HGG Advances最新文献

{"title":"Cardiovascular disease-associated non-coding variants disrupt GATA4-DNA binding and regulatory functions.","authors":"Edwin G Peña-Martínez, Jean L Messon-Bird, Jessica M Rodríguez-Ríos, Rosalba Velázquez-Roig, Diego A Pomales-Matos, Alejandro Rivera-Madera, Leandro Sanabria-Alberto, Adriana C Barreiro-Rosario, Juan A Figueroa-Rosado, Jeancarlos Rivera-Del Valle, Nicole E Muñoz-Páez, Esther A Peterson-Peguero, José A Rodríguez-Martínez","doi":"10.1016/j.xhgg.2025.100415","DOIUrl":"10.1016/j.xhgg.2025.100415","url":null,"abstract":"<p><p>Genome-wide association studies have identified thousands of cardiovascular disease (CVD)-associated variants, with over 90% of them being mapped within the non-coding genome. Non-coding variants in regulatory regions of the genome, such as promoters, enhancers, silencers, and insulators, can alter the function of tissue-specific transcription factors (TFs) and their gene regulatory function. In this work, we used a computational approach to identify and test CVD-associated single-nucleotide polymorphisms (SNPs) that alter the DNA binding of the human cardiac transcription factor GATA4. Using a gapped k-mer support vector machine (GKM SVM) model, we scored CVD-associated SNPs localized in gene regulatory elements in expression quantitative trait loci (eQTL) detected in cardiac tissue to identify variants altering GATA4-DNA binding. We prioritized four variants that resulted in a total loss of GATA4 binding (rs1506537 and rs56992000) or the creation of new GATA4 binding sites (rs2941506 and rs2301249). The identified variants also resulted in significant changes in transcriptional activity proportional to the altered DNA-binding affinities. In summary, we present a comprehensive analysis comprising in silico, in vitro, and cellular evaluation of CVD-associated SNPs predicted to alter GATA4 function.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100415"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411081","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":"Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL.","authors":"Elizabeth Carbonell, Sarah L Stenton, Vijay S Ganesh, Jialan Ma, Grace E VanNoy, Lynn Pais, John N Gaitanis, Melanie C O'Leary, Heidi L Rehm, Anne O'Donnell-Luria","doi":"10.1016/j.xhgg.2025.100419","DOIUrl":"10.1016/j.xhgg.2025.100419","url":null,"abstract":"<p><p>Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100419"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477101","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 chromosomal challenge of human embryos: Mechanisms and fundamentals.","authors":"Anna Ivanova, Elena Korchivaia, Maria Semenova, Igor Lebedev, Ilya Mazunin, Ilya Volodyaev","doi":"10.1016/j.xhgg.2025.100437","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100437","url":null,"abstract":"<p><p>Chromosomal abnormalities in human pre-implantation embryos, originating from either meiotic or mitotic errors, present a significant challenge in reproductive biology. Complete aneuploidy is primarily linked to errors during the resumption of meiosis in oocyte maturation, which increase with maternal age, while mosaic aneuploidies result from mitotic errors after fertilization. The biological causes of these abnormalities are increasingly becoming a topic of interest for research groups and clinical specialists. This review explores the intricate processes of meiotic and early mitotic divisions in embryos, shedding light on the mechanisms that lead to changes in chromosome number in daughter cells. Key factors in meiotic division include difficulties in spindle assembly without centrosomes, kinetochore (KT) orientation disturbances, and inefficient cell-cycle checkpoints. The weakening of cohesion molecules that bind chromosomes, exacerbated by maternal aging, further complicates chromosomal segregation. Mitotic errors in early development are influenced by defects in sperm centrosomes, KT misalignment, and the gradual depletion of maternal regulatory factors. Coupled with the inactive or partially active embryonic genome, this depletion increases the likelihood of chromosomal aberrations. While various theoretical mechanisms for these abnormalities exist, current data remain insufficient to determine their exact contributions. Continued research is essential to unravel these complex processes and improve outcomes in assisted reproductive technologies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100437"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019109","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":"Revisiting variation in the somatic mutation landscape of non-small cell lung cancer.","authors":"Vaibhavi Pathak, Koichi Tazaki, Minal Çalışkan","doi":"10.1016/j.xhgg.2025.100420","DOIUrl":"10.1016/j.xhgg.2025.100420","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is driven by a diverse array of somatic mutations. The vast majority of literature on NSCLC is based on targeted assays or small sample sizes, limiting the ability to provide a comprehensive view of NSCLC mutation profiles. Here, we analyzed genome-wide screen data (including whole genome sequencing and whole exome sequencing) from 1,874 NSCLC subjects to identify molecular subtypes and putative driver genes and to explore the effect of intrinsic and extrinsic factors on somatic mutation profiles. We showed that genome-wide screen data support existing knowledge, such as the TP53:KRAS mutation co-occurrence pattern as a key distinctive feature, but do not reveal additional broad molecular subtypes. In contrast, we demonstrated that low-frequency molecular subtypes or potential driver genes continue to be identified. Using driver gene identification algorithms, we found 50 potential driver genes including ANG, CDK10, CTDSP2, HOXA5, RBP4, and SPHK2, which show evidence of positive selection in NSCLC. Finally, we provided insights into the intrinsic and extrinsic covariates associated with the NSCLC somatic mutation landscape, while confirming associations with ethnicity (TP53 and EGFR), NSCLC subtype (14 genes including KRAS, NFE2L2, and STK11), and smoking history (KRAS, CSMD3, and TP53), we dismissed gene-level associations with sex when other covariates are controlled for. The results presented here represent a concise up-to-date summary of variation in the somatic mutation landscape and carry importance for NSCLC geneticists, medical practitioners, and drug discovery scientists.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100420"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143504490","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":"Multifaceted analysis of noncoding and coding de novo variants implicates NOTCH signaling pathway in tetralogy of Fallot in Chinese population.","authors":"Qiongfen Lin, Detao Zhang, Peter J Gruber, Paul Kwong-Hang Tam, Vincent Chi-Hang Lui, Zhongluan Wu, Haifa Hong, Kenneth R Chien, Pak Chung Sham, Clara Sze-Man Tang","doi":"10.1016/j.xhgg.2025.100414","DOIUrl":"10.1016/j.xhgg.2025.100414","url":null,"abstract":"<p><p>Tetralogy of Fallot (TOF) is the most common cyanotic heart defect in neonates. While there is compelling evidence of genetic contribution to the etiology of TOF, the contribution of noncoding variants to the development of the defect remains unexplored. Potentially damaging noncoding de novo variants (NC DNVs) were detected from 141 Chinese nonsyndromic TOF trios (CHN-TOF) and compared with those detected in the Pediatric Cardiac Genomics Consortium (PCGC). Bioinformatic analyses on noncoding and previously detected coding DNVs were performed to identify developmental pathways affected in TOF. Chinese but not PCGC-TOF patients showed a notably increased burden of putative damaging NC DNVs (n = 249). In Chinese, NC and coding DNVs were predominantly associated with cardiomyocyte differentiation and with chamber/valve/aorta development, respectively, producing a combined enrichment in NOTCH signaling (p = 1.1 × 10^-6) and outflow tract morphogenesis (p = 2.2 × 10^-5). Genes with NC DNVs (e.g., EFNB2, HEY2, and PITX2) interacted with NOTCH1 and FLT4 in a tight STRING protein-protein interaction (PPI) network. During the in vitro cardiac differentiation process, these noncoding candidate genes, which harbored potentially damaging regulatory NC DNVs, exhibited co-expression with NOTCH signaling genes and demonstrated dysregulated gene expression at various differentiation stages following NOTCH1 downregulation. In summary, our findings highlight a significant contribution of NC DNVs to TOF and suggest the presence of population genetic heterogeneity. Integrative analyses implicate dysregulation of NOTCH signaling, with converging influences from both coding and noncoding variants, in TOF within the Chinese population.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100414"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374823","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":"Trans-ancestry genome-wide association study of childhood body mass index identifies novel loci and age-specific effects.","authors":"Carolina G Downie, Poojan Shrestha, Samson Okello, Mohammad Yaser, Harold H Lee, Yujie Wang, Mohanraj Krishnan, Hung-Hsin Chen, Anne E Justice, Geetha Chittoor, Navya Shilpa Josyula, Sheila Gahagan, Estela Blanco, Raquel Burrows, Paulina Correa-Burrows, Cecilia Albala, José L Santos, Bárbara Angel, Betsy Lozoff, Fernando Pires Hartwig, Bernardo Horta, Karisa Roxo Brina, Carmen R Isasi, Qibin Qi, Linda C Gallo, Krista M Perreira, Bharat Thyagarajan, Martha Daviglus, Linda Van Horn, Franklyn Gonzalez, Jonathan P Bradfield, Hakon Hakonarson, Struan F A Grant, Jennifer E Below, Janine Felix, Mariaelisa Graff, Kimon Divaris, Kari E North","doi":"10.1016/j.xhgg.2025.100411","DOIUrl":"10.1016/j.xhgg.2025.100411","url":null,"abstract":"<p><p>Over the past 30 years, obesity prevalence has markedly increased globally, including among children. Although genome-wide association studies (GWASs) have identified over 1,000 genetic loci associated with obesity-related traits in adults, the genetic architecture of childhood obesity is less well characterized. Moreover, most childhood obesity GWASs have been restricted to severely obese children, in relatively small sample sizes, and in primarily European-ancestry populations. To identify genetic loci associated with early-childhood body mass index (BMI), we performed GWAS of BMI Z scores in eight ancestrally diverse cohorts: ZOE 2.0 cohort, the Santiago Longitudinal Study (SLS), the Vanderbilt University BioVU biobank, the Geisinger MyCode Health Initiative biobank, Study of Latino (SOL) Youth, Pelotas (Brazil) Birth Cohort, Cameron County Hispanic Cohort (CCHC), and Viva La Familia cohort. We subsequently performed inverse-variance-weighted fixed-effect meta-analysis of these results with previously published GWAS summary statistics of BMI Z scores of children in the Early Growth Genetics (EGG) Consortium and the Norwegian Mother and Child Cohort (MoBa), constituting a final total of 84,804 individuals. We identified 39 genome-wide significant loci associated with childhood BMI, including three putatively novel loci (EFNA5 and DTWD2, RP11-2N5.1 on chromosome 5, and LSM14A on chromosome 19). We also observed a dynamic nature of genetic loci-BMI associations across the life course, with distinct effects across childhood and adulthood, highlighting possible critical periods for early-childhood interventions. These findings strengthen calls for larger population-based studies of children across age strata and across diverse populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100411"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068459","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":"Context-specific eQTLs provide deeper insight into causal genes underlying shared genetic architecture of COVID-19 and idiopathic pulmonary fibrosis.","authors":"Trisha Dalapati, Liuyang Wang, Angela G Jones, Jonathan Cardwell, Iain R Konigsberg, Yohan Bossé, Don D Sin, Wim Timens, Ke Hao, Ivana Yang, Dennis C Ko","doi":"10.1016/j.xhgg.2025.100410","DOIUrl":"10.1016/j.xhgg.2025.100410","url":null,"abstract":"<p><p>Most genetic variants identified through genome-wide association studies (GWASs) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). Therefore, it is hypothesized but largely untested that integration of disease GWAS with context-specific eQTLs will reveal the underlying genes driving disease associations. We used colocalization and transcriptomic analyses to identify shared genetic variants and likely causal genes associated with critically ill COVID-19 and idiopathic pulmonary fibrosis. We first identified five genome-wide significant variants associated with both diseases. Four of the variants did not demonstrate clear colocalization between GWAS and healthy lung eQTL signals. Instead, two of the four variants colocalized only in cell type- and disease-specific eQTL datasets. These analyses pointed to higher ATP11A expression from the C allele of rs12585036, in monocytes and in lung tissue from primarily smokers, which increased risk of idiopathic pulmonary fibrosis (IPF) and decreased risk of critically ill COVID-19. We also found lower DPP9 expression (and higher methylation at a specific CpG) from the G allele of rs12610495, acting in fibroblasts and in IPF lungs, and increased risk of IPF and critically ill COVID-19. We further found differential expression of the identified causal genes in diseased lungs when compared to non-diseased lungs, specifically in epithelial and immune cell types. These findings highlight the power of integrating GWASs, context-specific eQTLs, and transcriptomics of diseased tissue to harness human genetic variation to identify causal genes and where they function during multiple diseases.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100410"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060892","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":"Using genetics, genomics, and transcriptomics to identify therapeutic targets in juvenile idiopathic arthritis.","authors":"Evan Tarbell, James N Jarvis","doi":"10.1016/j.xhgg.2025.100424","DOIUrl":"10.1016/j.xhgg.2025.100424","url":null,"abstract":"<p><p>Despite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who have had JIA continue to have active disease and have developed functional limitations. Medication side effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA (when compared to healthy control subjects). Of the 28 candidates, the strongest new target to emerge was homeodomain-interacting protein kinase 1 (HIPK1), which suppresses T cell activation and is within the PTPN22 locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls, and PML, a known coregulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100424"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11994403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626245","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":"Advancing genetic services in African healthcare: Challenges, opportunities, and strategic insights from a scoping review.","authors":"Karen Kengne Kamga, Pallissa Fonkam Marlyse, Seraphin Nguefack, Ambroise Wonkam","doi":"10.1016/j.xhgg.2025.100439","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100439","url":null,"abstract":"<p><p>The implementation of genetic medicine services in African healthcare systems is a complex process that presents both challenges and opportunities. The primary objective of this study was to provide evidence-based recommendations to policymakers and healthcare organizations to help ensure the successful integration of genetic services into African healthcare systems. To achieve this goal, we conducted a scoping review of peer-reviewed studies published between 2003 and 2023. The studies were sourced from PubMed, Scopus, and Africa-wide information databases. We based their findings on eight relevant research studies conducted between 2016 and 2023, covering a wide range of genetic topics in six African countries, including Cameroon, Kenya, Nigeria, Rwanda, South Africa, and Tanzania. The studies identified several challenges associated with the implementation of genetic services in African healthcare systems. These challenges include a lack of awareness and education about genetic diseases, barriers to genetic testing, resource limitations, ethical dilemmas, and challenges in follow-up and retention. However, the authors also highlighted opportunities and strategies for successful implementation, emphasizing preventive measures through community engagement, advocacy, and supportive networks. Apart from the potential to improve healthcare outcomes, implementing genetic services in Africa presents opportunities and challenges for healthcare and biotech companies. To address gaps in disease awareness, we recommend that healthcare providers should invest in education, collaborate with local institutions, and utilize digital platforms. Furthermore, businesses should explore innovative, cost-effective genetic testing models and create dialog platforms like online forums to positively impact African health care.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100439"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054259","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":"Pitfalls in performing genome-wide association studies on ratio traits.","authors":"Zachary R McCaw, Rounak Dey, Hari Somineni, David Amar, Sumit Mukherjee, Kaitlin Sandor, Theofanis Karaletsos, Daphne Koller, Hugues Aschard, George Davey Smith, Daniel MacArthur, Colm O'Dushlaine, Thomas W Soare","doi":"10.1016/j.xhgg.2025.100406","DOIUrl":"10.1016/j.xhgg.2025.100406","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) are often performed on ratios composed of a numerator trait divided by a denominator trait. Examples include body mass index (BMI) and the waist-to-hip ratio, among many others. Explicitly or implicitly, the goal of forming the ratio is typically to adjust for an association between the numerator and denominator. While forming ratios may be clinically expedient, there are several important issues with performing GWAS on ratios. Forming a ratio does not \"adjust\" for the denominator in the sense of conditioning on it, and it is unclear whether associations with ratios are attributable to the numerator, the denominator, or both. Here we demonstrate that associations arising in ratio GWAS can be entirely denominator driven, implying that at least some associations uncovered by ratio GWAS may be due solely to a putative adjustment variable. In a survey of 10 common ratio traits, we find that the ratio model disagrees with the adjusted model (performing GWAS on the numerator while conditioning on the denominator) at around 1/3 of loci. Using BMI as an example, we show that variants detected by only the ratio model are more strongly associated with the denominator (height), while variants detected by only the adjusted model are more strongly associated with the numerator (weight). Although the adjusted model provides effect sizes with a clearer interpretation, it is susceptible to collider bias. We propose and validate a simple method of correcting for the genetic component of collider bias via leave-one-chromosome-out polygenic scoring.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100406"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012953","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}