HGG Advances最新文献

{"title":"Identifying genes associated with obstructive congenital heart defects using a family-based genetic random field method.","authors":"Manyan Huang, Nianjun Liu, Stephanie M Ware, John S Witte, Bruce D Gelb, Wendy N Nembhard, Martha Werler, Meredith M Howley, Lorenzo Botto, A J Agopian, Omobola O Oluwafemi, Mary M Jenkins, Lynn M Almli, Andy Olshan, Paul A Romitti, Gary Shaw, Ming Li","doi":"10.1016/j.xhgg.2026.100648","DOIUrl":"10.1016/j.xhgg.2026.100648","url":null,"abstract":"<p><p>Congenital heart defects (CHDs) are the most common major congenital anomalies and the leading cause of infant mortality attributable to birth defects. Although substantial progress has been made in the identification of single-nucleotide variants associated with CHDs, the genetic etiology of CHDs remains largely unknown. While many studies have focused on common variants, efforts are underway to identify rare variants with heterogeneous effects on CHD development. We applied a family-based genetic random field (FGRF) method to buccal cell DNA specimens collected for the National Birth Defects Prevention Study, including 1,123 case families and 1,481 control families. We and others previously showed that the FGRF method was able to identify rare genetic variants associated with disease outcomes in the presence of disease heterogeneity. In this study, we conducted gene-based association tests for 24,270 genes and identified that SLC44A2 was significantly associated with obstructive CHD risk after Bonferroni adjustment for multiple testing, representing the most robust signal observed in our analyses, while other phase-specific findings require further validation. Our subsequent gene set enrichment analyses supported the likely role of this gene in the biological pathways relevant to CHD development. Our study is complementary to existing genome-wide association studies on CHD risk, providing additional insights into the genetic etiology of these birth defects.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100648"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148399555","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 ABCA2-associated neurodevelopmental phenotype.","authors":"Kaisa T Oja, Karit Reinson, Mihkel Ilisson, Daima Örd, Monica H Wojcik, Eleanor G Seaby, Bryan M Wittmann, Adam D Kennedy, Karen DeBalsi, Christiane Zweier, Georgia Vasileiou, Issam A Alkhawaja, Thomas Wirth, Steffen Syrbe, Konrad Platzer, Suad Alyamani, Fowzan S Alkuraya, David Ros-Pardo, Iñigo Marcos-Alcalde, Paulino Gómez-Puertas, Marie Vidailhet, Ke Su, Shaohua Fan, Yu Ma, Yi Wang, Alessandra Renieri, Anna Maria Pinto, Farah Almadhoun, Andrea K Petersen, Kari Magnussen, Olaf Bodamer, Talal Alanzi, Sarar Mohamed, Hadeel Alrabee, Bader Alhaddad, Khadijah Bakur, Nicole Fleischer, Amber Begtrup, Tõnis Örd, Sander Pajusalu, Katrin Õunap","doi":"10.1016/j.xhgg.2026.100638","DOIUrl":"10.1016/j.xhgg.2026.100638","url":null,"abstract":"<p><p>The ATP-binding cassette subfamily A member 2 (ABCA2) gene encodes an ABC transporter protein. Bi-allelic loss-of-function variants in ABCA2 have been associated with an intellectual disability disorder. We aimed to delineate the phenotypic spectrum of individuals with monoallelic (MV) or bi-allelic (BV) variants in the ABCA2 gene. We collected clinical data via questionnaires and literature review. The ABCA2 protein was constructed using homology modeling. Untargeted plasma metabolomics was performed at Metabolon. A docetaxel toxicity cell culture model system was used to study the effects of plasmid-encoded ABCA2 and four ABCA2 variants (p.Asp615Glu [c.1845C>A], p.Phe754Ser [c.2261T>C], p.Ile786del [c.2356_2358del], and p.Arg926Trp [c.2776C>T]) on cell viability. Seventeen individuals with seventeen candidate ABCA2 variants were identified (seven MVs and ten BVs). Protein modeling predicted a likely significant impact for eight of 13 assessed variants. In cell viability assays, enforced expression of wild-type ABCA2 reduced viability in docetaxel-exposed cells. In contrast, none of the four variants affected viability, suggesting a loss or a marked reduction in transporter function. Untargeted metabolomics of three samples from two individuals showed a trend toward lower levels of polyunsaturated acylcarnitines. This study describes 17 individuals with candidate variants in the ABCA2 gene. The cell viability assays revealed that four variants (p.Asp615Glu, p.Phe754Ser, p.Ile786del, and p.Arg926Trp) had an altered ability to function as a transporter compared to wild-type ABCA2. Further studies are needed to clarify the pathomechanism of ABCA2 and the clinical significance of the variants.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100638"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148333424","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":"Multi-omic characterization of the Hispanic/Latino blood lipidome reveals an additional locus and attenuated genetic prediction.","authors":"Wanying Zhu, Hung-Hsin Chen, Heather M Highland, Corey Giles, Peter J Meikle, Phillip Lin, Lauren E Petty, Hannah G Polikowsky, Alex S Petty, Mohammad Y Anwar, Xinruo Zhang, Joanne E Curran, Elizabeth G Frankel, Rashedeh Roshani, Joshua M Landman, Gabriela S Castrodad-Rivera, Caroline Herndon, Joseph B McCormick, Susan P Fisher-Hoch, Penny Gordon-Larsen, Eric R Gamazon, Kari E North, Jennifer E Below","doi":"10.1016/j.xhgg.2026.100664","DOIUrl":"10.1016/j.xhgg.2026.100664","url":null,"abstract":"<p><p>While lipids have been extensively investigated, genetic regulation of the circulating lipidome in diverse populations remains poorly understood. We conducted a lipidome-wide genome-wide association study (GWAS) of 830 lipid species in 2,287 Hispanic/Latino participants and performed predictive modeling across omics layers. We identified 7,593 genome-wide significant SNPs mapping to 208 genes. Conditional analysis disentangled the long-range linkage disequilibrium artifacts from the pleiotropic FADS1/2/3 cluster. Separately, we discovered an association at the GPLD1 locus for a circulating ceramide. Colocalization revealed shared genetic architecture with conventional lipids alongside distinct, species-specific pathways. Incorporating Native/Indigenous American expression quantitative trait loci (eQTLs) within a multi-omic framework uncovered 62 likely regulatory genes missed by European-centric gene expression models. Finally, genetically regulated predictive models demonstrated performance declining from transcriptomics to proteomics to lipidomics, reflecting increased distance from gene action along the molecular cascade. Our study provides a genetic landscape of lipid metabolism in a highly burdened population and highlights the challenges in predicting lipid abundance.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100664"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148819790","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 association meta-analysis is susceptible to confounding by between-study cryptic relatedness.","authors":"Tiffany Tu, Alejandro Ochoa","doi":"10.1016/j.xhgg.2026.100657","DOIUrl":"10.1016/j.xhgg.2026.100657","url":null,"abstract":"<p><p>Meta-analysis of genome-wide association studies (GWASs) has important advantages, but it assumes that studies are independent, which does not hold when there is relatedness between studies. As a motivating example, recent work suggested applying sex-stratified meta-analysis to correct for participation bias, without considering that men and women from the same population will be highly related. Our theory demonstrates how cryptic relatedness results in correlated test statistics between studies, inflating meta-analysis. We characterize the effects of different between-study relatedness scenarios, particularly population structure and recent family relatedness, on meta-analysis type I error control and power. We simulated data with no family relatedness between subpopulations, family relatedness within subpopulations, family relatedness across subpopulations, and a single population with family relatedness. We evaluated joint GWAS, standard meta-analysis, and our proposed meta-analysis method for correlated studies (R package metalcor) on both binary and quantitative traits. In scenarios with family relatedness, standard sex-stratified meta-analysis exhibits severe inflation and lower area under the curve (AUC) than joint and subpopulation meta-analyses, which our method improves by modeling correlation. Genomic control also corrects for inflation but does not alter calibrated power and may fail under high power and high polygenicity. Inflation in standard meta-analysis increases with sample size, which our proposed method avoids. Analysis of real datasets confirms severe inflation for standard sex-stratified meta-analysis in family studies but a negligible effect for population studies with up to 10,000 individuals. Meta-analyses of studies of the same population have increased risk of between-study cryptic relatedness and should be avoided.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100657"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148593685","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":"EndoPRS-SS: Summary-statistic based incorporation of endophenotypes to improve risk prediction.","authors":"Elena V Kharitonova, Brian Chen, Quan Sun, Franklin Ockerman, Chang Chen, Laura Y Zhou, Shulan Tian, Hongyuan Cao, Carole Ober, Nancy J Cox, Ran Tao, Yun Li","doi":"10.1016/j.xhgg.2026.100677","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100677","url":null,"abstract":"<p><p>Endophenotypes are critical biological markers with genetic links to disease progression. We previously developed endoPRS, a multi-trait polygenic risk score (PRS) method that leverages endophenotype data to improve disease risk prediction. However, endoPRS requires individual-level genotype-phenotype data for model fitting, restricting its broader use. To address this, we introduce endoPRS-SS, an extension which enables PRS inference using genome-wide association study (GWAS) summary statistics and LD reference panels. Through simulation and real data analysis, we demonstrate that endoPRS-SS maintains the predictive accuracy of endoPRS, while increasing computational efficiency up to 90-fold. We also extend the endoPRS framework to support the incorporation of multiple endophenotypes simultaneously and find that multi-endophenotype PRS outperform single-endophenotype PRS. Notably, incorporating both monocyte count and executive function scores significantly improves Alzheimer's disease prediction for Europeans in the UK Biobank cohort. These extensions expand the scope of endoPRS and strengthen its utility for large-scale genetic risk assessment.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100677"},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115884","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 homozygous missense variant in NRROS gene is associated with intracranial calcifications, neurodegeneration, and severe infantile epilepsy syndrome.","authors":"Mythily Ganapathi, Sean D Fraser, Joseph W Ryu, Georgette Bruenner, Daniel Page, Lisa J Randall, Charles A LeDuc, Shefali Karkare, Ingo Helbig, Amanda J McPartland, Patricia A Lanzano, Peyman Bizargity, Fraser D Russell, Robert J Harvey, Wendy K Chung","doi":"10.1016/j.xhgg.2026.100676","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100676","url":null,"abstract":"<p><p>Biallelic loss-of-function variants in NRROS (Negative regulator of reactive oxygen species, previously LRRC33) cause a progressive neurodegenerative disorder characterized by early-onset seizures with brain calcifications. To date, 16 affected individuals from 13 unrelated families have been reported for this condition. We describe two siblings from a consanguineous family with this disorder, carrying a homozygous NRROS missense variant (c.1222A>C, p.(Asn408His), NM_198565.3). The mutational spectrum of NRROS disorder is characterized primarily by loss-of-function variants, with only four missense variants identified in affected individuals to date p.(Leu10Pro), p.(Leu62Pro), p.(Leu86Pro), and p.(Asn408His). We characterized these missense variants using silico predictions, molecular modelling and in-vitro cellular localization studies. In silico tools predict that p.(Leu10Pro) alters signal peptide cleavage, while p.(Asn408His) impedes N-linked glycosylation. Molecular modelling suggests that p.(Leu62Pro) and p.(Leu86Pro) variants may destabilize NRROS structure, while p.(Asn408His) interferes with NRROS glycosylation. In-vitro studies overexpressing HA-tagged NRROS wild type and missense variants in HEK293 cells showed altered subcellular distribution patterns for the variant proteins. In summary, we report a homozygous missense variant in NRROS associated with severe infantile epilepsy syndrome with intracranial calcifications, and neurodegeneration.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100676"},"PeriodicalIF":3.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076166","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 variance QTL approach to uncover gene-fish oil supplement interaction loci for 14 circulating unsaturated fatty acid traits.","authors":"Susan Adanna Ihejirika, Eunice Stephen, Kaixiong Ye","doi":"10.1016/j.xhgg.2026.100675","DOIUrl":"10.1016/j.xhgg.2026.100675","url":null,"abstract":"<p><p>Gene-environment interactions (GEIs) contribute to circulating polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid (MUFA) profiles. GEIs may partly explain differences in trait variance across genotype groups. To identify GEIs for circulating unsaturated fatty acids, we adopted a two-stage strategy. First, we detected quantitative trait loci associated with trait variance (vQTLs). Second, we tested these vQTLs for interaction with fish oil supplements (FOS). We performed genome-wide vQTL screens for 14 plasma PUFA and MUFA phenotypes in a UK Biobank subset of up to 200,736 participants. At the genome-wide significance threshold (p < 5.0 x 10^-8), we identified 172 vQTL-trait pairs across all 14 traits, and 16 of these vQTLs had no marginal genetic effect on the corresponding trait. We found 46 non-overlapping loci across all phenotypes, with an average of 12 vQTLs per trait. Omega-6% and PUFA% had the most independent vQTLs (N = 24) while DHA% and Omega-3% had the least (N = 1 and 2, respectively). For each of the 172 vQTL-trait pairs, we tested the interaction effect of the vQTL with FOS on the corresponding trait. We found six significant interaction signals in DHA, DHA%, Omega-3, Omega-3%, LA, and Omega-6/Omega-3 ratio, mapping to the FADS1/2 locus and the ZPR1 and SUGP1/TM6SF2 genes, two additional loci not detected in our prior genome-wide interaction scan. Our results provide a comprehensive resource of vQTLs and gene-FOS interactions shaping the circulating levels of unsaturated fatty acids.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100675"},"PeriodicalIF":3.1,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002786","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":"Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction.","authors":"Sofia Douzgou Houge, Cecilie Bredrup, Ragnhild Wivestad Jansson, Ognjen Bojovic, Bayan M Aljamal, Maha Al-Otaibi, Astrid S Plomp, Mahdi M Motazacker, Maria M van Genderen, Anne Mellgren, Hisham Alkuraya, Omar Hikmat, Bjørn Ivar Haukanes, Fowzan S Alkuraya, Gunnar Douzgos Houge","doi":"10.1016/j.xhgg.2026.100622","DOIUrl":"10.1016/j.xhgg.2026.100622","url":null,"abstract":"<p><p>DSCAM occupies a 1-Mb locus in the original Down syndrome critical region on chromosome 21q22 and encodes a neuronal cell adhesion molecule of importance for brain and eye development. Singleton individuals, both born to first-cousin parents, with intellectual disability and homozygous DSCAM loss-of-function variants were reported in 2017 and in 2021, the latter also presenting with nystagmus and visual impairment. We present a cohort of five individuals, four new, including two sibling pairs with homozygosity or compound heterozygosity for predicted loss-of-function DSCAM variants. We identify a common clinical pattern of moderate to severe neurodevelopmental delay with poor language development, risk of focal seizures with onset in infancy, and nystagmus with poor vision. Electroretinography in two of the affected revealed cone-pathway dysfunction with a b-wave pattern indicating main dysfunction at the level of the cone-associated bipolar cells of the central retina. Our electroclinical findings are in line with previous DSCAM knockout chicken and mice studies that evidenced disturbed horizontal and vertical patterning of the retina. Taken together, we delineate a rare syndromic form of recessive intellectual disability with a distinctive type of visual impairment.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100622"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13199882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821722","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":"Bayesian Mendelian randomization methods for index trait bias correction in subsequent trait genome-wide association studies.","authors":"Nimish Adhikari, Kathryn L Lunetta, David R Gagnon, Gina M Peloso","doi":"10.1016/j.xhgg.2026.100592","DOIUrl":"10.1016/j.xhgg.2026.100592","url":null,"abstract":"<p><p>Index trait bias (also called index event bias) can occur in genetic studies due to conditioning on incident trait, which can bias genetic associations with subsequent traits. We propose the use of two Bayesian Mendelian randomization (MR) methods (Bayesian weighted MR [BWMR] and MR-HORSE) to correct index trait bias in genome-wide association studies (GWASs) of subsequent traits. We compare these Bayesian MR methods to previously proposed methods for index trait bias through a simulation study. We observe that BWMR has similar type I error compared to using an inverse variance weighted MR, weighted median MR, and Dudbridge but has an inflated type I error compared to SlopeHunter. MR-HORSE and SlopeHunter have similar type I errors for smaller correlations between incident and subsequent traits; however, MR-HORSE and SlopeHunter have better controlled type I error for a large negative correlation and large positive correlation, respectively. All methods have comparable power across correlations between incident and subsequent traits. We applied the methods to a GWAS of subsequent acute ischemic stroke (AIS) or 3-point major adverse cardiovascular event after an incident AIS event in the Million Veteran Program and for fasting insulin adjusted for body mass index, and we observed slight differences in the results between the correction methods. We observed that a single index trait bias correction method is not optimal across all scenarios; therefore, applying multiple methods and checking for consistency between the estimates could provide an approach to determine the presence of and correction for index trait bias.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100592"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147475578","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 a modular massively parallel reporter assay to discover context-dependent regulatory activity in type 2 diabetes-linked noncoding regions.","authors":"Adelaide Tovar, Yasuhiro Kyono, Kirsten Nishino, Maya Bose, Arushi Varshney, Stephen C J Parker, Jacob O Kitzman","doi":"10.1016/j.xhgg.2026.100606","DOIUrl":"10.1016/j.xhgg.2026.100606","url":null,"abstract":"<p><p>Most complex trait association signals reside in the noncoding genome, where defining function is challenging. MPRAs (massively parallel reporter assays) offer a scalable means to test variants' regulatory impacts but are typically cell-type agnostic, pairing cloned fragments with generic \"housekeeping\" promoters. To explore MPRAs' context sensitivity, we screened a panel of nearly 12,000 fragments across >300 diabetes- and metabolic-trait-associated regions in a pancreatic β cell line model. We compared activity when fragments were placed up- versus downstream of a reporter gene and combined with the synthetic housekeeping promoter super core promoter 1 (SCP1) versus the physiologically relevant human insulin (INS) gene promoter. We identified clear effects of MPRA construct design on regulatory activity. A subset of fragments (n = 702/11,656) displayed positional bias, evenly distributed across up- and downstream preferences. Promoter choice also influenced MPRA activity (n = 698/11,656), mostly biased toward the cell-specific INS promoter (73.4%). A screen for sequence annotations associated with INS promoter preference revealed enrichment for HNF1 binding motifs. HNF1 family transcription factors are key regulators of glucose metabolism disrupted in maturity-onset diabetes of the young (MODY), suggesting genetic convergence between rare coding variants that cause MODY and common type 2 diabetes (T2D)-associated regulatory regions. A follow-up HNF1-focused MPRA highlighted several instances where motif deletion or mutation disrupted regulatory activity specifically in the context of the INS1 promoter and in the β cell model but not in another diabetes-relevant cell type, skeletal muscle. These results identify technical factors that may require careful consideration while designing MPRA experiments.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100606"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639767","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}