HGG Advances最新文献

{"title":"A personalized genomic-medicine approach to rare genomic disorders associated with simple chromosomal structural variants.","authors":"Dezső David, Joana Fino, Márcia Rodrigues, Sofia S Nunes, Rui Gonçalves, João Parente Freixo, Oana Moldovan, Inês Carvalho, Natália Oliva-Teles, Ana Rita Soares, Irén Haltrich, Mingyang Yu, Zirui Dong, Margarida Venâncio, Cynthia C Morton","doi":"10.1016/j.xhgg.2026.100649","DOIUrl":"10.1016/j.xhgg.2026.100649","url":null,"abstract":"<p><p>Chromosomal structural-variant (CSV)-associated conditions, or genomic disorders (GDs), remain a diagnostic challenge. Our cohort included 26 individuals with severe unselected phenotypes associated with simple CSVs, as well as two clinically unaffected individuals. Long-insert short-read (LI-SR) and short-insert whole-genome sequencing (SI-WGS) were applied to capture the full spectrum of structural and small sequence variants, complemented by whole-blood transcriptome profiling in 12 individuals. Genome-wide, pathway-stratified, and candidate gene-based phenotype-overlap analyses, together with pathway enrichment analysis, were performed to define the spectrum of pathogenic variants and underlying molecular mechanisms, thereby enabling comprehensive phenotype-genotype correlations and to assess the diagnostic yield and suitability of the applied WGS technologies within a genome-first personalized genomic-medicine (PGM) framework. Among disease-causing genes, eight were affected by gene disruption or position effects leading to autosomal dominant (AD) neurodevelopmental GDs, six were identified in individuals with benign simple CSVs with AD conditions caused by small sequence variants, and one case was attributed to a digenic combination of distinct variant types. Candidate disease-associated genes included FLT1 (RASopathies), SSBP3 (chromatinopathies), the ARL14EP-DT/FSHB locus, and position-effect-affected genes ZC4H2 and EDA2R, supported by phenotypic, transcriptomic, and pathway enrichment data. This integrative PGM approach-combining WGS, transcriptomic profiling providing orthogonal functional evidence, and detailed phenotyping-improves diagnostic yield, shortens the diagnostic odyssey, facilitates functional genome annotation, and enables the identification of previously unreported disease associations. These findings support SI-WGS as a first-tier diagnostic strategy for SV-associated conditions and highlight its potential utility in prenatal diagnosis and personalized medicine.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100649"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148399546","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":"Psychometric validation of the education and assessment of genetic literacy or the EAGL measure.","authors":"Lily S Barna, Yi Liao, Michael R Wierzbicki, Gabriela M Ramírez-Renta, Kimberly A Kaphingst, Chris Gunter","doi":"10.1016/j.xhgg.2026.100651","DOIUrl":"10.1016/j.xhgg.2026.100651","url":null,"abstract":"<p><p>Genetic literacy is an integral measure for examining society's interaction with genetics, but widely used \"genetic literacy\" measures lack both knowledge comprehension measures and psychometric validation. To address these issues, we validated the education and assessment of genetic literacy (EAGL) measure in 2,708 US English-speaking general public participants, using both exploratory and confirmatory factor analysis. In addition to standard subjective and objective knowledge subscales, our measure's distinct knowledge comprehension subscale focuses on autism as an example of a complex condition. Regression analyses showed a statistically significant interaction when looking at education and personal connection to autism in relation to knowledge comprehension (F = 3.68, p = 0.003). Separately, those in our sample with a connection to autism scored higher only on the subjective knowledge section (F = 19.52, p < 0.001), concurring with previous demonstrations of a subjective-objective knowledge gap in science literacy. We then explored geographic location as one potential factor in genetic literacy and found that, contrary to expectations, metropolitan vs. non-metropolitan status had no significant main effects on literacy levels. After the validation process, we have two multi-domain measures that accurately capture the construct of genetic literacy and are available for wide use: the 46-question EAGL-long, which has previously been tested with thousands of participants, and the validated 17-question EAGL-short. The instruments will allow researchers to accurately gauge the complex genetic literacy levels of any population they wish to survey, helping to create more targeted and productive genetic communication interventions and educational materials.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100651"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13396853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413319","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":"Sources of distrust in precision medicine research: Findings from a focus group study with adults with disabilities.","authors":"Katharine Peglow, Alejandra N Aguirre, Magdalena Eitenberger, Sandra Soo-Jin Lee, Shawneequa Callier, Paul Spicer, Howard A Rosenblum, Maya Sabatello","doi":"10.1016/j.xhgg.2026.100661","DOIUrl":"10.1016/j.xhgg.2026.100661","url":null,"abstract":"<p><p>People with disabilities comprise a large population in the US and experience significant health disparities. Their inclusion in precision medicine research (PMR) has clinical, public, and social justifications and is crucial for them to benefit from the scientific advancements of PMR. Yet, research indicates that adults with disabilities are underrepresented in general (non-disability-specific) PMR and that distrust may affect participation decisions. However, the sources of distrust in PMR among adults with disabilities are understudied, a first necessary step toward gaining trust. We report findings from 21 focus groups that explored the sources of trust and distrust in PMR among US-based adults self-reporting as being blind/low-vision, deaf/hard of hearing (HoH), or with mobility disabilities. Data analysis revealed six key sources of distrust in PMR: (1) negative interactions with clinical staff, (2) healthcare system barriers, (3) negative societal attitudes, (4) discriminatory behaviors in daily life, (5) group harm, and (6) (in)accessibility. We identified a strong spillover effect from experiences in clinical care, the broader healthcare system, and daily life settings to PMR and found that the sources of distrust were often intertwined. Our analysis also found differences by disability subgroups and that disability experiences intersect with other forms of marginalization to affect trust in PMR. We contextualize our findings in light of the literature on disability studies and the ethical discourse on civic responsibility for research participation, highlight key issues that could inform efforts to build trust, and point to possible future research.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100661"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13571127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798834","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":"Inherited predisposition to increased systemic inflammation predicts a broad class of disease phenotypes.","authors":"Harkeran K Jandu, Ayokunle Olowofela, Megan Shuey, Kali Quade, Bjoernar Tuftin, Laura M Raffield, Yun Li, Nancy Cox, Paul L Auer, Sarah L Kerns","doi":"10.1016/j.xhgg.2026.100671","DOIUrl":"10.1016/j.xhgg.2026.100671","url":null,"abstract":"<p><p>Chronic, low-grade systemic inflammation is a polygenic trait captured with the INFLA-score, a composite of C-reactive protein, platelet count, leukocyte count, and granulocyte-to-lymphocyte ratio. We derived a polygenic risk score from the INFLA-score (iPRS) in a multi-ancestry population from the UK Biobank (n = 421,368), then evaluated and used it in a phenome-wide association study among participants in the All of Us (AoU) Research Program. The multi-ancestry iPRS was tested for association with the INFLA-score in AoU (n = 4,833 with biomarker data) via linear regression, adjusting for age, sex, and genetically determined principal components (PCs), and with 2,821 phecodeX-defined phenotypes in AoU (n = 265,068) via logistic regression, adjusting for sex, age, electronic health record (EHR) length, race, ethnicity, and PCs. The iPRS predicted the INFLA-score (R² = 0.026, beta = 0.980, p < 2 × 10^-16) and was associated with 47 phenotypes (Bonferroni-corrected p < 0.05). The strongest associations were with blood-related phenotypes: elevated white blood cell count (odds ratio [OR] = 1.19, p = 3.85 × 10^-66), thrombocytopenia (OR = 0.86, p = 5.70 × 10^-44), platelet defects (OR = 0.86, p = 2.47 × 10^-43), neutropenia (OR = 0.86, p = 5.52 × 10^-18), and myeloproliferative disorder (OR = 1.2, p = 2.77 × 10^-15). Others included celiac disease (OR = 0.713, p = 2.98 × 10^-46), ankylosing spondylitis (OR = 1.4, p = 1.33 × 10^-17), hypertension (OR = 1.04, p = 4.56 × 10^-15), rheumatoid arthritis (OR = 1.09, p = 1.02 × 10^-13), and hematuria (OR = 1.05, p = 1.96 × 10^-10). Removing major histocompatibility complex SNPs abolished associations with known autoimmune diseases, while all other associations remained. We replicated 17 (42.5%) of 40 significant phenotypes available in the Vanderbilt University Medical Center's BioVU. Our findings demonstrate that systemic inflammation can be predicted using the iPRS across multiple ancestries, and the iPRS is associated with numerous clinical endpoints. This multi-ancestry iPRS may have future utility in stratifying risk for inflammation-driven conditions across diverse populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100671"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892638","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":"Cyclin C nuclear release and mitochondrial dysfunction define molecular signatures of MED13L syndrome.","authors":"Alicia N Campbell, Kendall N Jung, Steven J Doyle, Ekaterina Lebayle, Barbara Corneo, Joanna Feng, Christopher L Ricupero, Jennifer M Bain, Randy Strich","doi":"10.1016/j.xhgg.2026.100670","DOIUrl":"10.1016/j.xhgg.2026.100670","url":null,"abstract":"<p><p>The mediator kinase module (MKM) coordinates transcriptional programs regulating cellular metabolism, stress responses, and differentiation. Heterozygous variants of MED13L, a core MKM component, cause a neurodevelopmental disorder characterized by variable intellectual disability, developmental delay, hypotonia and motor impairment, and congenital anomalies. However, the molecular basis underlying this clinical heterogeneity is poorly defined. Previously, we identified mitochondrial dysfunction and aberrant nuclear release of another MKM component, cyclin C (CCNC), in a single fibroblast line derived from an individual with MED13L syndrome. Here, we expand these studies across 12 fibroblast lines derived from individuals with 11 distinct MED13L variants. We identify mitochondrial dysfunction as a consistent feature of MED13L variation, characterized by reduced mitochondrial ATP production, decreased mitochondrial DNA abundance, elevated reactive oxygen species, and impaired transcription of genes involved in mitochondrial biogenesis. In parallel, all variant lines exhibit aberrant cytoplasmic CCNC localization, consistent with its established role in mitochondrial fission. Longitudinal analyses further reveal progressive declines in mitochondrial function along with markers associated with premature cellular aging. Importantly, the severity of mitochondrial dysfunction shows an association with variant position within MED13L and with clinical functional measures, suggesting that mutation location may partially predict disease severity. Together, these findings establish mitochondrial dysfunction as a consistent cellular feature of MED13L heterozygosity and identify CCNC mislocalization as a candidate biomarker of MKM disruption. More broadly, this work reveals an intersection between transcriptional control and mitochondrial homeostasis in MED13L syndrome, forming the framework for biomarker-driven therapeutic development in MED13L-associated and related neurodevelopmental disorders.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100670"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892562","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":"Variant harmonization critically determines polygenic score transferability for lipid traits in Samoan populations.","authors":"Toni-Ann J Yapp, Mohanraj Krishnan, Shuwei Liu, Samantha L Manna, Hong Cheng, Take Naseri, Muagututuʻa Sefuiva Reupena, Satupaʻitea Viali, John Tuitele, Ranjan Deka, Nicola L Hawley, Stephen T McGarvey, Daniel E Weeks, Ryan L Minster, Jenna C Carlson","doi":"10.1016/j.xhgg.2026.100663","DOIUrl":"10.1016/j.xhgg.2026.100663","url":null,"abstract":"<p><p>Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa. Polygenic scores (PGSs) for lipid traits offer promise for improved CVD risk prediction; however, their performance in Pacific Islander populations-comprising only 0.002% of genome-wide association study (GWAS) participants as of 2024-remains unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TGs), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990-2010. PGSs from Graham et al. and Kanoni et al. multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel, and performance was assessed via incremental R² from linear mixed models with bootstrapped confidence intervals. HDL-C showed the highest performance (incremental R² 5.0%-15.0%), followed by TC (5.0%-10.7%), LDL-C (5.7%-8.6%), and TG (3.5%-7.0%). Critically, meaningful LDL-C performance was achieved only with the genome-wide PRS-CS score (99.6%-99.7% variant matching), while a curated pruning-and-thresholding score achieved ∼9% matching and near-zero performance. These findings establish systematic lipid PGS benchmarks in Samoans, demonstrating meaningful transferability when genome-wide variant coverage is ensured, and highlight variant harmonization as a critical precondition for PGS deployment in underrepresented populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100663"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798880","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":"Gene-environment interactions contribute to blood pressure variation across global populations.","authors":"Khushi Goda, Noah Klimkowski Arango, Francesco Tiezzi, Trudy F C Mackay, Fabio Morgante","doi":"10.1016/j.xhgg.2026.100656","DOIUrl":"10.1016/j.xhgg.2026.100656","url":null,"abstract":"<p><p>Understanding the interplay between genetics and environment is essential for elucidating the biological basis of complex traits such as blood pressure (BP). Although gene-environment interactions (G×E) contribute to BP variation, their role in multi-ancestry cohorts remains underexplored. We hypothesize that G×E may explain additional variance in BP across diverse populations, where environmental exposures and genetic backgrounds are more heterogeneous. Here, we evaluate the importance of G×E on diastolic pressure (DP), systolic pressure (SP), and pulse pressure (PP) in a multi-ethnic subset of 24,000 UK Biobank individuals. We considered 23 lifestyle variables as the environmental exposures and estimated variance components attributed to genetic effects, environmental effects, and gene-environment interactions. Our results revealed that G×E accounts for 7% of variance in DP, 4% in SP, and 3% in PP. While these estimates are not statistically different from the ones obtained from an analysis restricted to White British individuals using the same lifestyle variables and methodology (4%, 3%, and 4% for DP, SP, and PP, respectively), the point estimate for DP is almost twice as large in the multi-ethnic sample. Including G×E in the models did not improve out-of-sample prediction accuracy. We also performed a G×E genome-wide association study (G×E-GWAS) to uncover individual interactions affecting BP traits. Although no interaction surpassed genome-wide significance, suggestive hits were enriched in BP-relevant pathways. Our hypothesis-generating study suggests that higher environmental and genetic heterogeneity in multi-ethnic cohorts may amplify the role of G×E for some traits and serves as a basis for future studies with larger sample sizes and higher power.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100656"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148585384","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":"Expanding the clinical and molecular spectrum of TUBB2B through distinct variants identified across multiple families.","authors":"Shaghayegh T Beheshti, Angad Jolly, Ahmed K Saad, Haowei Du, Lauren E Westerfield, Chloe Munderloh, Divya Kalra, Yifan Wu, Yi Chen, Marie-Claude Gingras, Shalini N Jhangiani, Sarenur Yilmaz, Maha S Zaki, Daniel G Calame, Davut Pehlivan, Richard A Gibbs, Richard A Lewis, James R Lupski, Jennifer E Posey","doi":"10.1016/j.xhgg.2026.100654","DOIUrl":"10.1016/j.xhgg.2026.100654","url":null,"abstract":"<p><p>TUBB2B encodes a β-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in TUBB2B are associated with neurodevelopmental disorders including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, most likely reflecting variant-specific effects on microtubule formation and stability. Homozygous TUBB2B variants are exceedingly rare, with one family reported to date. We describe five individuals in four families with rare TUBB2B variants. Four variants are described, including a previously reported de novo missense variant, c.292G>A (GenBank: NM_178012.5) (p.Gly98Arg), with potential phenotypic expansion including panhypopituitarism; a previously reported de novo missense variant, c.605T>C (GenBank: NM_178012.5) (p.Ile202Thr), showing interindividual heterogeneity; a de novo missense variant, c.43C>A (GenBank: NM_178012.5) (p.Gln15Lys) at a polyamination site critical for microtubule stability; and a homozygous missense variant within a region of absence of heterozygosity in two siblings from consanguineous parents, c.145G>A (GenBank: NM_178012.5) (p.Val49Ile). Both individuals also carry a pathogenic homozygous truncating ALKBH8 variant c.1675del (GenBank: NM_138775.3) (p.Arg559Alafs∗56), representing a potential dual molecular diagnosis driving clinical features reflective of contributions from both genes. These reports expand the clinical spectrum of TUBB2B-related tubulinopathies, illustrate phenotypic heterogeneity, and provide insights into disease mechanisms including effects at polyamination sites and rare recessive inheritance, underscoring the need for nuanced genotype-phenotype interpretation in diagnostic and counseling contexts.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100654"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473190","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":"Leveraging the genetics of human face shape boosts the discovery of orofacial cleft risk loci.","authors":"Noah Herrick, Seppe Goovaerts, Alexandra Manchel, Myoung Keun Lee, Xinyi Zhang, Amy Davies, Jenna C Carlson, Elizabeth J Leslie-Clarkson, Sarah J Lewis, Mary L Marazita, Justin Cotney, Peter Claes, John R Shaffer, Seth M Weinberg","doi":"10.1016/j.xhgg.2026.100655","DOIUrl":"10.1016/j.xhgg.2026.100655","url":null,"abstract":"<p><p>Several lines of evidence suggest that normal-range facial features and nonsyndromic orofacial clefts (OFCs) exhibit a shared genetic basis. Approaches designed to leverage this relationship hold the possibility of revealing new OFC risk loci by boosting discovery power. To test this idea, we applied a pleiotropy-informed genome-wide association study (GWAS) method (conditional false discovery rate [cFDR]-GWAS) with summary statistics from large, independent European GWASs of normal facial shape (n = 4,680; n = 3,566) and nonsyndromic cleft lip with or without cleft palate (nsCL/P; n = 3,969). The cFDR approach identified 21 independent genomic loci significantly associated with nsCL/P, providing further evidence of the interconnected genetic architecture between these traits. The five original nsCL/P GWAS signals were detected and joined by nine additional loci previously implicated in other OFC association studies. The remaining seven loci represent new nsCL/P genomic regions, and three of these replicated (p < 0.05) in an independent nsCL/P cohort: ASPSCR1, MSX2, and RALYL. A relaxed 10% cFDR-GWAS threshold identified 15 more independent loci with comparable effect sizes to those detected at the strict 5% threshold, two of which replicated: FHOD3 and SMARCA2. Gene expression patterns in major cell types and spatial transcriptomics data highlighted our gene candidates' roles in craniofacial development. In conclusion, applying an empirical Bayesian strategy to draw on association signals from genetically related traits can boost the power to identify and prioritize OFC risk loci missed by agnostic gene mapping approaches. These results hold promise that the cFDR-GWAS approach may be able to enhance our understanding of the genetic architecture of other structural birth defects.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100655"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148550882","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":"Massively parallel functional profiling prioritizes breast cancer risk variants and implicates CCDC88C in ER-positive breast cancer.","authors":"Kate Mackie, Harriet Kemp, Andrea Gunnell, James B Studd, Molly Went, Philip Law, Katarzyna Tomczyk, Rafaela Ferreira, Ernesto Lopez, Selin Sevgi, Yunjiao Lu, Alisa Zvereva, Nick Orr, Richard S Houlston, Nichola Johnson, Olivia Fletcher, Syed Haider","doi":"10.1016/j.xhgg.2026.100674","DOIUrl":"10.1016/j.xhgg.2026.100674","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs), combined with fine-mapping, have identified 196 independent signals associated with breast cancer risk. Deciphering the functional basis of these associations can inform our understanding of the biology and etiology of breast cancer. Decoding GWAS risk associations is challenging due to linkage disequilibrium between variants and because most variants map to non-coding regions, influencing breast cancer risk via cis-regulatory mechanisms that modulate the expression of target genes. To prioritize variants with allele-specific regulatory activity at breast cancer risk loci, we carried out a lentivirus-based massively parallel reporter assay (lentiMPRA) to screen 5,116 credible causal variants (CCVs) across these signals. We identified 709 variants mapping to 140 risk regions that are associated with significant variation between reference (REF) and alternative (ALT) alleles. A follow-up investigation at 14q32.11 revealed that rs7153397 may influence breast cancer risk through expression of CCDC88C, which in turn could impact prognosis. These findings provide a prioritized set of functional variants for downstream analyses, advancing our understanding of breast cancer risk mechanisms.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100674"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991655","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}