HGG Advances最新文献

{"title":"Routine RNA-based analysis of potential splicing variants facilitates genomic diagnostics and reveals limitations of in silico prediction tools.","authors":"Mark Drost, Jordy Dekker, Federico Ferraro, Esmee Kasteleijn, Marije Verschuren, Evelien Kroon, Hannie C W Douben, Inte Vogt, Leontine van Unen, Marianne Hoogeveen-Westerveld, Peter Elfferich, Rachel Schot, Camilla Calandrini, Esther Korpershoek, Frank Sleutels, Hennie B R Brüggenwirth, Iris R Hollink, Lisette Meerstein-Kessel, Lies H Hoefsloot, Marjon van Slegtenhorst, Martina Wilke, Marjolein J A Weerts, Rick van Minkelen, Anja Wagner, Arjan Bouman, Barbara W van Paassen, Grazia M Verheijen-Mancini, Ingrid M B H van de Laar, Anneke J A Kievit, Judith M A Verhagen, Kyra E Stuurman, Laura Donker Kaat, Marieke F van Dooren, Marja W Wessels, Rogier A Oldenburg, Shimriet Zeidler, Tessa van Dijk, Tahsin Stefan Barakat, Virginie J M Verhoeven, Yolande van Bever, Yvette van Ierland, Natalja Bannink, Silvana van Koningsbruggen, Phillis Lakeman, Lisette Leeuwen, Nienke E Verbeek, Margje Sinnema, Malou Heijligers, Christi J van Asperen, Jasper J Saris, Mark Nellist, Tjakko J van Ham","doi":"10.1016/j.xhgg.2025.100521","DOIUrl":"10.1016/j.xhgg.2025.100521","url":null,"abstract":"<p><p>DNA variants affecting pre-mRNA splicing are an important cause of genetic disorders and remain challenging to interpret without experimental data. Although variant classification guidelines recommend experimental characterization of variant splicing effects, the added value of routine diagnostic investigation of patient mRNA splicing has not been systematically described. Here, we assessed the utility of pre-mRNA splicing analysis in a diagnostic setting for 202 suspected splice-altering variants from individuals referred for genetic testing. Pre-mRNA splicing was assessed in patient cells by RT-PCR, followed by agarose gel electrophoresis and Sanger sequencing and/or exon trapping assays. An effect on pre-mRNA splicing was demonstrated in 63% (n = 128/202) of the tested variants. Among the 177 variants initially classified as variants of uncertain significance (VUS), 54% (n = 96/177) were reclassified based on pre-mRNA splicing analysis, including 48% (n = 85/177) that were upgraded to likely pathogenic or pathogenic. We benchmarked the splice prediction algorithms SpliceAI, SQUIRLS, SPiP, and Pangolin, the tools integrated in Alamut on this clinically relevant and experimentally validated dataset, and the CAGI6 splicing VUS dataset and found variable performance dependent on variant type and location. No single tool classified all variants equally well. We describe several examples of hard-to-predict effects and unexpected results highlighting the limitations of prediction tools, including a not previously described variant type affecting U12-splice site subtype. In summary, we provide a framework for RNA-based analysis in a molecular diagnostic setting, demonstrate the added value of routine testing of RNA from individuals with suspected splice-altering variants, and highlight the limitations of in silico prediction tools.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100521"},"PeriodicalIF":3.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132002","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":"Genome-wide association study reveals genetic mechanisms underlie eye disorders and comorbidities.","authors":"Chia-Ni Hsiung, Wen-Cheng Chou, Chih-Hsiung Hsu, Linyi Chen","doi":"10.1016/j.xhgg.2025.100520","DOIUrl":"10.1016/j.xhgg.2025.100520","url":null,"abstract":"<p><p>Eye diseases, including cataracts, glaucoma, diabetes retinopathy, and age-related macular degeneration, are major global health challenges and leading causes of blindness. This study leveraged genome-wide association studies (GWASs) involving over 100,000 individuals, integrating data from the Taiwan Biobank and National Health Insurance Research Database, to identify genetic loci associated with disease onset. Our findings suggest that these conditions are influenced by multifactorial etiologies, as pleiotropic loci including rs10811660, rs4710941, rs2283228, and rs7646518 were identified, linking ocular diseases to metabolic conditions. Notably, a strong genetic correlation was observed between cataract and depression. Mendelian randomization analysis further demonstrated a causal effect of depression on cataract risk, implicating shared biological pathways, particularly oxytocin signaling, in disease pathophysiology. This finding revealed a functional genetic variant near the OXTR gene, highlighting its potential as a causal candidate for genetic diagnosis in precision health. By bridging the gap between genetic discovery and clinical application, this research offers critical insights into shared genetic mechanisms across diverse health domains, paving the way for innovative diagnostic and therapeutic strategies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100520"},"PeriodicalIF":3.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Karnataka Individual Genome Project expands the human reference landscape to include South Asia.","authors":"Apoorva Ganesh, Anisha Mhatre, Yash Chindarkar, Moushmi Goswami, Prakruti Mishra, Aditya Sharma, Manjushri Kalpande, Febina Ravindran, Subhashini Srinivasan, Bibha Choudhary","doi":"10.1016/j.xhgg.2025.100516","DOIUrl":"10.1016/j.xhgg.2025.100516","url":null,"abstract":"<p><p>Assembling individual genomes remains an expensive endeavor, hindering large-scale comparative human genomics. So far, chromosome-level assemblies of only a few individuals, including PR1 (Puerto Rican), Ash1 (Ashkenazi Jew), Han1 (Southern Han Chinese), and CHM13 (Northern European) have been reported. Here, we present a chromosome-level genome assembly of a non-International Genome Sample Resource (IGSR) and non-Genome in a Bottle individual from the Indian subcontinent (KIn1) obtained using a cost-effective approach. We achieved an N50 of 141 Mb and an L50 of 9-very close to the maximum achievable N50 of 147 Mb and minimum achievable L50 of 8, respectively, for human genomes. We also generated chromosome-level assemblies for other individuals from the Indian diaspora, including PJL1 from Punjab, Lahore (HG03492), GIH1 from Gujarat (NA20847), BIB1 from Bangladesh (HG03009), and ITU1 from Andhra Pradesh (HG04217), all represented in IGSR, by scaffolding the publicly available respective contigs and Hi-C data. Here, we demonstrate that by comparing these individual genomes with those reported elsewhere, the configuration of inversion 8p23.1 in KIn1, Han1, GIH1, and BIB1 is similar to that in hg38, here to referred as 8p23.1std. The inverted configuration, 8p23.1inv, is present in CHM13, PJL1, Ash1, and PR1. We also find evidence of all three large known inversions in the p-arm of chromosome 16, with prevalence among South Asians. In chromosome 5, one of the reported inversions is present in all assemblies except hg38 and Ash1. Finally, we investigate the large inversions that are unique to KIn1.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100516"},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087377","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":"Asparaginyl-tRNA synthetase (NARS1) variants implicated in dominant neurological phenotypes display dominant-negative properties.","authors":"Sheila M Peeples, Keyana Blake, Brendan L M Sutton, Marina Konyukh, Stephan Züchner, Tanya Stojkovic, Jonathan Baets, Anthony Antonellis","doi":"10.1016/j.xhgg.2025.100519","DOIUrl":"10.1016/j.xhgg.2025.100519","url":null,"abstract":"<p><p>Aminoacyl-tRNA synthetases (ARSs) are essential, ubiquitously expressed enzymes that ligate amino acids to cognate tRNAs in the cytoplasm and mitochondria. To date, seven dimeric ARS enzymes have been implicated in dominant inherited neuropathy, suggesting that tRNA charging-exacerbated by a dominant-negative effect-is a component of the peripheral nervous system (PNS) phenotype. Interestingly, heterozygosity for missense and protein-truncating variants in the gene encoding dimeric, cytoplasmic asparaginyl-tRNA synthetase (NARS1) have been associated with distinct clinical phenotypes where patients present with either an isolated PNS neuropathy or with a complex phenotype that includes both PNS and central nervous system (CNS) features. Thus, NARS1 variants are associated with a spectrum of dominant neurological diseases. Here, we test pathogenic NARS1 variants for dominant-negative properties to determine if this mechanism is a common feature of ARS-related dominant neurological disease. Furthermore, we assess if variable dominant-negative effects explain the observed clinical heterogeneity. We performed yeast complementation assays to test NARS1 variants in isolation, which revealed loss-of-function effects. To test for dominant-negative properties, we co-expressed mutant human NARS1 with wild-type human NARS1. These studies revealed that NARS1 variants interact with the wild-type subunit and that the majority of variants repress the ability of the wild-type allele to support cellular growth, consistent with a dominant-negative effect. Furthermore, our data suggest that NARS1 variants associated with CNS and PNS phenotypes have a more severe dominant-negative effect compared with those associated with an isolated PNS phenotype.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100519"},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087663","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":"Bi-allelic INTU variants define a ciliopathy disorder characterized by orofacial, digital, and cardiac anomalies.","authors":"Rebekah Rushforth, Kurt Reynolds, Steven I Estes, Daniel K Nolan, Mari Mori, Daniel C Koboldt, Jesse M Hunter, Rolf W Stottmann","doi":"10.1016/j.xhgg.2025.100518","DOIUrl":"10.1016/j.xhgg.2025.100518","url":null,"abstract":"<p><p>The primary cilium is a small organelle that plays key roles in cellular signaling. Defects in primary cilia formation, morphology, and function cause a heterogeneous group of developmental syndromes termed ciliopathies. The inturned planar cell polarity protein (INTU) gene acts in the CPLANE complex to facilitate ciliogenesis and support cilia signaling. Bi-allelic genetic variants in INTU have previously been reported in seven patients with pleiotropic disorders, but a core set of phenotypes from these patients has not been codified and functional studies into these variants have failed to fully demonstrate mechanistic perturbations caused by INTU dysfunction. Here, we report on a person with cardiac abnormalities, distinctive craniofacial features, developmental delays, tongue hamartomas, bilateral clinodactyly, and polydactyly of the left great toe. Trio whole-exome sequencing identified compound heterozygous variants in the INTU gene. Functional studies provide evidence that these INTU variants confer human disease through altered ciliogenesis and/or cilia signaling. Furthermore, we suggest that this study along with previous reports sufficiently establishes an association between a pleiotropic disorder and variants in the INTU gene to enhance clinical interpretation of INTU variants in future studies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100518"},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087297","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":"Aberrant N-glycosylation may be a therapeutic target in carriers of a common and highly pleiotropic variant in the manganese transporter ZIP8.","authors":"Vartika Tomar, John Kang, Ruxian Lin, Steven R Brant, Mark Lazarev, Caitlin Tressler, Kristine Glunde, Natasha Zachara, Joanna Melia","doi":"10.1016/j.xhgg.2025.100517","DOIUrl":"10.1016/j.xhgg.2025.100517","url":null,"abstract":"<p><p>The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDGs). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense variant in a manganese transporter ZIP8 has exposed under-appreciated roles for Mn homeostasis and aberrant Mn-dependent glycosyltransferases activity leading to defective N-glycosylation in complex human diseases. Here, we test the hypothesis that aberrant N-glycosylation contributes to the disease pathogenesis of ZIP8 A391T-associated Crohn disease. Analysis of N-glycan branching in intestinal biopsies demonstrates perturbation in active Crohn disease and a genotype-dependent effect characterized by increased truncated N-glycans. A mouse model of ZIP8 391-Thr recapitulates the intestinal glycophenotype of patients carrying ZIP8 variants. Borrowing from therapeutic strategies employed in the treatment of patients with CDGs, oral monosaccharide therapy with N-acetylglucosamine ameliorates the epithelial N-glycan defect, bile acid dyshomeostasis, intestinal permeability, and susceptibility to chemical-induced colitis in a mouse model of ZIP8 391-Thr. Together, these data support ZIP8 391-Thr alters N-glycosylation to contribute to disease pathogenesis, challenging the clinical paradigm that CDGs are limited to patients with rare diseases. Critically, the defect in glycosylation can be targeted with monosaccharide supplementation, providing an opportunity for genotype-driven, personalized medicine.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100517"},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081946","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":"Pathway-specific polygenic scores substantially increase the discovery of gene-adiposity interactions impacting liver biomarkers.","authors":"Kenneth E Westerman, Daniel I Chasman, W James Gauderman, Arun Durvasula","doi":"10.1016/j.xhgg.2025.100515","DOIUrl":"10.1016/j.xhgg.2025.100515","url":null,"abstract":"<p><p>Polygenic scores (PGSs) are appealing for detecting gene-environment interactions due to the aggregation of genetic effects and reduced multiple testing burden compared to single-variant genome-wide interaction studies (GWISs). However, standard PGSs reflect many different biological mechanisms, limiting interpretation and potentially diluting pathway-specific interaction signals. Previous work has uncovered a significant genome-wide PGS×Adiposity signal impacting liver function, but there is an opportunity for additional and more interpretable discoveries. Here, we leveraged pathway-specific polygenic scores (pPGSs) to discover mechanism-specific gene-adiposity interactions. We tested for body mass index (BMI) interactions impacting three liver-related biomarkers (ALT, AST, and GGT) using (1) a standard, genome-wide PGS, (2) an array of pPGSs containing variant subsets derived from KEGG pathways, and (3) a GWIS. For ALT, we identified 49 significant pPGS×BMI interactions at a Bonferroni corrected p < 2.7 × 10^-4, 80% of which were not explained by genes close to the 8 loci found in the associated GWIS. Across all biomarkers, we found interactions with 83 unique pPGSs. We tested alternate pathway collections (hallmark, KEGG Medicus), finding that the choice of pathway collection strongly impacts discovery. Our findings reinforced known biology (e.g., glycerolipid metabolism and hepatic lipid export affecting ALT release) and captured additional phenomena (e.g., actin cytoskeleton remodeling-associated variants alter the liver's robustness to lipid mechanical stress and thus GGT release). These results support the use of pPGSs for well powered and interpretable discovery of pPGS×E interactions with adiposity-related exposures for liver biomarkers and motivate future studies using a broader collection of exposures and outcomes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100515"},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056085","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":"PATJ deficiency leads to cystic kidney disease and related ciliopathies.","authors":"Daniel Epting, Daniela A Braun, Eva Decker, Elisabeth Ott, Tobias Eisenberger, Nadine Bachmann, Pavel Nedvetsky, Michael P Krahn, Friedhelm Hildebrandt, Carsten Bergmann","doi":"10.1016/j.xhgg.2025.100514","DOIUrl":"10.1016/j.xhgg.2025.100514","url":null,"abstract":"<p><p>Cystic kidney disease and related ciliopathies are caused by pathogenic variants in genes that commonly result in ciliary dysfunction. For a substantial number of individuals affected by those cilia-related diseases, the causative gene remains unknown. Using massively parallel sequencing, we here identified a pathogenic bi-allelic variant in the gene encoding PALS1-associated tight junction protein ([PATJ] also known as inactivation-no-afterpotential D-like, INADL) in an individual with ciliopathy. The affected fetus carried the homozygous truncating PATJ nonsense variant c.830delC (p.Pro277fsX), and presented with a syndromic phenotype mainly characterized by polycystic kidney disease and hydrocephalus. Using zebrafish (Danio rerio) as a vertebrate in vivo model organism, we could validate our patient findings and demonstrated a ciliopathy phenotype. In addition, we were able to address a hitherto not described role of Patj for cilia formation and function. Taken together, with the Crumbs cell polarity complex member PATJ, we add a new member to the large family of ciliopathy-related human disease proteins that is different from the classical ciliopathy protein classes, and may offer new perspectives for drug development.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100514"},"PeriodicalIF":3.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034299","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 robust pleiotropy method with applications to lipid traits and to inflammatory bowel disease subtypes with sample overlap.","authors":"Jiwon Park, Debashree Ray","doi":"10.1016/j.xhgg.2025.100501","DOIUrl":"10.1016/j.xhgg.2025.100501","url":null,"abstract":"<p><p>Pleiotropy, the phenomenon where a genetic region confers risk to multiple traits, is widely observed, even among seemingly unrelated traits. Knowledge of pleiotropy can improve understanding of biological mechanisms of diseases/traits, and can potentially guide identification of molecular targets or help predict side effects in drug development. However, statistical approaches for identifying pleiotropy genome-wide are limited, particularly for two correlated traits or case-control traits with unknown sample overlap or for disease traits from family studies. We proposed PLACO+, an improved version of our pleiotropic analysis under composite null hypothesis method based on GWAS summary statistics from two traits. PLACO+ uses an inflated variance model to allow for fractions of variants to be associated with none or only one trait under the null. It is genome-wide scalable, where analytical p value is computed as a weighted sum of extreme tail probabilities of bivariate normal product distribution. Simulations for both population-based and family-based designs demonstrate well-calibrated type I errors at stringent levels and substantially improved power of PLACO+ over conventional approaches. We illustrate PLACO+ on inflammatory bowel disease subtypes with shared controls and on correlated lipid traits with unknown sample overlap. In particular, PLACO+ revealed pleiotropic regions between triglyceride and high-density lipoprotein levels that conventional approaches missed and all of which were replicated in a larger GWAS of these lipid traits. This further demonstrates the utility of PLACO+ in discovering genetic associations of traits with modest sample sizes by leveraging information from another correlated trait.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100501"},"PeriodicalIF":3.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006676","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":"Genetics of SSRI antidepressant use and relationship to psychiatric and medical traits.","authors":"Daniel Levey, Marco Galimberti, Joseph Deak, Priya Gupta, Stefany L L Empke, Keyrun Adhikari, Kelly Harrington, Rachel Quaden, J J Michael Gaziano, Murray B Stein, Joel Gelernter","doi":"10.1016/j.xhgg.2025.100500","DOIUrl":"10.1016/j.xhgg.2025.100500","url":null,"abstract":"<p><p>Antidepressants are among the most-prescribed drugs worldwide, and selective serotonin reuptake inhibitors (SSRIs) are among the most prescribed antidepressants, most commonly used for major depression. We sought to increase our understanding of the biological relationships between SSRI use and a range of psychiatric traits by conducting a genome-wide association study (GWAS) in two large datasets, the UK Biobank (UKB) and the US Million Veteran Program (MVP). GWAS was conducted across 22 autosomes and the X chromosome in 777,952 individuals of European ancestry (191,800 SSRI users, 586,152 control individuals) and 112,526 individuals of African ancestry (53,499 SSRI users, 59,027 control individuals). We identified 40 genome-wide significant (GWS) loci, including two on the X chromosome. Using linkage disequilibrium score regression, we detected strong genetic correlations between MVP and the independent UKB cohort for specific SSRIs (fluoxetine rg = 0.82, citalopram rG = 0.89) as well as with headaches (rG = 0.80), major depressive disorder (MDD; rG = 0.77), and spondylosis (rG = 0.84), suggesting stability in trait definition across cohorts. To evaluate differences in genomic variance captured by SSRI use vs. MDD, we performed a comparative rG analysis and found significant differences, most notably for educational attainment (SSRI rG = -0.38, MDD rG = -0.26), cognitive performance (SSRI rG = -0.31, MDD rG = -0.15), and depression (SSRI rG = 0.80, MDD rG = 0.97). In MVP, SSRI use showed greater locus discovery than MDD (28 vs. 17 loci); comparison to a prior GWAS of anxiety symptoms identified only five loci. SSRI use is likely a partial proxy for MDD, while also reflecting distinct features relevant to related disorders such as anxiety.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100500"},"PeriodicalIF":3.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993728","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}