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Transcriptome-wide analyses delineate the genetic architecture of expression variation in atopic dermatitis. 转录组分析描述了特应性皮炎表达变异的遗传结构。
IF 3.3
HGG Advances Pub Date : 2025-04-10 Epub Date: 2025-02-26 DOI: 10.1016/j.xhgg.2025.100422
Charalabos Antonatos, Dimitra Mitsoudi, Alexandros Pontikas, Adam Akritidis, Panagiotis Xiropotamos, Georgios K Georgakilas, Sophia Georgiou, Aikaterini Tsiogka, Stamatis Gregoriou, Katerina Grafanaki, Yiannis Vasilopoulos
{"title":"Transcriptome-wide analyses delineate the genetic architecture of expression variation in atopic dermatitis.","authors":"Charalabos Antonatos, Dimitra Mitsoudi, Alexandros Pontikas, Adam Akritidis, Panagiotis Xiropotamos, Georgios K Georgakilas, Sophia Georgiou, Aikaterini Tsiogka, Stamatis Gregoriou, Katerina Grafanaki, Yiannis Vasilopoulos","doi":"10.1016/j.xhgg.2025.100422","DOIUrl":"10.1016/j.xhgg.2025.100422","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) for atopic dermatitis (AD) have uncovered 81 risk loci in European participants; however, translating these findings into functional and therapeutic insights remains challenging. We conducted a transcriptome-wide association study (TWAS) in AD leveraging cis-eQTL data from sun exposed (n = 517), non-sun exposed skin (n = 602) and whole blood (n = 670) tissues and the latest GWAS of AD in Europeans (n = 864982). We implemented the OTTERS pipeline that combines polygenic risk score (PRS) techniques accommodating diverse assumptions in the architecture of gene regulation. We also used differential expression meta-analysis and co-expression networks (n = 186) to characterize the transcriptomic landscape of AD. We identified 176 gene-tissue associations covering 126 unique genes (53 previously unreported). Most TWAS risk genes were identified by adaptive PRS frameworks, with non-significant differences compared with clumping and thresholding approaches. TWAS risk genes were enriched in allergic reactions (e.g., AQP7, AFF4), skin barrier integrity (e.g., ACER3), and inflammatory pathways (e.g., TAPBPL). By integrating co-expression networks of lesional AD skin, we identified 16 hub genes previously identified as TWAS risk genes (six previously unreported) that orchestrate inflammatory responses (e.g., HSPA4) and keratinization (e.g., LCE3E, LCE3D), serving as potential drug targets through drug-gene interactions. Consistent associations between all analyses were reported for FOSL1 and RORC. Collectively, our findings provide additional risk genes for AD with potential implications in therapeutic approaches.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100422"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524639","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}
引用次数: 0
Unbiased causal inference with Mendelian randomization and covariate-adjusted GWAS data. 用孟德尔随机化和协变量校正的GWAS数据进行无偏因果推理。
IF 3.3
HGG Advances Pub Date : 2025-04-10 Epub Date: 2025-01-30 DOI: 10.1016/j.xhgg.2025.100412
Peiyao Wang, Zhaotong Lin, Wei Pan
{"title":"Unbiased causal inference with Mendelian randomization and covariate-adjusted GWAS data.","authors":"Peiyao Wang, Zhaotong Lin, Wei Pan","doi":"10.1016/j.xhgg.2025.100412","DOIUrl":"10.1016/j.xhgg.2025.100412","url":null,"abstract":"<p><p>Mendelian randomization (MR) facilitates causal inference with observational data using publicly available genome-wide association study (GWAS) results. In a GWAS, one or more heritable covariates may be adjusted for to estimate the direct effects of SNPs on a focal trait or to improve statistical power, which may introduce collider bias in SNP-trait association estimates, thus affecting downstream MR analyses. Numerical studies suggested that using covariate-adjusted GWAS summary data might introduce bias in univariable Mendelian randomization (UVMR), which can be mitigated by multivariable Mendelian randomization (MVMR). However, it remains unclear and even mysterious why/how MVMR works; a rigorous theory is needed to explain and substantiate the above empirical observation. In this paper, we derive some analytical results when multiple covariates are adjusted for in the GWAS of exposure and/or the GWAS of outcome, thus supporting and explaining the empirical results. Our analytical results offer insights to how bias arises in UVMR and how it is avoided in MVMR, regardless of whether collider bias is present. We also consider applying UVMR or MVMR methods after collider-bias correction. We conducted extensive simulations to demonstrate that with covariate-adjusted GWAS summary data, MVMR had an advantage over UVMR by producing nearly unbiased causal estimates; however, in some situations it is advantageous to apply UVMR after bias correction. In real data analyses of the GWAS data with body mass index (BMI) being adjusted for metabolomic principal components, we examined the causal effect of BMI on blood pressure, confirming the above points.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100412"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075715","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}
引用次数: 0
Multi-tissue transcriptome-wide association study identifies novel candidate genes and pleiotropy effects across four abdominal hernia subtypes. 多组织转录组关联研究确定了四种腹疝亚型的新候选基因和多效性效应。
IF 3.3
HGG Advances Pub Date : 2025-04-09 DOI: 10.1016/j.xhgg.2025.100436
Dima L Chaar, Chen Jiang, Brandon Cowan, Sahil Patel, Mark Kvale, Jie Yin, Rouzbeh Mostaedi, Nadav Ahituv, Eric Jorgenson, Thomas J Hoffmann, Hélène Choquet
{"title":"Multi-tissue transcriptome-wide association study identifies novel candidate genes and pleiotropy effects across four abdominal hernia subtypes.","authors":"Dima L Chaar, Chen Jiang, Brandon Cowan, Sahil Patel, Mark Kvale, Jie Yin, Rouzbeh Mostaedi, Nadav Ahituv, Eric Jorgenson, Thomas J Hoffmann, Hélène Choquet","doi":"10.1016/j.xhgg.2025.100436","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100436","url":null,"abstract":"<p><p>Abdominal hernias are caused by the protrusion of an organ or tissue through a weakened abdominal wall. Genome-wide association studies (GWASs) have identified 81 genetic susceptibility loci for different hernia subtypes, with 26 loci associated with more than one hernia type; however, additional work is needed to prioritize causal genes at known GWAS loci, identify novel ones, and characterize shared genetic effects across hernia subtypes. We conduct transcriptome-wide association study (TWAS) analyses of four hernia subtypes (i.e., inguinal, umbilical, ventral, femoral) using GWAS summary statistics from up to 57,291 hernia cases and 436,717 controls of European ancestry. Our TWAS, which leveraged imputed gene expression from 54 tissues, identifies 211 unique genes, of which 85 did not overlap with known hernia-associated loci. We also investigate patterns of pleiotropy and identify four genes (LYPLAL1-AS1, RIMKLBP2, AL513283.1, and EFEMP1) associated with all four hernia subtypes. Our findings enhance understanding of transcriptomic mechanisms through which hernias develop.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100436"},"PeriodicalIF":3.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988280","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}
引用次数: 0
Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4. 家族性肌萎缩侧索硬化症4型中显性SETX突变的等位基因特异性沉默
IF 3.3
HGG Advances Pub Date : 2025-04-08 DOI: 10.1016/j.xhgg.2025.100435
Audrey Winkelsas, Athena Apfel, Brian Johnson, George Harmison, Kimberly Diaz Perez, Dongjun Li, Vivian G Cheung, Christopher Grunseich
{"title":"Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.","authors":"Audrey Winkelsas, Athena Apfel, Brian Johnson, George Harmison, Kimberly Diaz Perez, Dongjun Li, Vivian G Cheung, Christopher Grunseich","doi":"10.1016/j.xhgg.2025.100435","DOIUrl":"10.1016/j.xhgg.2025.100435","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele while sparing the wild-type allele and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100435"},"PeriodicalIF":3.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812657","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}
引用次数: 0
Multiple molecular diagnoses identified through genome sequencing in individuals with suspected rare disease. 通过基因组测序在疑似罕见疾病的个体中鉴定出多种分子诊断。
IF 3.3
HGG Advances Pub Date : 2025-04-07 DOI: 10.1016/j.xhgg.2025.100430
Alka Malhotra, Erin Thorpe, Alison J Coffey, Revathi Rajkumar, Josephine Adjeman, Naomi Dianne Naa Adjeley Adjetey, Sharron Aglobitse, Felix Allotey, Todor Arsov, Joyce Ashong, Ebenezer Vincent Badoe, Donald Basel, Yvonne Brew, Chester Brown, Kerri Bosfield, Kari Casas, Mario Cornejo-Olivas, Laura Davis-Keppen, Abbey Freed, Kate Gibson, Parul Jayakar, Marilyn C Jones, Martina Kawome, Aimé Lumaka, Ursula Maier, Prince Makay, Gioconda Manassero, Marilyn Marbell-Wilson, Charles Marcuccilli, Diane Masser-Frye, Julie McCarrier, Hannah-Sharon Mills, Jeny Balazar Montoya, Gerrye Mubungu, Mamy Ngole, Jorge Perez, Eniko Pivnick, Milagros M Duenas-Roque, Hildegard Pena Salguero, Arturo Serize, Marwan Shinawi, Fabio Sirchia, Claudia Soler-Alfonso, Alan Taylor, Lauren Thompson, Gail Vance, Adeline Vanderver, Keith Vaux, Danita Velasco, Samuel Wiafe, Ryan J Taft, Denise L Perry, Akanchha Kesari
{"title":"Multiple molecular diagnoses identified through genome sequencing in individuals with suspected rare disease.","authors":"Alka Malhotra, Erin Thorpe, Alison J Coffey, Revathi Rajkumar, Josephine Adjeman, Naomi Dianne Naa Adjeley Adjetey, Sharron Aglobitse, Felix Allotey, Todor Arsov, Joyce Ashong, Ebenezer Vincent Badoe, Donald Basel, Yvonne Brew, Chester Brown, Kerri Bosfield, Kari Casas, Mario Cornejo-Olivas, Laura Davis-Keppen, Abbey Freed, Kate Gibson, Parul Jayakar, Marilyn C Jones, Martina Kawome, Aimé Lumaka, Ursula Maier, Prince Makay, Gioconda Manassero, Marilyn Marbell-Wilson, Charles Marcuccilli, Diane Masser-Frye, Julie McCarrier, Hannah-Sharon Mills, Jeny Balazar Montoya, Gerrye Mubungu, Mamy Ngole, Jorge Perez, Eniko Pivnick, Milagros M Duenas-Roque, Hildegard Pena Salguero, Arturo Serize, Marwan Shinawi, Fabio Sirchia, Claudia Soler-Alfonso, Alan Taylor, Lauren Thompson, Gail Vance, Adeline Vanderver, Keith Vaux, Danita Velasco, Samuel Wiafe, Ryan J Taft, Denise L Perry, Akanchha Kesari","doi":"10.1016/j.xhgg.2025.100430","DOIUrl":"10.1016/j.xhgg.2025.100430","url":null,"abstract":"<p><p>Genome sequencing is a powerful and comprehensive test that detects multiple variants of different types. The interrogation of variants across the genome enables the identification of multiple molecular diagnoses (MMDs) in a single individual. In this retrospective study, we describe individuals in whom MMDs were associated with the proband's indication for testing (IFT), secondary findings, or incidental findings. An MMD is considered where at least one of the findings is associated with the primary IFT and all variants are classified as either likely pathogenic or pathogenic. Clinical genome sequencing was performed for all individuals as part of the iHope program at the Illumina Laboratory Services between September 2017 and December 2023. The iHope cohort included 1,846 affected individuals, with 872 (47.2%) found to have at least one likely pathogenic or pathogenic variant associated with the primary IFT. Of these, 81 (9.3%) individuals had multiple clinically significant molecular findings, including 76 individuals with reported variants associated with 2 different conditions, and 5 individuals with more than 2 molecular findings. A total of 32 individuals (3.7%) had at least 2 molecular diagnoses related to the primary IFT, while in 49 (5.6%) individuals, the variant(s) reported for the second condition constituted a secondary or incidental finding. Our study highlights that among individuals with a likely pathogenic or pathogenic finding identified through genome sequencing, 9% have MMDs, which may have been missed with different testing methods. Of note, approximately 60% of the 81 individuals with an MMD had a potentially actionable secondary or incidental finding.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100430"},"PeriodicalIF":3.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804350","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}
引用次数: 0
Severe Joubert syndrome in family with homozygous POC1B p.Arg106Pro variant is due to a co-inherited deep-intronic mutation in the neighboring CEP290 gene. 纯合子POC1B p.a g106pro突变家族的严重Joubert综合征是由于邻近CEP290基因的共遗传深内含子突变引起的。
IF 3.3
HGG Advances Pub Date : 2025-03-31 DOI: 10.1016/j.xhgg.2025.100429
Christian Betz, Björn Reusch, Thomas Langmann, Sandra Habbig, Bodo B Beck, Hanno J Bolz
{"title":"Severe Joubert syndrome in family with homozygous POC1B p.Arg106Pro variant is due to a co-inherited deep-intronic mutation in the neighboring CEP290 gene.","authors":"Christian Betz, Björn Reusch, Thomas Langmann, Sandra Habbig, Bodo B Beck, Hanno J Bolz","doi":"10.1016/j.xhgg.2025.100429","DOIUrl":"10.1016/j.xhgg.2025.100429","url":null,"abstract":"<p><p>\"En bloc\" inheritance of point mutations in adjacent genes has rarely been described. We have previously reported a family with severe, mostly early-lethal Joubert syndrome (JBTS) with early-onset severe retinal dystrophy (EOSRD) and polycystic kidney disease (PKD), which at that time had been attributed to a homozygous pathogenic missense variant, p.Arg106Pro (c.317G>C), in the ciliary POC1B gene. Because this and other POC1B variants were, in subsequent studies, only reported in patients with non-syndromic childhood or early-adult-onset macular dystrophy, we have now reassessed our index patient by long-read high-fidelity (HiFi) whole-genome sequencing (LR-WGS). We identified a homozygous deep-intronic variant, c.2818-657T>G, in CEP290, a JBTS/Meckel syndrome-associated gene on chromosome 12q21, only 1.28 Mb from the N terminus of POC1B. cDNA analysis revealed aberrant splicing with the frame-shifting inclusion of 37 bp from CEP290 intron 25, predicting the loss of CEP290 function. EOSRD and PKD can fully be ascribed to this CEP290 variant, whose effect outshines the \"background\" non-syndromic POC1B retinopathy and co-segregates with the severe syndromic phenotype. Our novel findings in this family no longer justify POC1B as a JBTS gene. This co-inheritance of two ciliopathies, with the clinically decisive variant hidden deep in an intron, exemplifies the importance of WGS for achieving the complete diagnosis in challenging cases.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100429"},"PeriodicalIF":3.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765313","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}
引用次数: 0
Enhancing polygenic scores for cardiometabolic traits through tissue- and cell-type-specific functional annotations. 通过组织和细胞类型特异性功能注释增强心脏代谢性状的多基因评分。
IF 3.3
HGG Advances Pub Date : 2025-03-25 DOI: 10.1016/j.xhgg.2025.100427
Kristjan Norland, Daniel J Schaid, Iftikhar J Kullo
{"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":"2025-03-25","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}
引用次数: 0
Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men. 揭示非洲男性雄激素性脱发的遗传结构和进化根源。
IF 3.3
HGG Advances Pub Date : 2025-03-24 DOI: 10.1016/j.xhgg.2025.100428
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
{"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<sup>-5</sup>, r<sup>2</sup> < 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":"2025-03-24","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}
引用次数: 0
Identification of de novo variants in KCTD10 as a proposed cause for multiple congenital anomalies. 鉴定KCTD10的新生变异是多种先天性异常的一个拟议原因。
IF 3.3
HGG Advances Pub Date : 2025-03-21 DOI: 10.1016/j.xhgg.2025.100426
Michelle M Morrow, Erin Torti, Bobbi McGivern, Ryan Gates, Mir Reza Bekheirnia, Nasim Bekheirnia, Leandra Folk, Shannon Holtrop, Timothy Blake Palculict, Olivia L Redlich, Adi Reich, Maria J Guillen Sacoto, Lisong Shi, Ingrid M Wentzensen, Kirsty McWalter
{"title":"Identification of de novo variants in KCTD10 as a proposed cause for multiple congenital anomalies.","authors":"Michelle M Morrow, Erin Torti, Bobbi McGivern, Ryan Gates, Mir Reza Bekheirnia, Nasim Bekheirnia, Leandra Folk, Shannon Holtrop, Timothy Blake Palculict, Olivia L Redlich, Adi Reich, Maria J Guillen Sacoto, Lisong Shi, Ingrid M Wentzensen, Kirsty McWalter","doi":"10.1016/j.xhgg.2025.100426","DOIUrl":"10.1016/j.xhgg.2025.100426","url":null,"abstract":"<p><p>To date, the KCTD10 gene (MIM: 608726) has not been definitively associated with a human disease, although studies in animal models suggest that it plays a role in embryonic development. We have identified multiple unrelated individuals with de novo missense variants and overlapping phenotypes, including congenital heart anomalies and congenital anomalies in other organ systems, in our internal database. This report includes a detailed description of the genotype and phenotype for two consented individuals and aggregate data of additional individuals who were not available for case-specific publication. Based on the data presented here, we propose that damaging de novo missense KCTD10 variants are associated with an autosomal dominant phenotype that includes cardiac and other congenital anomalies. We encourage additional studies to further characterize this condition and identify a mechanism for disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100426"},"PeriodicalIF":3.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693620","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}
引用次数: 0
Togaram1 is expressed in the neural tube and its absence causes neural tube closure defects. Togaram1 在神经管中表达,它的缺失会导致神经管闭合缺陷。
IF 3.3
HGG Advances Pub Date : 2025-01-09 Epub Date: 2024-10-09 DOI: 10.1016/j.xhgg.2024.100363
Yanyan Wang, Nadine Kraemer, Joanna Schneider, Olaf Ninnemann, Kai Weng, Michael Hildebrand, Joshua Reid, Na Li, Hao Hu, Shyamala Mani, Angela M Kaindl
{"title":"Togaram1 is expressed in the neural tube and its absence causes neural tube closure defects.","authors":"Yanyan Wang, Nadine Kraemer, Joanna Schneider, Olaf Ninnemann, Kai Weng, Michael Hildebrand, Joshua Reid, Na Li, Hao Hu, Shyamala Mani, Angela M Kaindl","doi":"10.1016/j.xhgg.2024.100363","DOIUrl":"10.1016/j.xhgg.2024.100363","url":null,"abstract":"<p><p>Neural tube closure defect pathomechanisms in human embryonic development are poorly understood. Here we identified spina bifida patients expressing novel variants of the TOGARAM gene family. TOGARAM1 has been associated with the ciliopathy Joubert syndrome, but its connection to spina bifida and role in neural development is unknown. We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects. Neural stem cells from Togaram1 knockout embryos showed reduced cilia and defects in Shh signaling. Overexpression in IMCD3 and HEK293 cells of TOGARAM1 carrying the variant found in the spina bifida patient resulted in cilia defect along with reduced pericentriolar material one (PCM1), a critical constituent of centriolar satellites involved in transporting proteins toward the centrosome and primary cilia. Our results demonstrate the role of TOGARAM1 in regulating Shh signaling during early neural development that is critical for neural tube closure and elucidates potential mechanisms whereby the ciliopathy-associated gene TOGARAM1 gives rise to spina bifida aperta in humans.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100363"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393898","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}
引用次数: 0
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