HGG Advances最新文献

{"title":"Long-read sequencing is required for precision diagnosis of incontinentia pigmenti.","authors":"Monica H Wojcik, Robin D Clark, Abdallah F Elias, Casie A Genetti, Jill A Madden, Dana Simpson, Linda Golkar, Miranda P G Zalusky, Angela L Miller, Araceli Rodriguez, Joy Goffena, Camille A Dash, Nikhita Damaraju, Sophia B Gibson, Sophie H R Storz, Zachary B Anderson, Jonas A Gustafson, Isabelle Thiffault, Emily G Farrow, Tomi Pastinen, Jasmine Lin, Jennifer T Huang, Alan H Beggs, Pankaj B Agrawal, David T Miller, Danny E Miller","doi":"10.1016/j.xhgg.2025.100468","DOIUrl":"10.1016/j.xhgg.2025.100468","url":null,"abstract":"<p><p>Incontinentia pigmenti (IP) is caused by loss-of-function variants in IKBKG, with molecular genetic diagnosis complicated by a pseudogene. We describe seven individuals from three families with IP but negative clinical genetic testing in whom long-read sequencing identified causal variants, including one family with the common exon 4-10 deletion not identified by conventional clinical genetic testing. Concurrent methylation analysis explained disease severity in one individual who died from neurologic complications, identified a mosaic variant in an individual with an atypical presentation, and confirmed skewed X chromosome inactivation in an XXY individual.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100468"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294994","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":"A variant in RNF212B may contribute to female infertility and recurrent pregnancy loss.","authors":"Michelle E Darko, Michelle Kappy, Daniel Rabizadeh, Chaim Jalas, Eric J Forman, Paula Brady, Zev Williams","doi":"10.1016/j.xhgg.2025.100443","DOIUrl":"10.1016/j.xhgg.2025.100443","url":null,"abstract":"<p><p>Women with genetic causes of infertility are more likely to experience recurrent pregnancy loss (RPL). Advances in whole-genome sequencing (WGS) have allowed for the improved detection of such genes. One reproductively young patient with a history of RPL underwent 5 in vitro fertilization cycles with nearly complete arrest of blastocyst development and ubiquitous aneuploidy of maternal origin in arrested embryos. Here, we present the discovery of a gene variant, RNF212B, as a potential genetic cause of female infertility and RPL. DNA was extracted and submitted for WGS. After filtering out variants with Genome Aggregation Database allele frequencies exceeding 0.25%, we identified 87 unique variants and conducted a literature search to identify potential associations with infertility. PGT-A analysis of arrested embryos revealed extensive aneuploidies affecting many chromosomes in all embryos. Maternal WGS revealed a homozygous stop-gain mutation in the RNF212B gene. RNF212 has been shown to interact with proteins involved in meiotic recombination, including DMC1 and DNA repair protein RAD51. This homozygous nonsense mutation in the RNF212B gene may be responsible for the presence of aberrant oogonium and for disrupting the meiotic recombination process, thereby contributing to female infertility and RPL.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100443"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999769","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":"Targeted long-read cDNA sequencing reveals novel splice-altering pathogenic variants causing retinal dystrophies.","authors":"Dalila Capasso, Roberta Zeuli, Gavin Arno, Michael Kwint, Raoul Timmermans, Karla A Ruiz-Ceja, Marianthi Karali, Francesca Simonelli, Sabrina Signorini, Enza Maria Valente, Frans P M Cremers, Sandro Banfi, Susanne Roosing, Daan M Panneman, Suzanne E de Bruijn","doi":"10.1016/j.xhgg.2025.100442","DOIUrl":"10.1016/j.xhgg.2025.100442","url":null,"abstract":"<p><p>Splice-altering variants are suggested to be responsible for part of the missing heritability of inherited retinal diseases (IRDs). The interpretation of these variants is challenging as functional evidence is required to validate pathogenicity. We explored the diagnostic value of a targeted long-read cDNA sequencing (lrcDNA-seq) approach to investigate IRD-associated splicing defects. For each affected individual, RNA was isolated from blood, and for each candidate gene, cDNA amplicons, spanning the complete open reading frame or multiple exons, were generated and subjected to long-read sequencing. We validated our approach by assessing previously described pathogenic splice-altering variants in IRD-associated genes. Next, we investigated six genetically unexplained affected individuals, each carrying pathogenic variant(s) in NMNAT1. In two probands, we provided functional validation for previously identified variants of uncertain significance present on the second allele. In four other subjects, lrcDNA-seq revealed the partial inclusion of an SVA_F retrotransposon in the NMNAT1 mRNA, predicted to introduce a premature stop codon. We showed that targeted lrcDNA-seq is effective in characterizing splice defects and in identifying novel splice-altering variants and uncovered the IRD genetic basis for six previously unexplained subjects. We believe that the implementation of this technique has the potential to contribute to an increased diagnostic rate of IRDs.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100442"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015315","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":"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":"10.1016/j.xhgg.2025.100454","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100454"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079822","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":"The ERBB2 c.1795C>T, p.Arg599Cys variant is associated with left ventricular outflow tract obstruction defects in humans.","authors":"Minna Ampuja, Sabina Ericsson, Ilkka Paatero, Iftekhar Chowdhury, Jenna Villman, Martin Broberg, Amanda Ramste, Diego Balboa, Tiina Ojala, Jessica X Chong, Michael J Bamshad, James R Priest, Markku Varjosalo, Riikka Kivelä, Emmi Helle","doi":"10.1016/j.xhgg.2025.100446","DOIUrl":"10.1016/j.xhgg.2025.100446","url":null,"abstract":"<p><p>Non-syndromic congenital heart defects (CHDs) are occasionally familial and left ventricular outflow tract obstruction (LVOTO) defects are among the subtypes with the highest hereditability. The aim of this study was to evaluate the pathogenicity of a heterozygous ERBB2 variant c.1795C>T, p.Arg599Cys identified in three families with LVOTO defects. Variant detection was done with exome sequencing. Western blotting, digital PCR, mass spectrometry (MS), MS microscopy, and flow cytometry were used to study the function of the ERBB2 variant c.1795C>T. Cardiac structure and function were studied in zebrafish embryos expressing human ERBB2 wild type or c.1795C>T. Proband-derived human induced pluripotent stem cell cardiomyocytes (hiPS-CMs) and endothelial cells (hiPS-ECs) were used for transcriptomic analyses. While phosphorylation of the ERBB2 p.Arg599Cys receptor was not altered, the variant affected dramatically the binding partners of the protein, indicating mislocalization of the mutant ERBB2 from plasma membrane to endoplasmic reticulum. Expression of human ERBB2 p.Arg599Cys in zebrafish embryos resulted in cardiomyocyte hypertrophy, increased cardiac wall thickness, and impaired fractional shortening. Transcriptomic analyses of hiPS-ECs and hiPS-CMs from an individual with the c.1795C>T variant showed aberrant expression of genes related to cardiovascular system development and abnormal response to oxidative stress in both cell types. In conclusion, the heterozygous variant ERBB2 c.1795C>T, p.Arg599Cys leads to abnormal cellular localization of the ERBB2 receptor and induces structural changes and dysfunction in the zebrafish embryo heart. This evidence expands previous findings from animal studies to humans and suggests variants in ERBB2 may be associated with CHD.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100446"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051136","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":"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":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015229","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":"Hypertension increases PPV for polycystic kidney disease in PKD1 and PKD2 variant carriers.","authors":"Natalie Telis, Lisa McEwen, Alexandre Bolze, Joshua H Lipschutz, Leon W Sweer, Daniel P Judge, Pamala A Pawloski, Joseph J Grzymski, Catherine Hajek, Kelly M Schiabor Barrett, Nicole L Washington, Elizabeth T Cirulli","doi":"10.1016/j.xhgg.2025.100444","DOIUrl":"10.1016/j.xhgg.2025.100444","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic form of KD. Although rare causal variants in the PKD1 and PKD2 genes have been identified, their penetrance and the disease progression and outcome are known to vary, and treatment efficacy in these carriers lags compared to patients with other forms of chronic KD (CKD). To develop a population screening strategy with high sensitivity to individuals likely to develop disease, we characterize the presentation and progression of ADPKD in variant carriers, identified in a multi-center all-comers cohort, as well as the UK Biobank. We show that the positive predictive value of hypertension for future diagnosis of KD is extremely high: 74% and 66% for PKD1 and PKD2, respectively. It is also highly preemptive, with hypertension occurring an average of 11 years before a KD diagnosis. Using pre-disease time point measurements of kidney function prior to their ADPKD diagnosis, we find that PKD1 and PKD2 variant carriers show significantly decreased kidney function (EGFR) an average of 5 years before their clinical diagnosis. Unlike other CKD patients, 54% of variant carriers with hypertension meet the diagnostic threshold for CKD years prior to their disease diagnosis, and their EGFRs are statistically indistinguishable from variant carriers who have already been diagnosed. These findings suggest that a population screening strategy using a combination of targeted sequencing and routine monitoring could identify cases of ADPKD with high sensitivity and support initiating treatment years prior to the current standard of care.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100444"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027451","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":"Polygenic risk scores for prostate cancer: Comparative evaluations in UK and Australian cohorts.","authors":"Hamzeh M Tanha, Matthew H Law, Nathan Ingold, Philip Ly, Catherine M Olsen, Nirmala Pandeya, David P Smith, Robert J MacInnis, David C Whiteman, Anne E Cust, Julia Steinberg","doi":"10.1016/j.xhgg.2025.100477","DOIUrl":"10.1016/j.xhgg.2025.100477","url":null,"abstract":"<p><p>Risk-based approaches offer promise for enhancing early detection of prostate cancer. Polygenic risk scores (PGSs) have emerged as a potential approach for risk stratification, though their performance varies by population. We evaluated nine PGSs (four existing, five new) for predicting 5-year prostate cancer risk across three international population-based prospective cohorts: UK Biobank (UKB), the Australian QSkin Sun and Health Study (QSkin), and Melbourne Collaborative Cohort Study (MCCS). We analyzed UKB European-ancestry (n = 184,010), South-Asian-ancestry (n = 5,097), and African-ancestry (n = 3,193), QSkin European-ancestry (n = 6,791), and MCCS European-ancestry (n = 1,809) male participants. We estimated age-specific 5-year prostate cancer risks (from population data) and PGS-adjusted risks (age-specific risks multiplied by PGS-based relative risks). Predictive performance was assessed using discrimination (AUC) and calibration. PGS significantly enhanced 5-year risk prediction over age alone, particularly for European ancestry (AUC increase 0.05-0.12, p < 10^-6). PGS performance was consistent across European-ancestry men in Australian and UK cohorts, and by pre-baseline prostate-specific antigen tests and family history in UKB. No single PGS outperformed others across all cohorts and ancestry groups. As an illustrative example for potential risk stratification, for a leading PGS in both Australian cohorts, we estimated the population-average 5-year risk at age 50 was reached 5 years earlier by individuals with 20% highest PGS451 and 5 years later by those with 20% lowest PGS451. In conclusion, rigorous analyses with consistent results from international cohorts support the potential of PGS to improve 5-year prostate cancer risk prediction. In the future, PGS may be improved further to enhance performance in diverse populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100477"},"PeriodicalIF":3.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12304678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592482","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":"Haploinsufficient variants in SMAD5 are associated with isolated congenital heart disease.","authors":"Dimuthu Alankarage, Iryna Leshchynska, Stephanie Portelli, Alena Sipka, Gillian M Blue, Victoria O'Reilly, Debjani Das, Emma M Rath, Annabelle Enriquez, Michael Troup, Miriam Fine, Nicola Poplawski, Maxim Verlee, David T Humphreys, Richard P Harvey, Gavin Chapman, Edwin P Kirk, David S Winlaw, Bert Callewaert, Wendy K Chung, David Ascher, Eleni Giannoulatou, Sally L Dunwoodie","doi":"10.1016/j.xhgg.2025.100478","DOIUrl":"10.1016/j.xhgg.2025.100478","url":null,"abstract":"<p><p>Mothers against decapentaplegic homolog 5 (SMAD5) is a transcriptional regulator that functions within the TGF-β signaling cascade. Evidence from animal studies show that it is crucial for dorsoventral patterning, left-right asymmetry, cardiac looping, and other embryonic processes. However, its role in human development has not been explored, and the contribution of SMAD5 variants to congenital disease is unknown. Here, we report SMAD5 variants identified in six unrelated families with seven individuals presenting with congenital heart disease (CHD). Isolated congenital heart defects are observed in six individuals who carry de novo or inherited missense, nonsense, frameshift, or copy-number variants in SMAD5. A multi-organ phenotype is observed in one individual with a de novo SMAD5 variant that alters an amino acid crucial for SMAD5 multimerization. Septal defects, identified in four individuals, are the most common cardiac lesion in our cohort, with hypoplastic left heart also observed in two individuals. In silico assessment of SMAD5 missense variants predicts disrupted binding to co-factors, and in vitro functional assessment shows changes in SMAD5 gene and protein expression, as well as impaired activation of a BMP4-responsive promoter by the variants. Our findings suggest haploinsufficiency as the underlying molecular mechanism in five of the six families, resulting in isolated CHD, with a SMAD5 dominant-negative variant identified in one family leading to multiple congenital defects. Here, we provide evidence that SMAD5 variants lead to CHD and offer a basis for future exploration of SMAD5 variants in both CHD and post-natal disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100478"},"PeriodicalIF":3.6,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576482","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":"GWAS and multi-omics integrative analysis reveal novel loci and their molecular mechanisms for circulating fatty acids.","authors":"Yitang Sun, Huifang Xu, Kaixiong Ye","doi":"10.1016/j.xhgg.2025.100470","DOIUrl":"10.1016/j.xhgg.2025.100470","url":null,"abstract":"<p><p>Previous genome-wide association studies (GWAS) have identified genetic loci associated with the circulating levels of fatty acids (FAs), but the biological mechanisms of these genetic associations remain largely unexplored. Here, we conducted GWAS to identify additional genetic loci for 19 circulating FA traits in UK Biobank participants of European ancestry (n = 239,268) and five other ancestries (n = 508-4,663). We leveraged the GWAS findings to characterize genetic correlations and colocalized regions among FAs, explore sex differences, examine FA loci influenced by lipoprotein metabolism, and apply statistical fine-mapping to pinpoint putative causal variants. We integrated GWAS signals with multi-omics quantitative trait loci (QTL) to reveal intermediate molecular phenotypes mediating the associations between the genetic loci and FA levels. We identified 215 genome-wide significant, independent loci for polyunsaturated fatty acid (PUFA)-related traits in European participants, 163 loci for monounsaturated fatty acid (MUFA)-related traits, and 119 loci for saturated fatty acid (SFA)-related traits, including 70, 61, and 54 novel loci, respectively. A novel locus for total FAs, the percentage of omega-6 PUFAs in total FAs, and total MUFAs (around genes GSTT1/2/2B) colocalized with QTL signals for all six molecular phenotypes examined, including gene expression, protein abundance, DNA methylation, splicing, histone modification, and chromatin accessibility. Across 19 FA traits, 35% of GWAS loci colocalized with QTL signals for at least one molecular phenotype. Our study identifies novel genetic loci for circulating FA levels and systematically uncovers their underlying molecular mechanisms.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100470"},"PeriodicalIF":3.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369236","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}