American journal of human genetics最新文献

{"title":"A calcium-sensing receptor allelic series and underdiagnosis of genetically driven hypocalcemia.","authors":"Jeremy B Chang, Connor P Barnhill, Alexander M Apostolov, Marcus M Soliai, Julian Hecker, Jovia L Nierenberg, Lyndsay M Stapleton Smith, Arun S Mathew, Xue Zeng, Jiayin Diao, C Dilanka Fernando, Qingwen Chen, Ben W Dulken, Aleksandr Petukhov, Russ Altman, Tracy M Josephs, Jessica A Lasky-Su, Caroline M Gorvin, Mary Scott Roberts, Scott H Adler, Jonathan C Fox, Christoph Lange, Sun-Gou Ji","doi":"10.1016/j.ajhg.2025.06.013","DOIUrl":"10.1016/j.ajhg.2025.06.013","url":null,"abstract":"<p><p>The availability of genomic sequencing has revealed that variants in genes that cause rare monogenic disorders are relatively common, which raises the question of variant pathogenicity. Autosomal-dominant hypocalcemia type 1 (ADH1) is a rare genetic form of hypoparathyroidism caused by gain-of-function (GoF) variants in the calcium-sensing receptor (CaSR) encoded by CASR. We examined the prevalence, penetrance, and expressivity of GoF CASR variants in the UK Biobank (UKB; n = 433,793), All of Us (AOU; n = 229,987), and Mass General Brigham Biobank (n = 39,081). Individuals with previously reported ADH1-associated variants indeed showed ADH1 symptoms, including hypocalcemia (60% in the UKB and 78% in AOU). However, less than half had an ADH1-relevant diagnosis code (17% in the UKB and 44% in AOU), suggesting that individuals with ADH1 are present in these biobanks but may be underdiagnosed. We then developed a scoring algorithm and identified nine low-frequency ADH1-associated variants, which were further validated using genetic sequencing of individuals with nonsurgical hypoparathyroidism (n = 169) and an in vitro functional assay. These nine variants have an intermediate effect and frequency relative to previously reported ADH1-associated variants, completing an allelic series with respect to serum calcium, and alone are responsible for a symptom burden roughly equivalent to all previously reported ADH1-associated variants. Our work indicates that hypocalcemia due to GoF in CASR with ADH1-associated symptoms is underdiagnosed, provides a deeper understanding of the genotype-phenotype relationship of CASR variants, and illustrates that variants in genes underlying rare disorders may cause a much greater symptom burden than currently appreciated.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1818-1832"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare-variant association studies: When are aggregation tests more powerful than single-variant tests?","authors":"Debraj Bose, Christian Fuchsberger, Michael Boehnke","doi":"10.1016/j.ajhg.2025.07.002","DOIUrl":"10.1016/j.ajhg.2025.07.002","url":null,"abstract":"<p><p>Because single-variant tests are not as powerful for identifying associations with rare variants as for common variants, aggregation tests pooling information from multiple rare variants within genes or other genomic regions were developed. While single-variant tests generally have yielded more associations, recent large-scale biobank studies have uncovered numerous significant findings through aggregation tests. We investigate the range of genetic models for which aggregation tests are expected to be more powerful than single-variant tests for rare-variant association studies. We consider a normally distributed trait following an additive genetic model with c causal out of v total rare variants in an autosomal gene/region with region heritability h², measured in n independent study participants. Analytic calculations assuming independent variants, for which we developed a user-friendly online tool, show that power depends on nh²,c, and v. These analytic calculations and simulations based on 378,215 unrelated UK Biobank participants revealed that aggregation tests are more powerful than single-variant tests only when a substantial proportion of variants are causal and that power is strongly dependent on the underlying genetic model and set of rare variants aggregated. For example, if we aggregate all rare protein-truncating variants (PTVs) and deleterious missense variants, aggregation tests are more powerful than single-variant tests for >55% of genes when PTVs, deleterious missense variants, and other missense variants have 80%, 50%, and 1% probabilities of being causal, with n=100,000 and h²=0.1%. With continued use of single-variant and aggregation tests in rapidly growing studies, our investigation sheds light on the situations favoring each test.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1948-1961"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TransferTWAS: A transfer learning framework for cross-tissue transcriptome-wide association study.","authors":"Daoyuan Lai, Han Wang, Tian Gu, Siqi Wu, Dajiang J Liu, Pak Chung Sham, Yan Dora Zhang","doi":"10.1016/j.ajhg.2025.06.006","DOIUrl":"10.1016/j.ajhg.2025.06.006","url":null,"abstract":"<p><p>Transcriptome-wide association studies (TWASs) utilize gene-expression data to explore the genetic basis of complex traits. A key challenge in TWASs is developing robust imputation models for tissues with limited sample sizes. This paper introduces transfer learning-assisted TWAS (TransferTWAS), a framework that adaptively transfers information from multiple tissues to improve gene-expression prediction in the target tissue. TransferTWAS employs a data-driven strategy that assigns higher weights to genetically similar external tissues. It outperforms other multi-tissue TWAS methods, such as the Unified Test for Molecular Signatures (UTMOST), which neglects tissue similarity, and Joint-Tissue Imputation (JTI), which relies on functional annotations to represent tissue similarity. Simulation studies demonstrate that TransferTWAS achieves the highest imputation accuracy, and analyses using the ROS/MAP and GEUVADIS datasets show a substantial power gain while maintaining control over type-I errors. Furthermore, analysis of the low-density lipoprotein cholesterol GWAS dataset and other complex traits demonstrates that TransferTWAS effectively identifies more associations compared with existing methods.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1936-1947"},"PeriodicalIF":8.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Public preferences for the value and implementation of genomic newborn screening: Insights from two discrete choice experiments in Australia.","authors":"Riccarda Peters, Stephanie Best, Fiona Lynch, Danya F Vears, Lilian Downie, Alison D Archibald, Sebastian Lunke, Zornitza Stark, Ilias Goranitis","doi":"10.1016/j.ajhg.2025.05.001","DOIUrl":"10.1016/j.ajhg.2025.05.001","url":null,"abstract":"<p><p>Integrating genomic sequencing into newborn screening (NBS) has transformative potential for the identification and management of genetic conditions. Using discrete choice experiment surveys, we elicited the preferences, values, and priorities of 2,509 members of the Australian public about the value (n = 1,504) and implementation (n = 1,005) of genomic NBS (gNBS). The Australian public demonstrated positive preference for gNBS, with 90% of respondents indicating an interest in gNBS results. Cost of screening was the most important attribute in people's decision about uptake of gNBS. Enabling diagnosis in more newborns increases the utility of gNBS. To enable these diagnoses, the public is willing to accept less restrictive models of gNBS in terms of the types of conditions included. However, there is disutility associated with including conditions that have less effective (or no) treatments available and including conditions with reduced penetrance. A gNBS program yielding 10-50 additional diagnoses per 1,000 newborns screened relative to standard NBS was valued by the Australian public at AU$4,600-$5,700 (US$2,990-$3,700) per newborn screened. Most participants (65%) preferred an opt-in type of consent and expressed a preference to receive high-chance results in person from a genetics professional, although telehealth and phone options were acceptable. Our findings should inform economic evaluation and future implementation for gNBS in the Australian and other healthcare systems.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1515-1527"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptome-wide Mendelian randomization and colocalization analyses uncover cell-specific mechanisms in atherosclerotic cardiovascular disease.","authors":"Anushree Ray, Paulo Alabarse, Rainer Malik, Muralidharan Sargurupremraj, Jürgen Bernhagen, Martin Dichgans, Sebastian-Edgar Baumeister, Marios K Georgakis","doi":"10.1016/j.ajhg.2025.06.001","DOIUrl":"10.1016/j.ajhg.2025.06.001","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) have identified numerous genetic loci influencing human disease risk; however, linking these to causal genes remains challenging, limiting opportunities for drug target discovery. Transcriptome-wide association studies (TWASs) address this by linking variants to gene expression but typically rely on bulk RNA sequencing, limiting cell-specific resolution. Here, we present a single-cell TWAS pipeline combining cis-Mendelian randomization (MR) with colocalization analyses at the single-cell level. As a case study, we examined how genetically proxied gene expression in immune cells influences atherosclerotic cardiovascular disease (ASCVD) risk. We integrated single-cell expression quantitative trait loci (sc-eQTLs) for 14 immune cell types with GWASs for coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. sc-cis-MR revealed 440 gene-outcome associations across cell types, 88% of which were missed by bulk TWASs, despite the considerably smaller sample size of the sc-eQTL dataset. Of these associations, 21 were replicated with external cis-eQTLs and colocalized with ASCVD GWAS signals. Expanding on previous evidence linking genetically proxied LIPA expression in whole blood to coronary artery disease, we found genetic variants influencing LIPA expression, particularly in monocytes, to drive associations with coronary artery disease, large artery atherosclerotic stroke, and subclinical atherosclerosis traits. A phenome-wide association study confirmed these findings without evidence of associations with unexpected clinical outcomes. scRNA sequencing and immunohistochemistry of human carotid plaques revealed high LIPA expression in plaque macrophages. Our pipeline enables the discovery of cell-specific expression patterns that drive genetic predisposition to human disease, potentially impacting target selection for cell-tailored therapeutics.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1597-1609"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.","authors":"Michele Nicastro, Alexa M C Vermeer, Pieter G Postema, Rafik Tadros, Forrest Z Bowling, Hildur M Aegisdottir, Vinicius Tragante, Lukas Mach, Alex V Postma, Elisabeth M Lodder, Karel van Duijvenboden, Rob Zwart, Leander Beekman, Lingshuang Wu, Sean J Jurgens, Paul A van der Zwaag, Mariëlle Alders, Mona Allouba, Yasmine Aguib, J Luis Santome, David de Una, Lorenzo Monserrat, Antonio M A Miranda, Kazumasa Kanemaru, James Cranley, Ingeborg E van Zeggeren, Eleonora M A Aronica, Michela Ripolone, Simona Zanotti, Gardar Sveinbjornsson, Erna V Ivarsdottir, Hilma Hólm, Daníel F Guðbjartsson, Ástrós Th Skúladóttir, Kári Stefánsson, Lincoln Nadauld, Kirk U Knowlton, Sisse Rye Ostrowski, Erik Sørensen, Ole Birger Vesterager Pedersen, Jonas Ghouse, Søren A Rand, Henning Bundgaard, Henrik Ullum, Christian Erikstrup, Bitten Aagaard, Mie Topholm Bruun, Mette Christiansen, Henrik K Jensen, Deanna Alexis Carere, Christopher T Cummings, Kristen Fishler, Pernille Mathiesen Tørring, Klaus Brusgaard, Trine Maxel Juul, Lotte Saaby, Bo Gregers Winkel, Jens Mogensen, Francesco Fortunato, Giacomo Pietro Comi, Dario Ronchi, J Peter van Tintelen, Michela Noseda, Michael V Airola, Imke Christiaans, Arthur A M Wilde, Ronald Wilders, Sally-Ann Clur, Arie O Verkerk, Connie R Bezzina, Najim Lahrouchi","doi":"10.1016/j.ajhg.2025.04.016","DOIUrl":"10.1016/j.ajhg.2025.04.016","url":null,"abstract":"<p><p>POPDC2 encodes the Popeye domain-containing protein 2, which has an important role in cardiac pacemaking and conduction, due in part to its cyclic AMP (cAMP)-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia, and morpholino-mediated knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in four families with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. Using homology modeling, we show that the identified variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies, we demonstrated that, in contrast with wild-type POPDC2, variants found in affected individuals failed to increase TREK-1 current density. While muscle biopsy of an affected individual did not show clear myopathic disease, it showed significantly reduced abundance of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in either protein. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and POPDC2 was most prevalent in AV node, AV node pacemaker, and AV bundle cells. Using population-level genetic data of more than 1 million individuals, we show that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for bi-allelic variants in POPDC2 causing a Mendelian autosomal recessive cardiac syndrome.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1681-1698"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic contributions to epigenetic-defined endotypes of allergic phenotypes in children.","authors":"Emma E Thompson, Xiaoyuan Zhong, Peter Carbonetto, Andréanne Morin, Jason Willwerscheid, Cynthia M Visness, Leonard B Bacharier, Meyer Kattan, George T O'Connor, Katherine Rivera-Spoljaric, Robert A Wood, Diane R Gold, Gurjit K Khurana Hershey, Christine C Johnson, Rachel L Miller, Christine M Seroogy, Edward M Zoratti, Peter J Gergen, Albert M Levin, Matthew C Altman, Tina Hartert, Matthew Stephens, Daniel J Jackson, James E Gern, Christopher G McKennan, Carole Ober","doi":"10.1016/j.ajhg.2025.05.006","DOIUrl":"10.1016/j.ajhg.2025.05.006","url":null,"abstract":"<p><p>Asthma is a common respiratory disease, with contributions from both genes and the environment and significant heterogeneity in underlying endotypes; yet, little is known about the relative contributions of each to these endotypes. To address this gap, we used nasal mucosal cell DNA methylation (DNAm) and gene expression and genotypes for 284 children in the Urban Environment and Childhood Asthma (URECA) birth cohort. Using an unbiased data-reduction approach and 37,256 CpGs on a custom-content Asthma&Allergy array, empirical Bayesian factorization was implemented to identify three DNAm signatures that were associated with phenotypes reflecting allergic diseases (allergic asthma and allergic rhinitis), allergic sensitization (atopy) (specific and total immunoglobulin E), and/or type 2 inflammation (eosinophil count and fractional exhaled nitric oxide [FeNO]). These associations were replicated in the Infant Susceptibility to Pulmonary Infections and Asthma (INSPIRE) and the Children's Respiratory Environment Workgroup (CREW) cohorts. The genes that were correlated with each signature in URECA reflected three cardinal endotypes of asthma: inhibited immune response to microbes, impaired epithelial barrier integrity, and activated type 2 immune pathways. To estimate the genetic contributions to these signatures, we used a common set of genotypes available in the three cohorts. The joint SNP heritability of each signature was 0.21 (p = 0.037), 0.26 (p = 1.7 × 10^-8), and 0.17 (p = 7.7 × 10^-6), respectively. The heritabilities of the DNAm signatures suggest that genetic variation contributes significantly to epigenetic signatures of allergic phenotypes and that susceptibility to the development of specific endotypes of asthma is present at birth and is poised to mediate individual epigenetic responses to early-life environments.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 7","pages":"1610-1624"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward whole-genome inference of polygenic scores with fast and memory-efficient algorithms.","authors":"Shadi Zabad, Chirayu Anant Haryan, Simon Gravel, Sanchit Misra, Yue Li","doi":"10.1016/j.ajhg.2025.05.002","DOIUrl":"10.1016/j.ajhg.2025.05.002","url":null,"abstract":"<p><p>With improved whole-genome sequencing and variant imputation techniques, modern genome-wide association studies (GWASs) have enriched our understanding of the landscape of genetic associations for thousands of disease phenotypes. However, translating the marginal associations for millions of genetic variants to integrated polygenic risk scores (PRSs) that capture their joint effects on the phenotype remains a major challenge. Due to technical and statistical constraints, commonly used PRS methods in this setting either perform heuristic pruning and thresholding or overlook most genetic association signals by restricting inference to small variant sets, such as HapMap3. Here, we present a set of algorithmic improvements and compact data structures that enable scaling summary-statistics-based PRS inference to tens of millions of variants while avoiding numerical instabilities common in such high-dimensional settings. These enhancements consist of highly compressed linkage-disequilibrium (LD) matrix format, which integrates with streamlined and parallel coordinate-ascent updating schemes. When incorporated into our existing PRS method (VIPRS), the proposed algorithms yield over 50-fold reductions in storage requirements and lead to orders-of-magnitude improvements in runtime and memory efficiency. The updated VIPRS software can now perform variational Bayesian regression over 1.1 million HapMap3 variants in under a minute. Using this scalable implementation, we applied VIPRS to 75 of the most heritable, continuous phenotypes in the UK Biobank, leveraging marginal associations for up to 18 million bi-allelic variants. These experiments demonstrated that VIPRS is 1-2 orders of magnitude more efficient than popular baselines while being competitive with the best-performing methods in terms of prediction accuracy.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1528-1546"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.","authors":"Hana Antonicka, Woranontee Weraarpachai, Katherine M Szigety, Robert Kopajtich, James B Gibson, Johan L K Van Hove, Marisa W Friederich, Piervito Lopriore, Christiane Neuhofer, Roxanne A Van Hove, Michel A Cole, Richard Reisdorph, James T Peterson, Katherine J Dempsey, Rebecca D Ganetzky, Michelangelo Mancuso, Holger Prokisch, Eric A Shoubridge","doi":"10.1016/j.ajhg.2025.05.007","DOIUrl":"10.1016/j.ajhg.2025.05.007","url":null,"abstract":"<p><p>Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia. Among the three subjects, we identified three missense variants and two frameshift variants leading to a premature stop codon. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. These cases of mitochondrial disease associated with bi-allelic variants in FASTKD5 add to a growing list of primary genetic mutations causing Leigh syndrome associated with complex IV deficiency.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1699-1710"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural selection acting on complex traits hampers the predictive accuracy of polygenic scores in ancient samples.","authors":"Valeria Añorve-Garibay, Emilia Huerta-Sanchez, Mashaal Sohail, Diego Ortega-Del Vecchyo","doi":"10.1016/j.ajhg.2025.05.009","DOIUrl":"10.1016/j.ajhg.2025.05.009","url":null,"abstract":"<p><p>The prediction of phenotypes from ancient humans has gained interest due to its potential to investigate the evolution of complex traits. These predictions are commonly performed using polygenic scores computed with DNA information from ancient humans along with genome-wide association study (GWAS) data from present-day humans. However, numerous evolutionary processes could impact these phenotypic predictions. In this work, we investigate how natural selection shapes the temporal dynamics of variants with an effect on the trait and how these changes impact phenotypic predictions for ancient individuals using polygenic scores. We find that stabilizing selection accelerates the loss of large-effect alleles contributing to trait variation. Conversely, directional selection accelerates the loss of small- and large-effect alleles that drive individuals farther away from the optimal phenotypic value. These phenomena result in specific shared genetic variation patterns between ancient and modern populations that hamper the accuracy of polygenic scores to predict phenotypes. Our results assume perfectly estimated effect sizes at the causal loci of complex traits segregating in a GWAS performed in the present and, therefore, provide a putatively loose upper bound on the polygenic score portability to predict traits in the past. Furthermore, we show how natural selection could impact the predictive accuracy of ancient polygenic scores for two widely studied traits: height and body mass index. Our results emphasize the importance of considering decreases on the reliability of polygenic scores to perform phenotypic predictions in ancient individuals due to allele frequency changes driving the loss of alleles via natural selection.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1547-1561"},"PeriodicalIF":8.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}