HGG Advances最新文献

{"title":"Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men.","authors":"Rohini Janivara, Ujani Hazra, Aaron Pfennig, Maxine Harlemon, Michelle S Kim, Muthukrishnan Eaaswarkhanth, Wenlong C Chen, Adebola Ogunbiyi, Paidamoyo Kachambwa, Lindsay N Petersen, Mohamed Jalloh, James E Mensah, Andrew A Adjei, Ben Adusei, Maureen Joffe, Serigne M Gueye, Oseremen I Aisuodionoe-Shadrach, Pedro W Fernandez, Thomas E Rohan, Caroline Andrews, Timothy R Rebbeck, Akindele O Adebiyi, Ilir Agalliu, Joseph Lachance","doi":"10.1016/j.xhgg.2025.100428","DOIUrl":"10.1016/j.xhgg.2025.100428","url":null,"abstract":"<p><p>Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male-pattern baldness comes from individuals of European descent. Here, we examined a dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using the Men of African Descent and Carcinoma of the Prostate Array. We first tested how genetic predictions of baldness generalize from Europe to Africa and found that polygenic scores from European genome-wide association studies (GWASs) yielded area under the curve statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness generalized poorly from European to African populations. Subsequently, we conducted an African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for age at recruitment, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p < 10^-5, r² < 0.2). Most baldness associations were autosomal, and the X chromosome does not seem to have a large impact on baldness in African men. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, within the limits of statistical power, we did not find evidence that continental differences in the genetic architecture of baldness are due to Neanderthal introgression. While most loci that are associated with androgenetic alopecia do not have large integrative haplotype scores or fixation index statistics, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how population genetic differences contribute to the limited portability of polygenic predictions across ancestries.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100428"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711435","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":"Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.","authors":"Sarah L Stenton, Kristen Laricchia, Nicole J Lake, Sushma Chaluvadi, Vijay Ganesh, Stephanie DiTroia, Ikeoluwa Osei-Owusu, Lynn Pais, Emily O'Heir, Christina Austin-Tse, Melanie O'Leary, Mayada Abu Shanap, Chelsea Barrows, Seth Berger, Carsten G Bönnemann, Kinga M Bujakowska, Dean R Campagna, Alison G Compton, Sandra Donkervoort, Mark D Fleming, Lyndon Gallacher, Joseph G Gleeson, Goknur Haliloglu, Eric A Pierce, Emily M Place, Vijay G Sankaran, Akiko Shimamura, Zornitza Stark, Tiong Yang Tan, David R Thorburn, Susan M White, Maha S Zaki, Eric Vilain, Monkol Lek, Heidi L Rehm, Anne O'Donnell-Luria","doi":"10.1016/j.xhgg.2025.100441","DOIUrl":"10.1016/j.xhgg.2025.100441","url":null,"abstract":"<p><p>Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is not always specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants. Here, we analyzed a cohort of 6,660 rare disease families (5,625 genetically undiagnosed [84%]) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium, as well as other rare disease cohorts. Using dedicated pipelines to address the technical challenges posed by the mtDNA-circular genome, variant heteroplasmy, and nuclear misalignment-we called single nucleotide variants, small insertions/deletions, and large mtDNA deletions from exome and/or genome sequencing data, in addition to RNA sequencing data when available. Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (1 large deletion, 8 reported pathogenic variants, and 1 previously unreported likely pathogenic variant), as well as candidate diagnostic variants in a further 11 undiagnosed families. In one additional undiagnosed proband, detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair. Overall, mtDNA variant calling from data generated by exome and genome sequencing-primarily for nuclear variant analysis-resulted in a genetic diagnosis for 0.2% of undiagnosed families affected by a broad range of rare diseases, as well as the identification of additional promising candidates in 0.2%.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100441"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050879","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":"Enhancing polygenic scores for cardiometabolic traits through tissue- and cell-type-specific functional annotations.","authors":"Kristjan Norland, Daniel J Schaid, Iftikhar J Kullo","doi":"10.1016/j.xhgg.2025.100427","DOIUrl":"10.1016/j.xhgg.2025.100427","url":null,"abstract":"<p><p>Functional genomic annotations can improve polygenic scores (PGS) within and between genetic ancestry groups. While general annotations are commonly used in PGS development, tissue- and cell-type-specific annotations derived from open chromatin and gene expression experiments may further enhance PGS for cardiometabolic traits. We developed PGS for 14 cardiometabolic traits in the UK Biobank using SBayesRC. We integrated GWAS summary statistics from FinnGen and GLGC with three annotation sources: (1) Baseline-LD model version 2.2 (general annotations), (2) cell-type-specific snATAC-seq peaks, and (3) tissue-specific eQTLs/sQTLs. We created PGS using two EUR LD reference panels (1.2 million [1.2M] HapMap3 variants and 7M imputed variants). Tissue- and cell-type-specific annotations showed stronger heritability enrichment than Baseline-LD annotations on average, particularly coronary snATAC-seq peaks and fine-mapped eQTLs. Without annotations, HapMap3 and 7M variant PGS performed similarly. However, with all annotations, 7M variant PGS outperformed HapMap3 variant PGS (8% average increase in relative performance in EUR). Compared to using no annotations, modeling Baseline-LD annotations improved performance by 5% for HapMap3 and 11% for 7M variant PGS, while modeling all annotations yielded improvements of 5% and 13%, respectively. Although annotations provided greater relative improvement for cross-ancestry prediction, they did not decrease the disparity in PGS performance between genetic ancestry groups. In conclusion, functional annotations improved PGS for cardiometabolic traits. Despite strong heritability enrichment, tissue- and cell-type-specific snATAC-seq and eQTL annotations provided marginal performance gains beyond general genomic annotations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100427"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12059674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A variant in RNF212B may contribute to female infertility and recurrent pregnancy loss.","authors":"Michelle E Darko, Michelle Kappy, Daniel Rabizadeh, Chaim Jalas, Eric J Forman, Paula Brady, Zev Williams","doi":"10.1016/j.xhgg.2025.100443","DOIUrl":"10.1016/j.xhgg.2025.100443","url":null,"abstract":"<p><p>Women with genetic causes of infertility are more likely to experience recurrent pregnancy loss (RPL). Advances in whole-genome sequencing (WGS) have allowed for the improved detection of such genes. One reproductively young patient with a history of RPL underwent 5 in vitro fertilization cycles with nearly complete arrest of blastocyst development and ubiquitous aneuploidy of maternal origin in arrested embryos. Here, we present the discovery of a gene variant, RNF212B, as a potential genetic cause of female infertility and RPL. DNA was extracted and submitted for WGS. After filtering out variants with Genome Aggregation Database allele frequencies exceeding 0.25%, we identified 87 unique variants and conducted a literature search to identify potential associations with infertility. PGT-A analysis of arrested embryos revealed extensive aneuploidies affecting many chromosomes in all embryos. Maternal WGS revealed a homozygous stop-gain mutation in the RNF212B gene. RNF212 has been shown to interact with proteins involved in meiotic recombination, including DMC1 and DNA repair protein RAD51. This homozygous nonsense mutation in the RNF212B gene may be responsible for the presence of aberrant oogonium and for disrupting the meiotic recombination process, thereby contributing to female infertility and RPL.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100443"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Common genetic modifiers influence cardiomyopathy susceptibility among the carriers of rare pathogenic variants.","authors":"Samantha J Klasfeld, Katherine A Knutson, Melissa R Miller, Eric B Fauman, Joanne Berghout, Rob Moccia, Hye In Kim","doi":"10.1016/j.xhgg.2025.100460","DOIUrl":"10.1016/j.xhgg.2025.100460","url":null,"abstract":"<p><p>Cardiomyopathy presents a significant medical burden due to frequent hospitalizations and invasive interventions. While cardiomyopathy is considered a rare monogenic disorder caused by rare pathogenic variants in a few genes, emerging evidence suggests that common genetic modifiers influence disease penetrance and clinical variability. Quantifying the interplay between common genetic modifiers and rare pathogenic variants is challenging due to the rarity of subjects with cardiomyopathy and pathogenic variant carriers. In this study, we utilized large-scale genetic and phenotypic data from the UK Biobank to refine the genetic architecture of hypertrophic and dilated cardiomyopathies. Using ClinVar annotations and variant effect prediction tools, we first identified known and predicted pathogenic variants and evaluated their association with disease risk, age of diagnosis, and quantitative cardiac phenotypes that reflect disease progression. We next examined the impact of polygenic risk scores on disease in the combined sets of known and predicted pathogenic variant carriers. Indeed, the polygenic risk scores were significantly associated with increased disease risk, with rare pathogenic variant carriers in the top 20% of polygenic risk having 5.7 and 2.3 times higher risk than those in the bottom 20% for hypertrophic and dilated cardiomyopathies, respectively. We observed stronger associations in the carrier sets that included predicted pathogenic variant carriers, suggesting improved statistical power. In summary, our study adds to the evidence that common genetic modifiers influence the cardiomyopathy disease risk among rare pathogenic variant carriers and illustrates the benefits and limitations of incorporating variant effect predictions to examine the polygenic influence in rare disease variant carriers.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100460"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136412","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":"Long-read sequencing is required for precision diagnosis of incontinentia pigmenti.","authors":"Monica H Wojcik, Robin D Clark, Abdallah F Elias, Casie A Genetti, Jill A Madden, Dana Simpson, Linda Golkar, Miranda P G Zalusky, Angela L Miller, Araceli Rodriguez, Joy Goffena, Camille A Dash, Nikhita Damaraju, Sophia B Gibson, Sophie H R Storz, Zachary B Anderson, Jonas A Gustafson, Isabelle Thiffault, Emily G Farrow, Tomi Pastinen, Jasmine Lin, Jennifer T Huang, Alan H Beggs, Pankaj B Agrawal, David T Miller, Danny E Miller","doi":"10.1016/j.xhgg.2025.100468","DOIUrl":"10.1016/j.xhgg.2025.100468","url":null,"abstract":"<p><p>Incontinentia pigmenti (IP) is caused by loss-of-function variants in IKBKG, with molecular genetic diagnosis complicated by a pseudogene. We describe seven individuals from three families with IP but negative clinical genetic testing in whom long-read sequencing identified causal variants, including one family with the common exon 4-10 deletion not identified by conventional clinical genetic testing. Concurrent methylation analysis explained disease severity in one individual who died from neurologic complications, identified a mosaic variant in an individual with an atypical presentation, and confirmed skewed X chromosome inactivation in an XXY individual.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100468"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted long-read cDNA sequencing reveals novel splice-altering pathogenic variants causing retinal dystrophies.","authors":"Dalila Capasso, Roberta Zeuli, Gavin Arno, Michael Kwint, Raoul Timmermans, Karla A Ruiz-Ceja, Marianthi Karali, Francesca Simonelli, Sabrina Signorini, Enza Maria Valente, Frans P M Cremers, Sandro Banfi, Susanne Roosing, Daan M Panneman, Suzanne E de Bruijn","doi":"10.1016/j.xhgg.2025.100442","DOIUrl":"10.1016/j.xhgg.2025.100442","url":null,"abstract":"<p><p>Splice-altering variants are suggested to be responsible for part of the missing heritability of inherited retinal diseases (IRDs). The interpretation of these variants is challenging as functional evidence is required to validate pathogenicity. We explored the diagnostic value of a targeted long-read cDNA sequencing (lrcDNA-seq) approach to investigate IRD-associated splicing defects. For each affected individual, RNA was isolated from blood, and for each candidate gene, cDNA amplicons, spanning the complete open reading frame or multiple exons, were generated and subjected to long-read sequencing. We validated our approach by assessing previously described pathogenic splice-altering variants in IRD-associated genes. Next, we investigated six genetically unexplained affected individuals, each carrying pathogenic variant(s) in NMNAT1. In two probands, we provided functional validation for previously identified variants of uncertain significance present on the second allele. In four other subjects, lrcDNA-seq revealed the partial inclusion of an SVA_F retrotransposon in the NMNAT1 mRNA, predicted to introduce a premature stop codon. We showed that targeted lrcDNA-seq is effective in characterizing splice defects and in identifying novel splice-altering variants and uncovered the IRD genetic basis for six previously unexplained subjects. We believe that the implementation of this technique has the potential to contribute to an increased diagnostic rate of IRDs.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100442"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mid-pass whole-genome sequencing in a Malagasy cohort uncovers body composition associations.","authors":"Iman Hamid, Séverine Nantenaina Stéphie Raveloson, Germain Jules Spiral, Soanorolalao Ravelonjanahary, Brigitte Marie Raharivololona, José Mahenina Randria, Mosa Zafimaro, Tsiorimanitra Aimée Randriambola, Rota Mamimbahiny Andriantsoa, Tojo Julio Andriamahefa, Bodonomena Fitahiana Laza Rafidison, Mehreen Mughal, Anne-Katrin Emde, Melissa Hendershott, Sarah LeBaron von Baeyer, Kaja A Wasik, Jean Freddy Ranaivoarisoa, Laura Yerges-Armstrong, Stephane E Castel, Rindra Rakotoarivony","doi":"10.1016/j.xhgg.2025.100454","DOIUrl":"10.1016/j.xhgg.2025.100454","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100454"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ERBB2 c.1795C>T, p.Arg599Cys variant is associated with left ventricular outflow tract obstruction defects in humans.","authors":"Minna Ampuja, Sabina Ericsson, Ilkka Paatero, Iftekhar Chowdhury, Jenna Villman, Martin Broberg, Amanda Ramste, Diego Balboa, Tiina Ojala, Jessica X Chong, Michael J Bamshad, James R Priest, Markku Varjosalo, Riikka Kivelä, Emmi Helle","doi":"10.1016/j.xhgg.2025.100446","DOIUrl":"10.1016/j.xhgg.2025.100446","url":null,"abstract":"<p><p>Non-syndromic congenital heart defects (CHDs) are occasionally familial and left ventricular outflow tract obstruction (LVOTO) defects are among the subtypes with the highest hereditability. The aim of this study was to evaluate the pathogenicity of a heterozygous ERBB2 variant c.1795C>T, p.Arg599Cys identified in three families with LVOTO defects. Variant detection was done with exome sequencing. Western blotting, digital PCR, mass spectrometry (MS), MS microscopy, and flow cytometry were used to study the function of the ERBB2 variant c.1795C>T. Cardiac structure and function were studied in zebrafish embryos expressing human ERBB2 wild type or c.1795C>T. Proband-derived human induced pluripotent stem cell cardiomyocytes (hiPS-CMs) and endothelial cells (hiPS-ECs) were used for transcriptomic analyses. While phosphorylation of the ERBB2 p.Arg599Cys receptor was not altered, the variant affected dramatically the binding partners of the protein, indicating mislocalization of the mutant ERBB2 from plasma membrane to endoplasmic reticulum. Expression of human ERBB2 p.Arg599Cys in zebrafish embryos resulted in cardiomyocyte hypertrophy, increased cardiac wall thickness, and impaired fractional shortening. Transcriptomic analyses of hiPS-ECs and hiPS-CMs from an individual with the c.1795C>T variant showed aberrant expression of genes related to cardiovascular system development and abnormal response to oxidative stress in both cell types. In conclusion, the heterozygous variant ERBB2 c.1795C>T, p.Arg599Cys leads to abnormal cellular localization of the ERBB2 receptor and induces structural changes and dysfunction in the zebrafish embryo heart. This evidence expands previous findings from animal studies to humans and suggests variants in ERBB2 may be associated with CHD.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100446"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic ancestry influences gene-environment interactions with sociocultural factors: Results from the Hispanic Community Health Study/Study of Latinos.","authors":"Jayati Sharma, Cristin E McArdle, Mariaelisa Graff, Christina Cordero, Martha Daviglus, Linda C Gallo, Carmen R Isasi, Tanika N Kelly, Krista M Perreira, Gregory A Talavera, Jianwen Cai, Kari E North, Lindsay Fernández-Rhodes, Genevieve L Wojcik","doi":"10.1016/j.xhgg.2025.100451","DOIUrl":"10.1016/j.xhgg.2025.100451","url":null,"abstract":"<p><p>Often, studies will aggregate all participants identified as Hispanic/Latino, despite genetic and environmental substructures, preventing the meaningful interrogation of the roles of genetics and environment in human health. Using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we examined how self-identified background group and genetic ancestry influence gene-environment interactions between body mass index (BMI) and a polygenic score for BMI (PGS_BMI). Participants (n = 7,075) identified with six background groups: Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American. Generalized linear models incorporating complex survey weighting were used to model BMI through joint and stratified (background group, estimated Amerindigenous [AME] ancestry) analyses including PGS_BMI and other health-related variables. Interaction effects were modeled between PGS_BMI and diet and age at immigration. Comparing pooled to background group-stratified analyses, we observe heterogeneous distributions of environmental and sociocultural variables, as well as differing associations with AME ancestry. Within the multivariate model, PGS_BMI performance decreased with increasing AME ancestry. After stratification, PGS-age-at-immigration interactions remained statistically significant in some strata: Mexican background individuals born in the US (50 states/DC) (β = 1.33, p < 0.01), Dominican background individuals 6-12 years old (β = 4.38, p < 0.001), and Cuban background individuals 0-5 years old (β = 2.20, p = 0.015) relative to those ≥ 21 years old at migration. It is vital to understand populations of interest to model them appropriately and prevent possible confounding or misinterpretation. While this work focuses specifically on Hispanic/Latino groups, these lessons are relevant to other groups as we diversify work to better understand gene-environment interactions.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100451"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}