The American Journal of Human Genetics This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability
We identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability. We show that LoF is associated with a specific methylation signature and that ZFHX3 targets promoters of genes implicated in neural development. Proteomics analysis indicates a contribution of ZFHX3 to chromatin remodeling and pre-messenger RNA processing. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 26, 2024 Category: Genetics & Stem Cells Authors: Mar ía del Rocío Pérez Baca, Eva Z. Jacobs, Lies Vantomme, Pontus Leblanc, Elke Bogaert, Annelies Dheedene, Laurenz De Cock, Sadegheh Haghshenas, Aidin Foroutan, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Chun-An Chen, Nurit Assia Batzir, Xia W Tags: Article Source Type: research

De novo variants in DENND5B cause a neurodevelopmental disorder
In this study, we identify de novo missense variants in DENND5B as the cause of a neurodevelopmental disorder with dysmorphism and epilepsy. We show that these variants impair intracellular vesicle trafficking, lipid uptake and intracellular distribution, and protein folding, leading to complex neurological manifestations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 21, 2024 Category: Genetics & Stem Cells Authors: Marcello Scala, Valeria Tomati, Matteo Ferla, Mariateresa Lena, Julie S. Cohen, Ali Fatemi, Elly Brokamp, Anna Bican, John A. Phillips, Mary E. Koziura, Michael Nicouleau, Marlene Rio, Karine Siquier, Nathalie Boddaert, Ilaria Musante, Serena Tamburro, Si Tags: Article Source Type: research

Alternative polyadenylation quantitative trait methylation mapping in human cancers provides clues into the molecular mechanisms of APA
We generated a comprehensive atlas of APA quantitative trait methylation sites (apaQTMs) across 21 different cancers (1,612 to 60,219 acting in cis and 4,448 to 142,349 in trans), which could be accessed at a web-based platform, Pancan-apaQTM. Our findings provided deeper mechanistic insights into the role of QTMs in diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 16, 2024 Category: Genetics & Stem Cells Authors: Yige Li, Jingwen Gong, Qingrong Sun, Eu Gene Vong, Xiaoqing Cheng, Binghong Wang, Ying Yuan, Li Jin, Eric R. Gamazon, Dan Zhou, Maode Lai, Dandan Zhang Tags: Article Source Type: research

Epigenome-wide association study of total nicotine equivalents in multiethnic current smokers from three prospective cohorts
In this large multiethnic epigenome-wide association study of total nicotine equivalents across three cohorts, we identified differential methylation at 408 CpG loci, of which 45 were novel and 51 were externally validated. Our findings highlight the generalizability of these internal smoking dose-related epigenetic modifications across multiple racial and ethnic populations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 16, 2024 Category: Genetics & Stem Cells Authors: Brian Z. Huang, Alexandra M. Binder, Brandon Quon, Yesha M. Patel, Annette Lum-Jones, Maarit Tiirikainen, Sharon E. Murphy, Lenora Loo, Alika K. Maunakea, Christopher A. Haiman, Lynne R. Wilkens, Woon-Puay Koh, Qiuyin Cai, Melinda C. Aldrich, Kimberly D. Tags: Article Source Type: research

The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function
Nine genes that potentially enhance the risk of Alzheimer disease (AD) were identified using a novel gene-constrained analytical method. One gene encoded heterotrimeric G protein beta family member GNB5. In AD model mice, Gnb5 heterozygosity enhanced the development of AD neuropathology. This method may be applicable to other polygenic diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 13, 2024 Category: Genetics & Stem Cells Authors: Jianhua Zhang, Mritunjay Pandey, Adam Awe, Nicole Lue, Claire Kittock, Emma Fikse, Katherine Degner, Jenna Staples, Neha Mokhasi, Weiping Chen, Yanqin Yang, Poorni Adikaram, Nirmal Jacob, Emily Greenfest-Allen, Rachel Thomas, Laura Bomeny, Yajun Zhang, Ti Tags: Article Source Type: research

The cells of the sensory epithelium, and not the stria vascularis, are the main cochlear cells related to the genetic pathogenesis of age-related hearing loss
Two recent studies that integrated genome-wide association study and single-cell transcriptomics analyses resulted in conflicting results as for the key cell types linked to the genetic pathogenesis of age-related hearing loss (ARHL). We show that cochlear epithelial cells, not stria vascularis cells, are the main cells for the pathogenesis of ARHL. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 7, 2024 Category: Genetics & Stem Cells Authors: Mai Eshel, Beatrice Milon, Ronna Hertzano, Ran Elkon Tags: Report Source Type: research

Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt
We describe a cohort of 18 individuals with germline variants in ZFX, which encodes a transcription factor not previously associated with a human disease. In addition to identifying recurrent clinical features, molecular characterization of variants in cultured cells, in silico modeling, and a zebrafish model suggest potential modes of pathogenicity. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 6, 2024 Category: Genetics & Stem Cells Authors: James L. Shepherdson, Katie Hutchison, Dilan Wellalage Don, George McGillivray, Tae-Ik Choi, Carolyn A. Allan, David J. Amor, Siddharth Banka, Donald G. Basel, Laura D. Buch, Deanna Alexis Carere, Ren ée Carroll, Jill Clayton-Smith, Ali Crawford, Morten Tags: Article Source Type: research

Transcriptome-wide association study of the plasma proteome reveals cis and trans regulatory mechanisms underlying complex traits
We performed TWAS for thousands of plasma proteins, comparing same-gene, cis, and trans effects across tissues. We show the heritable component of gene expression more strongly correlates with protein levels than with total observed expression and is therefore more useful in uncovering the functions of SNPs associated with complex traits. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 5, 2024 Category: Genetics & Stem Cells Authors: Henry Wittich, Kristin Ardlie, Kent D. Taylor, Peter Durda, Yongmei Liu, Anna Mikhaylova, Chris R. Gignoux, Michael H. Cho, Stephen S. Rich, Jerome I. Rotter, NHLBI TOPMed Consortium, Ani Manichaikul, Hae Kyung Im, Heather E. Wheeler Tags: Article Source Type: research

Insights into the mechanisms and structure of breakage-fusion-bridge cycles in cervical cancer using long-read sequencing
We used long-read whole-genome sequencing to characterize a panel of cervical cancer cell lines, identifying frequent amplification of the YAP1 oncogene through a telomere-deletion mechanism. YAP1 amplification marks a subset of cervical cancer with early diagnosis and is more common in minority populations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 1, 2024 Category: Genetics & Stem Cells Authors: Isabel Rodriguez, Nicole M. Rossi, Ayse G. Keskus, Yi Xie, Tanveer Ahmad, Asher Bryant, Hong Lou, Jesica Godinez Paredes, Rose Milano, Nina Rao, Sonam Tulsyan, Joseph F. Boland, Wen Luo, Jia Liu, Tim O ’Hanlon, Jazmyn Bess, Vera Mukhina, Daria Gaykalova Tags: Article Source Type: research

Using implementation science to evaluate a population-wide genomic screening program: Findings from the first 20,000 In Our DNA SC participants
We evaluated In Our DNA SC, a population-wide genomic screening program, through the RE-AIM framework. In 14  months, over 20,000 individuals enrolled, providing 14,053 samples. Pathogenic or likely pathogenic variants for a CDC Tier 1 condition were found in 137 individuals, with the majority of individuals agreeing to genetic counseling. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 1, 2024 Category: Genetics & Stem Cells Authors: Caitlin G. Allen, Kelly J. Hunt, Lori L. McMahon, Clay Thornhill, Amy Jackson, John T. Clark, Katie Kirchoff, Kelli L. Garrison, Kimberly Foil, Libby Malphrus, Samantha Norman, Paula S. Ramos, Kelly Perritt, Caroline Brown, Leslie Lenert, Daniel P. Judge Tags: Article Source Type: research

Cell-type deconvolution of bulk-blood RNA-seq reveals biological insights into neuropsychiatric disorders
Methods aimed at deconvolving cell-type-specific estimates of bulk gene expression offer a cost-effective way to investigate cell-type-specific eQTLs. Our study suggests that such computational approaches to a large sample with blood-based bulk RNA-seq significantly increase the opportunity to interpret the underlying biology of brain-specific disease susceptibility. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 1, 2024 Category: Genetics & Stem Cells Authors: Toni Boltz, Tommer Schwarz, Merel Bot, Kangcheng Hou, Christa Caggiano, Sandra Lapinska, Chenda Duan, Marco P. Boks, Rene S. Kahn, Noah Zaitlen, Bogdan Pasaniuc, Roel Ophoff Tags: Article Source Type: research

This Month in The Journal
Human genetic variation influences susceptibility to infectious disease. Antibodies, stable biological markers of the  response to infection, can be measured and leveraged to understand disease exposure, chronic infection state, and risk. Measured antibody titers in combination with genome-wide genotyping data can be used to identify common variants that influence both susceptibility and response to infectious dis ease. In this issue, Chong et al. perform a genome-wide association study of quantitative antibody responses to 45 antigens on the 9,611 individuals in the UK Biobank with both serology and imputed genetic data...
Source: The American Journal of Human Genetics - February 1, 2024 Category: Genetics & Stem Cells Authors: Alyson B. Barnes, Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Mutations in SAMD7 cause autosomal-recessive macular dystrophy with or without cone dysfunction
Macular dystrophies are a group of inherited eye diseases that affect the retina and significantly impair central visual functions. Here we report mutations in SAMD7 as a cause for autosomal-recessive macular dystrophy. This finding places SAMD7 as a gene crucial for human retinal function. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 24, 2024 Category: Genetics & Stem Cells Authors: Miriam Bauwens, Elifnaz Celik, Dinah Zur, Siying Lin, Mathieu Quinodoz, Michel Michaelides, Andrew R. Webster, Filip Van Den Broeck, Bart P. Leroy, Leah Rizel, Abigail R. Moye, Audrey Meunier, Hoai Viet Tran, Alexandre P. Moulin, Quinten Mahieu, Mattias V Tags: Report Source Type: research

Role of CAMK2D in neurodevelopment and associated conditions
CAMK2 disorder is a relatively new disorder where three of the four CAMK2s (CAMK2A, B, and G) are shown to cause neurodevelopmental disorders. In this paper we describe a cohort of eight individuals with neurodevelopmental disorders and cardiac abnormalities, having CAMK2D variants, proving all CAMK2s are important for normal development. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 24, 2024 Category: Genetics & Stem Cells Authors: Pomme M.F. Rigter, Charlotte de Konink, Matthew J. Dunn, Martina Proietti Onori, Jennifer B. Humberson, Matthew Thomas, Caitlin Barnes, Carlos E. Prada, K. Nicole Weaver, Thomas D. Ryan, Oana Caluseriu, Jennifer Conway, Emily Calamaro, Chin-To Fong, Wim W Tags: Article Source Type: research

CRISPR activation to characterize splice-altering variants in easily accessible cells
Tissue-specific gene expression is a major challenge in transcriptome-based rare-disease diagnostics. CRISPR activation is a recently developed tool to activate the expression of genes of interest in  vitro. Here, we apply CRISPR activation to clarify the functional impact of splice-altering variants in skin fibroblasts from individuals with neurogenetic diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 24, 2024 Category: Genetics & Stem Cells Authors: Thorkild Terkelsen, Nanna Steengaard Mikkelsen, Ebbe Norskov Bak, Johan Vad-Nielsen, Jenny Blechingberg, Simone Weiss, Simon Opstrup Drue, Henning Andersen, Brage Storstein Andresen, Rasmus O. Bak, Uffe Birk Jensen Tags: Article Source Type: research