American journal of human genetics最新文献_第5页

The Gabriella Miller Kids First Data Resource for genomic research in pediatric cancer and congenital anomalies 加布里埃拉·米勒儿童第一数据资源，用于儿童癌症和先天性异常的基因组研究

IF 9.8 1区生物学

American journal of human genetics Pub Date : 2026-08-17 DOI: 10.1016/j.ajhg.2026.07.010

David M. Higgins, Christopher Blackden, Miguel Brown, Christina Diaz, Leslie Duffy, Christopher Friedman, Yiran Guo, Mateusz Koptyra, Qi Li, Alex Lubneuski, Dan Miller, Bobby Moulder, Wendy Payton, Emily Reed, Whitney Rife, Alex Sickler, Natasha Singh, Amanda Warkow, Eric Wenger, Jessica Wong, Bo Zhang, Chuwei Zhong, Yuankun Zhu, Gaelle Altefrohne, Denis Beauregard, Jeremy Costanza, Evans Girard, Luc-Frederic Langis, Lucas Lemonnier, Adrian Paul, Céline Pelletier, Karine St-Onge, Jean-Philippe Thibert, Michele Mattioni, Surya Saha, Jared Rozowsky, Milos Trboljevac, Marko Zecevic, Jeff Knight, Gina Kuffel, Radhika Reddy, Pauline Ribeyre, Bailey Farrow, Yelena Cox, Andrew Ericson, Jamed Ferreris Vargas, Sophie Forman, Sofia Labrecque, Eric Torstenson, Kai Yin Ho, Nicole A. Vasilevsky, Emily Boja, Valerie Cotton, Danielle Daee, Marcia V. Fournier, Jaime M. Guidry Auvil, Andréa C. Harris, Huiqing Li, Lu Wang, Brandi Davis-Dusenbery, Melissa A. Haendel, Jena Lilly, Phillip B. Storm, Sam Volchenboum, Robert L. Grossman, Robert Carroll, Jack DiGiovanna, Deanne Taylor, Vincent Ferretti, Adam Resnick, Allison P. Heath

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Shared inheritance reveals landscape of somatic and germline cancer risk in TP53 共同遗传揭示了TP53中体细胞和种系癌症风险的格局

IF 9.8 1区生物学

American journal of human genetics Pub Date : 2026-08-17 DOI: 10.1016/j.ajhg.2026.07.011

Hamish A.J. MacGregor, Jamie R. Blundell, Douglas F. Easton

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Anthropometric and cardio-metabolic trait variation and genetic associations in sub-Saharan Africa 撒哈拉以南非洲的人体测量和心脏代谢性状变异及其遗传关联

IF 9.8 1区生物学

American journal of human genetics Pub Date : 2026-08-12 DOI: 10.1016/j.ajhg.2026.07.006

Matthew E.B. Hansen, Ujani Hazra, Michelle Kim, Srilakshmi M. Raj, Shaohua Fan, William Beggs, Sunungouko Wata Mpoloka, Gaonyadiwe George Mokone, Thomas Nyambo, Dawit Wolde Meskel, Gurja Belay, Jibril Hirbo, Alessia Ranciaro, Joseph Lachance, Sarah A. Tishkoff

引用次数: 0

Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes. 非蛋白质编码次要剪接体成分RNU6ATAC和RNU4ATAC的双等位基因变异导致综合征性单基因自身免疫性糖尿病。

IF 7.7 1区生物学

American journal of human genetics Pub Date : 2026-08-06 Epub Date: 2026-07-14 DOI: 10.1016/j.ajhg.2026.07.003

Matthew B Johnson, James Russ-Silsby, Paul A Blair, Molly Govier, Georgia Bonfield, Clara Domingo-Vila, Matthew N Wakeling, Richard A Oram, Sarah E Flanagan, Timothy I M Tree, Kashyap A Patel, Andrew T Hattersley, Elisa De Franco

引用次数: 0

This month in The Journal 本月的《华尔街日报》

IF 9.8 1区生物学

American journal of human genetics Pub Date : 2026-08-06 DOI: 10.1016/j.ajhg.2026.07.009

Paul W. Hook,Alyson B. Barnes

引用次数: 0

Position effect at the SOX3 locus by an interchromosomal insertion causes hereditary spastic paraplegia. 染色体间插入在SOX3位点的位置效应导致遗传性痉挛性截瘫。

IF 7.7 1区生物学

American journal of human genetics Pub Date : 2026-08-06 Epub Date: 2026-07-24 DOI: 10.1016/j.ajhg.2026.07.001

Thorkild Terkelsen, Veronica Yumiceba, Joshua Kim, Uirá Souto Melo, Esben Axelgaard, Fabia Febbraro, Anders Vermelin Gunnarsson, Saranya Balachandran, Mikkel Dahl-Jessen, Rikke Christensen, Brock Andrew Peters, Asan, Thomas Thelle, Mette Nyegaard, Rasmus O Bak, Mark Denham, Malte Spielmann, Uffe Birk Jensen

{"title":"Position effect at the SOX3 locus by an interchromosomal insertion causes hereditary spastic paraplegia.","authors":"Thorkild Terkelsen, Veronica Yumiceba, Joshua Kim, Uirá Souto Melo, Esben Axelgaard, Fabia Febbraro, Anders Vermelin Gunnarsson, Saranya Balachandran, Mikkel Dahl-Jessen, Rikke Christensen, Brock Andrew Peters, Asan, Thomas Thelle, Mette Nyegaard, Rasmus O Bak, Mark Denham, Malte Spielmann, Uffe Birk Jensen","doi":"10.1016/j.ajhg.2026.07.001","DOIUrl":"10.1016/j.ajhg.2026.07.001","url":null,"abstract":"Pathogenic rewiring of the three-dimensional (3D) genome architecture is increasingly being identified as the cause of genetic diseases, but recognizing the cis-regulatory effects of structural variation remains a challenge. The Xq27.1 region contains a quasi-palindrome identified as a pleiotropic hotspot for disease-causing interchromosomal insertions. In a large Danish family affected by X-linked recessive complex spastic paraplegia, we identified the segregation of a 149-kb interchromosomal insertion at Xq27.1 originating from 4q24. To understand the disease mechanism, we generated induced pluripotent stem cells (iPSCs) from affected individuals. Using CRISPR perturbation and neural differentiation experiments combined with high-throughput chromatin conformation capture (Hi-C) and transcriptomic analyses, we identify a 3D regulatory rewiring of SOX3 and transcriptional dysregulation of SOX3 targets in iPSC-derived neurons. Consistent with regulatory partitioning of the SOX3 topologically associating domain (TAD) in affected individuals, our experiments show that upstream cis-regulatory elements have a reduced ability to activate SOX3 expression and that the observed dysregulation depends on CTCF-binding sites within the insertion. This work provides mechanistic evidence that a position effect at the SOX3 locus can cause hereditary spastic paraplegia.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1736-1753"},"PeriodicalIF":7.7,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583423","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}

引用次数: 0

Response to Quinodoz and Leroy. 对喹诺多滋和勒罗伊的回应。

IF 7.7 1区生物学

American journal of human genetics Pub Date : 2026-08-06 DOI: 10.1016/j.ajhg.2026.06.011

Kirill Zaslavsky, Liyin Chen, Chloe Park, Emily M Place, Daniel Navarro-Gomez, Seyedeh M Zekavat, Christopher F Barile, Kinga M Bujakowska, Elizabeth J Rossin, Eric A Pierce

引用次数: 0

Mismapping of sequencing reads from polymorphic duplications generates spurious trans-eQTLs. 多态复制序列的错误定位会产生虚假的反式eqtl。

IF 7.7 1区生物学

American journal of human genetics Pub Date : 2026-08-06 Epub Date: 2026-07-28 DOI: 10.1016/j.ajhg.2026.07.004

Alber Aqil, Betty Y H Huang, Pavlos Pavlidis, Rajiv C McCoy, Omer Gokcumen

{"title":"Mismapping of sequencing reads from polymorphic duplications generates spurious trans-eQTLs.","authors":"Alber Aqil, Betty Y H Huang, Pavlos Pavlidis, Rajiv C McCoy, Omer Gokcumen","doi":"10.1016/j.ajhg.2026.07.004","DOIUrl":"10.1016/j.ajhg.2026.07.004","url":null,"abstract":"The discovery of trans-acting expression quantitative trait loci (trans-eQTLs) remains plagued by false positives. One unaddressed source of these false positives is polymorphic duplications absent in the reference genome. Specifically, RNA sequencing (RNA-seq) reads from a non-reference gene duplicate have the potential to erroneously map to the single reference copy of the gene. These mismapped RNA-seq reads could generate spurious trans-eQTLs that localize near the insertion site of the non-reference duplicate but appear to regulate the reference copy of the gene. In such scenarios, similarly mismapped DNA-seq reads would create apparent long-range linkage disequilibrium between the spurious trans-eQTL and its target gene's locus. We call this footprint \"mismapping linkage disequilibrium\" and use it to flag spurious trans-eQTLs. We applied this strategy to published trans-eQTLs from Genotype-Tissue Expression (GTEx) and newly generated trans-eQTLs from MAGE, both already filtered for calls attributable to cross-mappability of RNA-seq reads between reference duplicates. This strategy demonstrated that at least 15.4% and 6.1% of trans-eQTLs in GTEx and MAGE, respectively, are spurious due to non-reference polymorphic duplications. We find that spurious trans-eQTLs are more likely to have large effect sizes. Thus, we expect large-sample studies such as eQTLGen (n > 30,000), which are powered to detect many more small-effect trans-eQTLs, to harbor smaller proportions of spurious trans-eQTLs than smaller studies such as GTEx (n = 838) and MAGE (n = 731). The polymorphic duplication of DUSP22 demonstrates how mismapping linkage disequilibrium can uncover both false-positive trans-eQTLs and trans-acting splicing QTLs (trans-sQTLs). Overall, our study offers a practical metric to improve trans-eQTL filtering.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1604-1617"},"PeriodicalIF":7.7,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597684","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}

引用次数: 0

Transforming blood-derived episignatures into cell-type-agnostic classifiers: A shortcut to prenatal episignatures. 将血液衍生的表观特征转化为与细胞类型无关的分类：产前表观特征的捷径。

IF 7.7 1区生物学

American journal of human genetics Pub Date : 2026-08-06 Epub Date: 2026-07-23 DOI: 10.1016/j.ajhg.2026.06.017

Nikola Reko, Arteen Torabi-Marashi, Prajkta Kallurkar, Sarah J Goodman, Zain Awamleh, Andrei L Turinsky, Daria Grafodatskaya, Bianca E Russell, Karen Chong, Jung Min Ko, Ebba Alkhunaizi, David Chitayat, Elena Greenfeld, Stephen W Scherer, Elizabeth McCready, Rosanna Weksberg, Sanaa Choufani

{"title":"Transforming blood-derived episignatures into cell-type-agnostic classifiers: A shortcut to prenatal episignatures.","authors":"Nikola Reko, Arteen Torabi-Marashi, Prajkta Kallurkar, Sarah J Goodman, Zain Awamleh, Andrei L Turinsky, Daria Grafodatskaya, Bianca E Russell, Karen Chong, Jung Min Ko, Ebba Alkhunaizi, David Chitayat, Elena Greenfeld, Stephen W Scherer, Elizabeth McCready, Rosanna Weksberg, Sanaa Choufani","doi":"10.1016/j.ajhg.2026.06.017","DOIUrl":"10.1016/j.ajhg.2026.06.017","url":null,"abstract":"DNA methylation (DNAm) episignatures are stable disorder-specific epigenetic patterns that serve as valuable biomarkers for assessing variant pathogenicity and phenotypic outcomes in neurodevelopmental disorders (NDDs). However, episignatures derived from whole blood are inherently tissue- and cell-type specific, limiting their applicability in prenatal diagnostics. To explore the feasibility of developing episignatures capable of informing variant pathogenicity across tissues and developmental stages, we conducted a proof-of-concept study using Down syndrome, a common NDD caused by trisomy 21 (T21). We generated a blood-derived T21 episignature using a large cohort of 266 samples. Next, we used that episignature and publicly available DNAm data for 850 T21 and control samples across six different pre- and postnatal tissues to train machine-learning models, thereby enabling accurate prediction of T21 status across all tested tissues. Notably, our results show that models trained on postnatal blood-derived signatures as well as other tissues can generate cell-type-agnostic disease-specific patterns. This method also supported integrating well-characterized postnatal episignatures with a limited set of prenatal samples, which generated an episignature capable of accurately classifying prenatal samples. This approach forges a path for cross-tissue DNAm biomarker development and lays the groundwork for a workflow to rapidly integrate episignatures into prenatal diagnostics.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1665-1678"},"PeriodicalIF":7.7,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576804","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}

引用次数: 0

Allele frequency trajectories across age groups reveal ongoing natural selection shaping disease susceptibility. 不同年龄组的等位基因频率轨迹揭示了形成疾病易感性的持续自然选择。

IF 7.7 1区生物学

American journal of human genetics Pub Date : 2026-08-06 Epub Date: 2026-07-24 DOI: 10.1016/j.ajhg.2026.07.002

Jing-Lian Chen, Mei-Ling Kang, Cheng-Jui Lin, Yun-Hua Lo, Yann-Jang Chen, Hsiao-Hui Lee, Valis Tanapima, Chao-Kuang Lin, I-Hui Lee, Yoko Satta, Wen-Ya Ko

{"title":"Allele frequency trajectories across age groups reveal ongoing natural selection shaping disease susceptibility.","authors":"Jing-Lian Chen, Mei-Ling Kang, Cheng-Jui Lin, Yun-Hua Lo, Yann-Jang Chen, Hsiao-Hui Lee, Valis Tanapima, Chao-Kuang Lin, I-Hui Lee, Yoko Satta, Wen-Ya Ko","doi":"10.1016/j.ajhg.2026.07.002","DOIUrl":"10.1016/j.ajhg.2026.07.002","url":null,"abstract":"Understanding how selection shapes disease risk remains challenging. Variants influencing complex traits, including common diseases, can also impact fitness and thus be constrained by purifying selection. Consequently, genetic variance underlying disease susceptibility may be attributed to low-frequency, population-specific variants. We analyzed 509,817 genome-wide variants from 72,635 Han Taiwanese individuals to identify loci showing age-dependent allele frequency shifts that signal ongoing selection. After adjusting for potential age-related population structure, we detected 168 variants deviating from neutrality, with most showing declining frequencies in younger generations, consistent with purifying selection on deleterious alleles influencing disease risk. These variants were enriched for rare alleles (≤0.1%) and disease-associated variants. At BRCA1, we identified 16 rare pathogenic variants in strong linkage disequilibrium undergoing purifying selection that coexist with a positively selected haplotype, revealing temporally fluctuating selection; comparable patterns at BRCA2 and MLH1 suggest recurrent selective trade-offs in DNA repair genes. Phenome-wide association analysis across 30 hematologic and cardiometabolic traits linked a subset of candidates to increased erythrocyte volume and reduced hemoglobin concentration, suggesting subclinical physiological effects. These results demonstrate ongoing natural selection on disease-relevant variation, particularly affecting hematologic traits in the Han Taiwanese population, and highlight opportunities to refine precision-medicine risk models.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1585-1603"},"PeriodicalIF":7.7,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583399","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}

引用次数: 0