HGG Advances最新文献

{"title":"Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies.","authors":"Jocelyn N Plowman, Evanjalina J Matoy, Lavanya V Uppala, Samantha B Draves, Cynthia J Watson, Bridget A Sefranek, Mark L Stacey, Samuel P Anderson, Michael A Belshan, Elizabeth E Blue, Chad D Huff, Yusi Fu, Holly A F Stessman","doi":"10.1016/j.xhgg.2025.100453","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100453","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100453"},"PeriodicalIF":3.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136418","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":"Multidisciplinary stakeholder-informed identification of key characteristics for implementation of workplace genetic testing.","authors":"Elizabeth Charnysh, Kunal Sanghavi, Kerry A Ryan, Alyx Vogle, Alexandra Truhlar, Subhamoy Pal, Jonathan M Reader, J Scott Roberts, Charles Lee, Anya E R Prince, W Gregory Feero","doi":"10.1016/j.xhgg.2025.100458","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100458","url":null,"abstract":"<p><p>Workplace genetic testing (wGT) is an evolving model for genetic testing where employees are offered consumer genetic testing through employer-sponsored wellness programs. However, the potential harms, benefits and key characteristics for best implementation practices for wGT have yet to be defined. To address this issue, we conducted a three-round modified Delphi process, including multiple rounds of survey and a virtual deliberative workshop, with purposely chosen wGT stakeholders [employees, employers, ethical, legal, and social implications (ELSI) professionals, genetic testing industry representatives, and healthcare professionals] to share their perspectives. From the modified Delphi process, we identified 12 key characteristics for the implementation of wGT that were perceived to increase the potential for benefit while reducing the risk of potential harms. Most participants agreed that privacy/security, voluntariness, transparency, understanding and education, anti-discrimination, employee control, and evidence-based testing measures were both important (>90%) and necessary (>75%) for the implementation of wGT. However, some participants also expressed a lack of confidence in the likelihood of achieving these characteristics in wGT programs. Overall, stakeholders expressed qualified support for wGT at the conclusion of the modified Delphi process. Their perspectives on the topic varied over the course of the process and were at least partially contingent on whether the aforementioned 12 key characteristics were met. These findings help inform the establishment of a normative framework for wGT assessment.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100458"},"PeriodicalIF":3.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136415","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":"Common genetic modifiers influence cardiomyopathy susceptibility among the carriers of rare pathogenic variants.","authors":"Samantha J Klasfeld, Katherine A Knutson, Melissa R Miller, Eric B Fauman, Joanne Berghout, Rob Moccia, Hye In Kim","doi":"10.1016/j.xhgg.2025.100460","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100460","url":null,"abstract":"<p><p>Cardiomyopathy presents a significant medical burden due to frequent hospitalizations and invasive interventions. While cardiomyopathy is considered a rare monogenic disorder caused by rare pathogenic variants in a few genes, emerging evidence suggests that common genetic modifiers influence disease penetrance and clinical variability. Quantifying the interplay between common genetic modifiers and rare pathogenic variants is challenging due to the rarity of cardiomyopathy cases and pathogenic variant carriers. In this study, we utilized large-scale genetic and phenotypic data from the UK Biobank to refine the genetic architecture of hypertrophic and dilated cardiomyopathies. Using ClinVar annotations and variant effect prediction tools, we first identified known and predicted pathogenic variants and evaluated their association with disease risk, age of diagnosis, and quantitative cardiac phenotypes that reflect disease progression. We next examined the impact of polygenic risk scores on disease in the combined sets of known and predicted pathogenic variant carriers. Indeed, the polygenic risk scores were significantly associated with increased disease risk, with rare pathogenic variant carriers in the top 20% polygenic risk having 5.7- and 2.3-times higher risk than those in the bottom 20% for hypertrophic and dilated cardiomyopathy, respectively. We observed stronger associations in the carrier sets that included predicted pathogenic variant carriers, suggesting improved statistical power. In summary, our study adds to the evidence that common genetic modifiers influence the cardiomyopathy disease risk among rare pathogenic variant carriers and illustrates the benefits and limitations of incorporating variant effect predictions to examine the polygenic influence in rare disease variant carriers.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100460"},"PeriodicalIF":3.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136412","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":"A multi-level gene-diet interaction analysis of fish oil and 14 polyunsaturated fatty acid traits identifies the FADS and GRP12 loci.","authors":"Susan Adanna Ihejirika, Alexandra Huong Chiang, Aryaman Singh, Eunice Stephen, Han Chen, Kaixiong Ye","doi":"10.1016/j.xhgg.2025.100459","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100459","url":null,"abstract":"<p><p>Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (P < 5 × 10^-8) in the FADS1-FADS2 gene cluster for total omega-3, omega-3%, docosapentaenoic acid (DHA), DHA% and the omega-6 to omega-3 ratio. Among the interaction signals for omega-3%, the lead SNP, rs35473591 (C>CT, CT allele frequency = 0.34), had a lower association effect size in the FOS-taking group (β = 0.35 for allele C) than that in the group without FOS (β = 0.42). Likewise, the effect sizes of associations between FOS and omega-3% varied across the three genotype groups (β = 0.45, 0.50, and 0.59, respectively, in C/C, C/CT, and CT/CT). Our gene-level aggregate and transcriptome-wide interaction analyses identified significant signals at two loci, around FADS1-FADS2 and GRP12. The contribution of genome-wide gene-FOS interactions to phenotypic variance was statistically significant in omega-3-related traits. This systemic gene-FOS GWIS contributes to our understanding of the genetic architecture of circulating PUFAs underlying FOS response and informs personalized dietary recommendations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100459"},"PeriodicalIF":3.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128950","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":"Mid-pass whole-genome sequencing in a Malagasy cohort uncovers body composition associations.","authors":"Iman Hamid, Séverine Nantenaina Stéphie Raveloson, Germain Jules Spiral, Soanorolalao Ravelonjanahary, Brigitte Marie Raharivololona, José Mahenina Randria, Mosa Zafimaro, Tsiorimanitra Aimée Randriambola, Rota Mamimbahiny Andriantsoa, Tojo Julio Andriamahefa, Bodonomena Fitahiana Laza Rafidison, Mehreen Mughal, Anne-Katrin Emde, Melissa Hendershott, Sarah LeBaron von Baeyer, Kaja A Wasik, Jean Freddy Ranaivoarisoa, Laura Yerges-Armstrong, Stephane E Castel, Rindra Rakotoarivony","doi":"10.1016/j.xhgg.2025.100454","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100454","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100454"},"PeriodicalIF":3.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079822","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":"Polygenic risk score prediction accuracy convergence.","authors":"Léo Henches, Jihye Kim, Zhiyu Yang, Simone Rubinacci, Gabriel Pires, Clara Albiñana, Christophe Boetto, Hanna Julienne, Arthur Frouin, Antoine Auvergne, Yuka Suzuki, Sarah Djebali, Olivier Delaneau, Andrea Ganna, Bjarni Vilhjálmsson, Florian Privé, Hugues Aschard","doi":"10.1016/j.xhgg.2025.100457","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100457","url":null,"abstract":"<p><p>Polygenic risk scores (PRSs) models trained from genome-wide association study (GWAS) results are set to play a pivotal role in biomedical research addressing multifactorial human diseases. The prospect of using these risk scores in clinical care and public health is generating both enthusiasm and controversy, with varying opinions among experts about their strengths and limitations. The performance of existing polygenic scores is still limited but is expected to improve with increasing GWAS sample sizes and the development of new, more powerful methods. Theoretically, the variance explained by PRS can be as high as the total additive genetic variance, but it is unclear how much of that variance has already been captured by PRS. Here, we conducted a retrospective analysis to assess progress in PRS prediction accuracy since the publication of the first large-scale GWASs, using data from six common human diseases with sufficient GWAS information. We show that although PRS accuracy has grown rapidly over the years, the pace of improvement from recent GWAS has decreased substantially, suggesting that merely increasing GWAS sample sizes may lead to only modest improvements in risk discrimination. We next investigated the factors influencing the maximum achievable prediction using whole-genome sequencing data from 125K UK Biobank participants and state-of-the-art modeling of polygenic outcomes. Our analyses suggest that increasing the variant coverage of PRS-using either more imputed variants or sequencing data-is a key component for future improvements in prediction accuracy.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100457"},"PeriodicalIF":3.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081085","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 phenotypic spectrum of individuals with SLC16A2 variants in MCT8 deficiency.","authors":"Kirsty McWalter, Houda Zghal Eloumi, Richard Sidlow, Ben Willis, Andrew J Bauer","doi":"10.1016/j.xhgg.2025.100455","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100455","url":null,"abstract":"<p><p>Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked condition caused by pathogenic variants in the SLC16A2 gene, resulting in dysfunctional thyroid hormone transport throughout the body. Human Phenotype Ontology (HPO) terms provide a standardized clinical vocabulary of symptomology in human disease. Here, we contribute a cohort of individuals with fully categorized SLC16A2 variants and associated HPO terms to the phenotypic spectrum of MCT8 deficiency. We queried de-identified genetic data for SLC16A2 variants mostly determined through exome sequencing. Clinical abstraction of medical records was performed to generate HPO terms. In a cohort of 122 individuals with SLC16A2 variants, we identified 68 cases with likely pathogenic/pathogenic (L/PATH) variants and 54 individuals with variants of uncertain significance (VUS). Six hundred and eleven different HPO terms were retrieved for 108 individuals with characterized SLC16A2 variants. Common HPO terms included global developmental delay (79/108, 73.1%), generalized hypotonia (40/108, 37.0%), and delayed speech and language development (29/108, 26.9%). Some HPO terms associated with a severe MCT8 deficiency phenotype, such as failure to thrive, feeding difficulties, and delayed myelination, were more common in individuals with L/PATH variants than in those with VUS. HPO terms related to thyroid function and/or hormone levels were not commonly reported, with hypothyroidism the most frequently reported term, seen in six individuals. This study highlights the utility of comprehensive genetic testing and standardized clinical vocabulary in diagnosing rare genetic conditions. In MCT8 deficiency, this approach can help characterize genotype-phenotype correlations, expedite concurrent thyroid hormone testing, and improve patient and caregiver support.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100455"},"PeriodicalIF":3.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081091","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":"Interaction between genetic risk and comorbid conditions in endometriosis.","authors":"Isabelle M McGrath, Valentina Rukins, Triin Laisk, Sally Mortlock, Grant W Montgomery","doi":"10.1016/j.xhgg.2025.100456","DOIUrl":"10.1016/j.xhgg.2025.100456","url":null,"abstract":"<p><p>Endometriosis is a complex disease, and many genetic and environmental risk factors contribute to disease risk. The genetic risk of endometriosis has been well characterized in genome-wide association studies. While few physiological risk factors are known, endometriosis is associated with many comorbid disorders. This study examines the interplay between genetic risk factors, comorbid disorders, and endometriosis. Genetic and health record data from the UK Biobank (5,432 cases; 92,344 controls) and Estonian Biobank (3,824 cases; 15,296 controls) was used to estimate the correlation between comorbidity burden, endometriosis and genetic risk, and to estimate the interactive effects between endometriosis polygenic risk score (PRS) and diagnosis of prevalent comorbidities (uterine fibroids, heavy menstrual bleeding, dysmenorrhea, irritable bowel syndrome, diverticular disease, and asthma) on endometriosis prevalence. The comorbidity burden was significantly higher in endometriosis cases and was positively correlated with endometriosis PRS in women without endometriosis but negatively correlated in women with endometriosis. The absolute increase in endometriosis prevalence conveyed by the presence of several comorbidities (uterine fibroids, heavy menstrual bleeding, dysmenorrhea) was greater in individuals with a high endometriosis PRS compared to a low endometriosis PRS. These findings, consistent across two biobanks, highlight significant interactions between polygenic risk for endometriosis and the diagnosed comorbidities in endometriosis susceptibility that have implications for understanding the underlying mechanisms contributing to disease risk.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100456"},"PeriodicalIF":3.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081082","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":"Pathogenic PPP2R5D variants disrupt neuronal development and neurite outgrowth in patient-derived neurons that are reversed by allele-specific knockdown.","authors":"Randee E Young, Michael V Zuccaro, Charles A LeDuc, Noelle D Germain, Tae Hyun Kim, Patrick Sarmiere, Wendy K Chung","doi":"10.1016/j.xhgg.2025.100450","DOIUrl":"10.1016/j.xhgg.2025.100450","url":null,"abstract":"<p><p>A significant barrier to the treatment of neurodevelopmental disorders (NDDs) is a limited understanding of disease mechanisms. Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease. This study investigated the impact of pathogenic PPP2R5D variants on neuronal development and evaluated allele-specific knockdown as a potential therapeutic strategy. Induced pluripotent stem cells derived from individuals carrying the E198K and E420K variants, along with CRISPR-corrected isogenic controls, were differentiated into neural progenitors and cortical glutamatergic neurons. Patient-derived neural progenitors were hyper-proliferative, and glutamatergic neurons differentiated from these cells exhibited increased neurite outgrowth. Notably, neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function. RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient lines compared to their isogenic controls revealed disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance. To target pathogenic transcripts, antisense oligonucleotides (ASOs) were designed to selectively knock down the E198K allele, the most common disease-causing missense variant. The most effective ASOs reversed neurite outgrowth defects in patient-derived neurons. These findings uncover molecular mechanisms underlying PPP2R5D-related NDDs and support allele-specific knockdown as a potential therapeutic approach.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100450"},"PeriodicalIF":3.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017271","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":"Genetic ancestry influences gene-environment interactions with sociocultural factors: Results from the Hispanic Community Health Study/Study of Latinos.","authors":"Jayati Sharma, Cristin E McArdle, Mariaelisa Graff, Christina Cordero, Martha Daviglus, Linda C Gallo, Carmen R Isasi, Tanika N Kelly, Krista M Perreira, Gregory A Talavera, Jianwen Cai, Kari E North, Lindsay Fernández-Rhodes, Genevieve L Wojcik","doi":"10.1016/j.xhgg.2025.100451","DOIUrl":"10.1016/j.xhgg.2025.100451","url":null,"abstract":"<p><p>Often, studies will aggregate all participants identified as Hispanic/Latino, despite genetic and environmental substructures, preventing the meaningful interrogation of the roles of genetics and environment in human health. Using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we examined how self-identified background group and genetic ancestry influence gene-environment interactions between body mass index (BMI) and a polygenic score for BMI (PGS_BMI). Participants (n = 7,075) identified with six background groups: Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American. Generalized linear models incorporating complex survey weighting were used to model BMI through joint and stratified (background group, estimated Amerindigenous [AME] ancestry) analyses including PGS_BMI and other health-related variables. Interaction effects were modeled between PGS_BMI and diet and age at immigration. Comparing pooled to background group-stratified analyses, we observe heterogeneous distributions of environmental and sociocultural variables, as well as differing associations with AME ancestry. Within the multivariate model, PGS_BMI performance decreased with increasing AME ancestry. After stratification, PGS-age-at-immigration interactions remained statistically significant in some strata: Mexican background individuals born in the US (50 states/DC) (β = 1.33, p < 0.01), Dominican background individuals 6-12 years old (β = 4.38, p < 0.001), and Cuban background individuals 0-5 years old (β = 2.20, p = 0.015) relative to those ≥ 21 years old at migration. It is vital to understand populations of interest to model them appropriately and prevent possible confounding or misinterpretation. While this work focuses specifically on Hispanic/Latino groups, these lessons are relevant to other groups as we diversify work to better understand gene-environment interactions.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100451"},"PeriodicalIF":3.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015229","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}