Journal of translational genetics and genomics最新文献

{"title":"King syndrome: what’s in a name?","authors":"Laurie M. Connors","doi":"10.20517/JTGG.2021.17","DOIUrl":"https://doi.org/10.20517/JTGG.2021.17","url":null,"abstract":"© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42617198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydroxyurea treatment of sickle cell disease: towards a personalized model-based approach","authors":"A. Pandey, J. Estepp, D. Ramkrishna","doi":"10.20517/JTGG.2020.45","DOIUrl":"https://doi.org/10.20517/JTGG.2020.45","url":null,"abstract":"Hydroxyurea is a commonly used drug for the treatment of sickle cell disease. Several studies have demonstrated the efficacy of hydroxyurea in ameliorating disease pathophysiology. However, a lack of consensus on optimal dosing and the need for ongoing toxicity monitoring for myelosuppression limits its utilization. Pharmacokinetic (PK) and pharmacodynamic (PD) studies describe drug-body interactions, and hydroxyurea PK-PD studies have reported wide inter-patient variability. This variability can be explained by a mathematical model taking into consideration different sources of variation such as genetics, epigenetics, phenotypes, and demographics. A PK-PD model provides us with a tool to capture these variant responses of patients to a given drug. The development of an integrated population PK-PD model that can predict individual patient responses and identify optimal dosing would maximize efficacy, limit toxicity, and increase utilization. In this review, we discuss various treatment challenges associated with hydroxyurea. We summarize existing population PK-PD models of hydroxyurea, the gap in the existing models, and the gap in the mechanistic understanding. Lastly, we address how mathematical modeling can be applied to improve our understanding of hydroxyurea’s mechanism of action and to tackle the challenge of interpatient variability, dose optimization, and non-adherence.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43346167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prostate cancer in young men represents a distinct clinical phenotype: gene expression signature to predict early metastases.","authors":"Yuan C Ding,&nbsp;Huiqing Wu,&nbsp;Elai Davicioni,&nbsp;R Jeffrey Karnes,&nbsp;Eric A Klein,&nbsp;Robert B Den,&nbsp;Linda Steele,&nbsp;Susan L Neuhausen","doi":"10.20517/jtgg.2021.01","DOIUrl":"https://doi.org/10.20517/jtgg.2021.01","url":null,"abstract":"<p><strong>Aim: </strong>Several genomic signatures are available to predict Prostate Cancer (CaP) outcomes based on gene expression in prostate tissue. However, no signature was tailored to predict aggressive CaP in younger men. We attempted to develop a gene signature to predict the development of metastatic CaP in young men.</p><p><strong>Methods: </strong>We measured genome-wide gene expression for 119 tumor and matched benign tissues from prostatectomies of men diagnosed at ≤ 50 years and > 70 years and identified age-related differentially expressed genes (DEGs) for tissue type and Gleason score. Age-related DEGs were selected using the improved Prediction Analysis of Microarray method (iPAM) to construct and validate a classifier to predict metastasis using gene expression data from 1,232 prostatectomies. Accuracy in predicting early metastasis was quantified by the area under the curve (AUC) of receiver operating characteristic (ROC), and abundance of immune cells in the tissue microenvironment was estimated using gene expression data.</p><p><strong>Results: </strong>Thirty-six age-related DEGs were selected for the iPAM classifier. The AUC of five-year survival ROC for the iPAM classifier was 0.87 (95%CI: 0.78-0.94) in young (≤ 55 years), 0.82 (95%CI: 0.76-0.88) in middle-aged (56-70 years), and 0.69 (95%CI: 0.55-0.69) in old (> 70 years) patients. Metastasis-associated immune responses in the tumor microenvironment were more pronounced in young and middle-aged patients than in old ones, potentially explaining the difference in accuracy of prediction among the groups.</p><p><strong>Conclusion: </strong>We developed a genomic classifier with high precision to predict early metastasis for younger CaP patients and identified age-related differences in immune response to metastasis development.</p>","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":" ","pages":"50-61"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38933706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Talimogene laherparepvec and novel injectable oncolytic viruses in the management of metastatic melanoma","authors":"Frances G. Jenkins, J.E. Johnson, F. Collichio, D. Ollila","doi":"10.20517/jtgg.2021.29","DOIUrl":"https://doi.org/10.20517/jtgg.2021.29","url":null,"abstract":"and viruses Abstract Talimogene laherparepvec (T-VEC) is an oncolytic virus (OV) therapy derived from the JS1 strain of herpes simplex virus one that was approved by the Food and Drug Administration in 2015 to be administered as direct injection therapy for patients with melanoma. The anti-tumor effects of T-VEC are due to viral-mediated tumor cell lysis at the site of administration and a local, and in some cases systemic, anti-tumor response via T cell-mediated host immune response pathways aided by GM-CSF. T-VEC has shown promising results for metastatic melanoma, particularly in patients with skin, lymph node, and soft tissue metastases (stages IIIB, IIIC, and IVa). Studies have explored the utility of T-VEC as monotherapy, neoadjuvant therapy, and in combination with other immunotherapies and targeted therapies. T-VEC has proven to improve durable response rates and overall survival with a very tolerable safety profile. More research is needed to better understand which patients are most likely to benefit from T-VEC therapy, which combination therapies are most effective, and how to sequence multimodality therapy. Additionally, new OVs are currently in development and/or being studied in clinical trials. In this review, we will discuss T-VEC as a monotherapy, neoadjuvant therapy, and combination therapy, in addition to future directions for melanoma therapy as it pertains to new OVs. progression-free survival longer recruiting patients. The estimated completion date is in January 2022. Finally, a non-randomized, open-label, multicenter phase 1b/2 trial (MASTERKEY-318) is assessing the efficacy and safety of intratumoral T-VEC in liver tumors as either monotherapy or in combination with pembrolizumab [43] . The study involves two groups of patients, distinguished based on the underlying disease. Group A will involve patients with non-hepatocellular carcinoma (HCC) liver metastases, including melanoma. Group B will include patients with HCC. This study is currently recruiting patients and has an estimated completion date of October 25, 2022.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of NK cells in oncolytic viral therapy: a focus on hepatocellular carcinoma.","authors":"Frazer Warricker, Salim I Khakoo, Matthew D Blunt","doi":"10.20517/jtgg.2021.27","DOIUrl":"10.20517/jtgg.2021.27","url":null,"abstract":"<p><p>Natural killer (NK) cells have a key role in host anti-tumour immune responses via direct killing of tumour cells and promotion of adaptive immune responses. They are therefore attractive targets to promote the anti-tumour efficacy of oncolytic viral therapies. However, NK cells are also potent components of the host anti-viral immune response, and therefore have the potential for detrimental anti-viral responses, limiting the spread and persistence of oncolytic viruses. Oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma (HCC), a leading cause of cancer-related death with a high unmet clinical need. In this review, we highlight the role of NK cells in oncolytic virus therapy, their potential for improving treatment options for patients with HCC, and discuss current and potential strategies targeting NK cells in combination with oncolytic viral therapies.</p>","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":" ","pages":"304-322"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39712055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.","authors":"Amy Moore, Mitchell J Machiela, Moara Machado, Sophia S Wang, Eleanor Kane, Susan L Slager, Weiyin Zhou, Mary Carrington, Qing Lan, Roger L Milne, Brenda M Birmann, Hans-Olov Adami, Demetrius Albanes, Alan A Arslan, Nikolaus Becker, Yolanda Benavente, Simonetta Bisanzi, Paolo Boffetta, Paige M Bracci, Paul Brennan, Angela R Brooks-Wilson, Federico Canzian, Neil Caporaso, Jacqueline Clavel, Pierluigi Cocco, Lucia Conde, David G Cox, Wendy Cozen, Karen Curtin, Immaculata De Vivo, Silvia de Sanjose, Lenka Foretova, Susan M Gapstur, Hervè Ghesquières, Graham G Giles, Martha Glenn, Bengt Glimelius, Chi Gao, Thomas M Habermann, Henrik Hjalgrim, Rebecca D Jackson, Mark Liebow, Brian K Link, Marc Maynadie, James McKay, Mads Melbye, Lucia Miligi, Thierry J Molina, Alain Monnereau, Alexandra Nieters, Kari E North, Kenneth Offit, Alpa V Patel, Sara Piro, Vignesh Ravichandran, Elio Riboli, Gilles Salles, Richard K Severson, Christine F Skibola, Karin E Smedby, Melissa C Southey, John J Spinelli, Anthony Staines, Carolyn Stewart, Lauren R Teras, Lesley F Tinker, Ruth C Travis, Claire M Vajdic, Roel C H Vermeulen, Joseph Vijai, Elisabete Weiderpass, Stephanie Weinstein, Nicole Wong Doo, Yawei Zhang, Tongzhang Zheng, Stephen J Chanock, Nathaniel Rothman, James R Cerhan, Michael Dean, Nicola J Camp, Meredith Yeager, Sonja I Berndt","doi":"10.20517/jtgg.2021.08","DOIUrl":"10.20517/jtgg.2021.08","url":null,"abstract":"<p><strong>Aim: </strong>Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.</p><p><strong>Methods: </strong>We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.</p><p><strong>Results: </strong>We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, <i>P</i> = 1.6 × 10^-6) and FL (β = 11.4, SE = 5.82, <i>P</i> = 0.02) but not DLBCL (<i>P</i> = 1.0) or MZL (<i>P</i> = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, <i>P</i> = 2.4 × 10^-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity.</p><p><strong>Conclusion: </strong>Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.</p>","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"5 ","pages":"200-217"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10218204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward uncharted territory of cellular heterogeneity: advances and applications of single-cell RNA-seq.","authors":"Brandon Lieberman, Meena Kusi, Chia-Nung Hung, Chih-Wei Chou, Ning He, Yen-Yi Ho, Josephine A Taverna, Tim H M Huang, Chun-Liang Chen","doi":"10.20517/jtgg.2020.51","DOIUrl":"10.20517/jtgg.2020.51","url":null,"abstract":"<p><p>Among single-cell analysis technologies, single-cell RNA-seq (scRNA-seq) has been one of the front runners in technical inventions. Since its induction, scRNA-seq has been well received and undergone many fast-paced technical improvements in cDNA synthesis and amplification, processing and alignment of next generation sequencing reads, differentially expressed gene calling, cell clustering, subpopulation identification, and developmental trajectory prediction. scRNA-seq has been exponentially applied to study global transcriptional profiles in all cell types in humans and animal models, healthy or with diseases, including cancer. Accumulative novel subtypes and rare subpopulations have been discovered as potential underlying mechanisms of stochasticity, differentiation, proliferation, tumorigenesis, and aging. scRNA-seq has gradually revealed the uncharted territory of cellular heterogeneity in transcriptomes and developed novel therapeutic approaches for biomedical applications. This review of the advancement of scRNA-seq methods provides an exploratory guide of the quickly evolving technical landscape and insights of focused features and strengths in each prominent area of progress.</p>","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39255041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental and epileptic encephalopathies after negative or inconclusive genetic testing: what is next?","authors":"Á. Aledo-Serrano, R. Sánchez‐Alcudia, R. Toledano, I. García-Morales, Á. Beltrán-Corbellini, Isabel del Pino, A. Gil-Nagel","doi":"10.20517/jtgg.2021.40","DOIUrl":"https://doi.org/10.20517/jtgg.2021.40","url":null,"abstract":"The redefinition of classical electroclinical syndromes and the emergence of neurogenetics has led to a revolution in the field of developmental and epileptic encephalopathies (DEEs). In this context, advances in genetic techniques are leading to the final diagnosis of a large proportion of patients with DEE. However, up to 50% of patients with DEE remain undiagnosed. For patients with uncertain genetic etiology, there is a pressing need for the implementation of new targeted treatments and precision medicine. In some undiagnosed patients, genetic reanalysis with further in-depth or reverse phenotyping are valuable diagnostic tools to clarify new variants of uncertain significance. In other cases, the implementation of new bioinformatic algorithms is required for the update and reassessment of previously generated genetic data. Moreover, many other clinical tools have been developed for the management of patients of DEEs after a negative or inconclusive genetic testing. In this review, we highlight advances and limitations of new diagnostic strategies used in DEE patients without a known genetic etiology. Finally, we provide a wide perspective on aspects that will need further research, especially in non-Mendelian inheritance DEEs, such as those related to somatic mosaicism of the central nervous system or epigenetic and oligogenic mechanisms.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of interacting stress-related genes in lifespan regulation: insights for translating experimental findings to humans.","authors":"Anatoliy I Yashin, Deqing Wu, Konstantin Arbeev, Arseniy P Yashkin, Igor Akushevich, Olivia Bagley, Matt Duan, Svetlana Ukraintseva","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Aim: </strong>Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan.</p><p><strong>Methods: </strong>Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (<i>GCN2/EIF2AK4</i> and <i>CHOP/DDIT3</i>) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the <i>SNP-specific Interaction Polygenic Risk Score</i> (SIPRS).</p><p><strong>Results: </strong>Significant interactions have been found between SNPs from <i>GCN2/EIF2AK4</i> and <i>CHOP/DDI3T</i> genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study.</p><p><strong>Conclusion: </strong>Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.</p>","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"5 4","pages":"357-379"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39928012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duo Shared Genomic Segment analysis identifies a genome-wide significant risk locus at 18q21.33 in myeloma pedigrees.","authors":"Rosalie Griffin Waller,&nbsp;Michael J Madsen,&nbsp;John Gardner,&nbsp;Douglas W Sborov,&nbsp;Nicola J Camp","doi":"10.20517/jtgg.2021.09","DOIUrl":"10.20517/jtgg.2021.09","url":null,"abstract":"<p><strong>Aim: </strong>High-risk pedigrees (<i>HRPs</i>) are a powerful design to map highly penetrant risk genes. We previously described Shared Genomic Segment (SGS) analysis, a mapping method for single large extended pedigrees that also addresses genetic heterogeneity inherent in complex diseases. SGS identifies shared segregating chromosomal regions that may inherit in only a subset of cases. However, single large pedigrees that are individually powerful (at least 15 meioses between studied cases) are scarce. Here, we expand the SGS strategy to incorporate evidence from two extended HRPs by identifying the same segregating risk locus in both pedigrees and allowing for some relaxation in the size of each HRP.</p><p><strong>Methods: </strong>Duo-SGS is a procedure to combine single-pedigree SGS evidence. It implements statistically rigorous duo-pedigree thresholding to determine genome-wide significance levels that account for optimization across pedigree pairs. Single-pedigree SGS identifies optimal segments shared by case subsets at each locus across the genome, with nominal significance assessed empirically. Duo-SGS combines the statistical evidence for SGS segments at the same genomic location in two pedigrees using Fisher's method. One pedigree is paired with all others and the best duo-SGS evidence at each locus across the genome is established. Genome-wide significance thresholds are determined through distribution-fitting and the Theory of Large Deviations. We applied the duoSGS strategy to eleven extended, myeloma HRPs.</p><p><strong>Results: </strong>We identified one genome-wide significant region at 18q21.33 (0.85 Mb, <i>P</i> = 7.3 × 10^-9) which contains one gene, <i>CDH20</i>. Thirteen regions were genome-wide suggestive: 1q42.2, 2p16.1, 3p25.2, 5q21.3, 5q31.1, 6q16.1, 6q26, 7q11.23, 12q24.31, 13q13.3, 18p11.22, 18q22.3 and 19p13.12.</p><p><strong>Conclusion: </strong>Our results provide novel risk loci with segregating evidence from multiple HRPs and offer compelling targets and specific segment carriers to focus a future search for functional variants involved in inherited risk formyeloma.</p>","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"5 2","pages":"112-123"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39712056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}