Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

Type 2 Immunity and Age Modify Gene Expression of COVID19 Receptors in Eosinophilic Gastrointestinal Disorders

Infection with SARS-CoV-2 can lead to COVID-19. The gastrointestinal tract is now an appreciated portal of infection. SARS-CoV-2 enters host cells via angiotensin converting enzyme-2 (ACE2) and the serine protease TMPRSS2. Eosinophilic gastrointestinal disorders are inflammatory conditions caused by chronic type 2 (T2) inflammation. However, the effects of the T2 atopic inflammatory milieu on SARS-COV-2 viral entry gene expression in the GI tract is poorly understood. We analyzed tissue ACE2 and TMPRSS2 gene expression in pediatric eosinophilic esophagitis (EoE), eosinophilic gastritis (EG) and in normal adult esophagi using publicly available RNA sequencing datasets. Similar to findings evaluating the airway, there was no difference in tissue ACE2/TMPRSS2 expression in EoE or EG when compared to control non-EoE/EG esophagus/stomach. ACE2 gene expression was significantly lower in esophagi from children with or without EoE and from adults with EoE as compared to normal adult esophagi. Type 2 immunity and pediatric age could be protective for infection by SARS-CoV-2 in the gastrointestinal tract due to decreased expression of ACE2

The Pediatric Cell Atlas:Defining the Growth Phase of Human Development at Single-Cell Resolution

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). CONCLUSIONS: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. IMPACT: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.D F. Easton was recipient of the CR-UK grant C1287/A10118. R A. Eeles was recipient of the CR-UK grant C5047/A10692 and B E. Henderson was recipient of the NIH grant 1U19CA148537-01This is the author accepted manuscript. The final version is available via AACR at http://cebp.aacrjournals.org/content/early/2015/04/02/1055-9965.EPI-14-0317.long

Health state utilities associated with attributes of treatments for hepatitis C

BACKGROUND: Cost-utility analyses are frequently conducted to compare treatments for hepatitis C, which are often associated with complex regimens and serious adverse events. Thus, the purpose of this study was to estimate the utility associated with treatment administration and adverse events of hepatitis C treatments. DESIGN: Health states were drafted based on literature review and clinician interviews. General population participants in the UK valued the health states in time trade-off (TTO) interviews with 10- and 1-year time horizons. The 14 health states described hepatitis C with variations in treatment regimen and adverse events. RESULTS: A total of 182 participants completed interviews (50 % female; mean age = 39.3 years). Utilities for health states describing treatment regimens without injections ranged from 0.80 (1 tablet) to 0.79 (7 tablets). Utilities for health states describing oral plus injectable regimens were 0.77 (7 tablets), 0.75 (12 tablets), and 0.71 (18 tablets). Addition of a weekly injection had a disutility of −0.02. A requirement to take medication with fatty food had a disutility of −0.04. Adverse events were associated with substantial disutilities: mild anemia, −0.12; severe anemia, −0.32; flu-like symptoms, −0.21; mild rash, −0.13; severe rash, −0.48; depression, −0.47. One-year TTO scores were similar to these 10-year values. CONCLUSIONS: Adverse events and greater treatment regimen complexity were associated with lower utility scores, suggesting a perceived decrease in quality of life beyond the impact of hepatitis C. The resulting utilities may be used in models estimating and comparing the value of treatments for hepatitis C. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10198-014-0649-6) contains supplementary material, which is available to authorized users

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.This work was supported by NIH fellowship F32 GM106584 (AG), NIH grants R01 MH101244(A.G.), R01 CA188392 (B.P.), U01 CA194393(B.P.), R01 GM107427 (M.L.F.), R01 CA193910 (M.L.F./M.P.) and Prostate Cancer Foundation Challenge Award (M.L.F./M.P.). This study makes use of data generated by the Wellcome Trust Case Control Consortium and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium data is available on www.wtccc.org.uk. Funding for the Wellcome Trust Case Control Consortium project was provided by the Wellcome Trust under award 076113. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available online (http://www.UK10K.org). The PRACTICAL consortium was supported by the following grants: European Commission's Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative); Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), A Linneus Centre (Contract ID 70867902), Swedish Research Council (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), grants RO1CA056678, RO1CA082664 and RO1CA092579 from the US National Cancer Institute, National Institutes of Health; US National Cancer Institute (R01CA72818); support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296); NIH grants CA63464, CA54281 and CA098758; US National Cancer Institute (R01CA128813, PI: J.Y. Park); Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2–2009; DFNI-B01/28/2012); Cancer Research UK grants [C8197/A10123] and [C8197/A10865]; grant code G0500966/75466; NIHR Health Technology Assessment Programme (projects 96/20/06 and 96/20/99); Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK; The US Dept of Defense award W81XWH-04-1-0280; Australia Project Grant [390130, 1009458] and Enabling Grant [614296 to APCB]; the Prostate Cancer Foundation of Australia (Project Grant [PG7] and Research infrastructure grant [to APCB]); NIH grant R01 CA092447; Vanderbilt-Ingram Cancer Center (P30 CA68485); Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital (9N069 and X51003); Award Number P30CA042014 from the National Cancer Institute.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/0.1038/ncomms1097

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe