 × 10 −15 ).
more » ... also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 × 10 −6 ), 8q24 (rs1562430, P = 5.8 × 10 −7 ) and LSP1 (rs909116, P = 7.3 × 10 −7 ) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
doi:10.1038/ng.586 pmid:20453838 pmcid:PMC3632836 fatcat:b57ve7mxlvde7abbj7txzq4ryy

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features

Amélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou (+12 others)
2013 Journal of Clinical Investigation  
Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls.
more » ... e identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features. A The total risk score (0 = lowest risk → 5 = highest risk) is the sum of each score calculated per software (see Supplemental Methods): 0 if Polyphen-2 = "Benign," Sift = "Tolerated," SNAP = "Neural," Pmut = "Neutral," Align GVGD = "C0"; 1 if different than "benign," "tolerant," "neutral," or "C0." B 0 = no effect; 1 = mild effect on SIM1 activity with ARNT or ARNT2; 2 = strong effect on SIM1 activity with ARNT and ARNT2. MAF is according to the NHLBI Exome Project. NA, not available.
doi:10.1172/jci68035 pmid:23778136 pmcid:PMC3696559 fatcat:kbgzhinekfapfnaufhajx76t44

Open Targets Platform: supporting systematic drug–target identification and prioritisation

David Ochoa, Andrew Hercules, Miguel Carmona, Daniel Suveges, Asier Gonzalez-Uriarte, Cinzia Malangone, Alfredo Miranda, Luca Fumis, Denise Carvalho-Silva, Michaela Spitzer, Jarrod Baker, Javier Ferrer (+20 others)
2020 Nucleic Acids Research  
The Open Targets Platform ( provides users with a queryable knowledgebase and user interface to aid systematic target identification and prioritisation for drug discovery based upon underlying evidence. It is publicly available and the underlying code is open source. Since our last update two years ago, we have had 10 releases to maintain and continuously improve evidence for target–disease relationships from 20 different data sources. In addition, we have
more » ... rated new evidence from key datasets, including prioritised targets identified from genome-wide CRISPR knockout screens in 300 cancer models (Project Score), and GWAS/UK BioBank statistical genetic analysis evidence from the Open Targets Genetics Portal. We have evolved our evidence scoring framework to improve target identification. To aid the prioritisation of targets and inform on the potential impact of modulating a given target, we have added evaluation of post-marketing adverse drug reactions and new curated information on target tractability and safety. We have also developed the user interface and backend technologies to improve performance and usability. In this article, we describe the latest enhancements to the Platform, to address the fundamental challenge that developing effective and safe drugs is difficult and expensive.
doi:10.1093/nar/gkaa1027 pmid:33196847 fatcat:3qrm5q5turgulbvyj2kj6oy5c4

Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes

David Meyre, Nabila Bouatia-Naji, Agnès Tounian, Chantal Samson, Cécile Lecoeur, Vincent Vatin, Maya Ghoussaini, Christophe Wachter, Serge Hercberg, Guillaume Charpentier, Wolfgang Patsch, François Pattou (+11 others)
2005 Nature Genetics  
We identified a childhood obesity locus on chromosome 6q16.3-q24.2 1 that includes 2.4 Mb common to eight genome scans for Type 2 diabetes (T2D) or obesity 1-8 . Analysis of the ENPP1 (PC-1) gene, a candidate for insulin resistance 9,10 in 6,147 subjects revealed association between a three allele risk haplotype (K121Q/IVS20 delT-11/A>G +1044 TGA, QdelTG) and childhood obesity (OR=1.69, p=0.0006), and in adults with morbid or moderate obesity (OR= 1.50, p= 0.006, OR= 1.37, p= 0.02) and also
more » ... T2D (OR=1.56, p=0.00002). The Genotype IBD Sharing Test suggested a contribution of this obesity-associated ENPP1 risk haplotype to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and to their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesityassociated A>G +1044 TGA SNP, was found to be specific for pancreatic islet beta-cells, adipocytes and liver. These findings suggest a primary role for several variants of ENPP1 in mediating insulinresistance, in the development of both obesity and type 2 diabetes, suggesting an underlying molecular mechanism common to both widespread afflictions.
doi:10.1038/ng1604 pmid:16025115 pmcid:PMC2000804 fatcat:icbemwiobza4vgll3e2ddffzk4

Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert

Maya Ghoussaini, Honglin Song, Thibaud Koessler, Ali Amin Al Olama, Zsofia Kote-Jarai, Kristy E. Driver, Karen A. Pooley, Susan J. Ramus, Susanne Krüger Kjaer, Estrid Hogdall, Richard A. DiCioccio, Alice S. Whittemore (+21 others)
2008 Journal of the National Cancer Institute  
for the UK Genetic Prostate Cancer Study Collaborators/ British Association of Urological Surgeons' Section of Oncology and the UK ProtecT Study Collaborators Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its
more » ... telomeric end by c-MYC , two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated singlenucleotide polymorphisms across the region in four case -control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.
doi:10.1093/jnci/djn190 pmid:18577746 pmcid:PMC2902819 fatcat:jrs3cbzzobg5pmehze3ewwap3a

Genome-wide association analysis identifies three new breast cancer susceptibility loci

Maya Ghoussaini, Olivia Fletcher, Kyriaki Michailidou, Clare Turnbull, Marjanka K Schmidt, Ed Dicks, Joe Dennis, Qin Wang, Manjeet K Humphreys, Craig Luccarini, Caroline Baynes, Don Conroy (+170 others)
2012 Nature Genetics  
Ghoussaini et al.  ...  Ghoussaini Forest plots for the 3 SNPs showing evidence of association with breast cancer. Squares represent the estimated per-allele odds ratio (OR) for individual studies.  ... 
doi:10.1038/ng.1049 pmid:22267197 pmcid:PMC3653403 fatcat:73rnidpo6fgfrl7y5wjbvz6vky
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