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.

Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration
The authors describe four individuals with bi-allelic variants in NAE1, which encodes the NEDD8-activating enzyme E1 regulatory subunit and is essential for neddylation. By focusing on the biology underlying the rarest observed clinical features, they unveil the importance of neddylation for skeletal development and for maintaining cellular integrity during stress. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 5, 2023 Category: Genetics & Stem Cells Authors: Irena J.J. Muffels, Imre F. Schene, Holger Rehmann, Maarten P.G. Massink, Maria M. van der Wal, Corinna Bauder, Martha Labeur, Natalia G. Armando, Maarten H. Lequin, Michiel L. Houben, Jaques C. Giltay, Saskia Haitjema, Albert Huisman, Fleur Vansenne, Jud Tags: Article Source Type: research

Leveraging drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans
We have used drug perturbation to uncover genetic regulators in African American human hepatocytes. These findings can be used to understand previous genetic associations related to drug response, cardiovascular and lipid traits, and hemostatic phenotypes. We have also increased the diversity within multi-omic data. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 5, 2023 Category: Genetics & Stem Cells Authors: Yizhen Zhong, Tanima De, Mrinal Mishra, Juan Avitia, Cristina Alarcon, Minoli A. Perera Tags: Article Source Type: research

Probabilistic integration of transcriptome-wide association studies and colocalization analysis identifies key molecular pathways of complex traits
We introduce INTACT, a framework that integrates probabilistic evidence from transcriptome-wide association studies and colocalization analysis to implicate putative causal genes. Furthermore, we present INTACT-GSE, an algorithm for gene set enrichment analysis using INTACT output. These methods improve existing gene implication methods and identify key gene sets underlying complex traits. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 5, 2023 Category: Genetics & Stem Cells Authors: Jeffrey Okamoto, Lijia Wang, Xianyong Yin, Francesca Luca, Roger Pique-Regi, Adam Helms, Hae Kyung Im, Jean Morrison, Xiaoquan Wen Tags: Article Source Type: research

mBAT-combo: A more powerful test to detect gene-trait associations from GWAS data
We introduce mBAT-combo, a set-based test that is better powered than other methods to detect multi-SNP associations when SNP effects are mutually masked by linkage disequilibrium and find that such a masking effect phenomenon is common, if not ubiquitous, in complex traits. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 5, 2023 Category: Genetics & Stem Cells Authors: Ang Li, Shouye Liu, Andrew Bakshi, Longda Jiang, Wenhan Chen, Zhili Zheng, Patrick F. Sullivan, Peter M. Visscher, Naomi R. Wray, Jian Yang, Jian Zeng Tags: Article Source Type: research

Genotype first: Clinical genomics research through a reverse phenotyping approach
Phenotypic ascertainment and clinical informatics methods may inadvertently limit our understanding of the full phenotypic spectrum of a genetic condition. Recruiting individuals by genotype followed by deep phenotyping may expand our understanding of genotype-disease associations. We successfully tested this approach and outline how other institutions can replicate this model. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 5, 2023 Category: Genetics & Stem Cells Authors: Caralynn M. Wilczewski, Justice Obasohan, Justin E. Paschall, Suiyuan Zhang, Sumeeta Singh, George L. Maxwell, Morgan Similuk, Tyra G. Wolfsberg, Clesson Turner, Leslie G. Biesecker, Alexander E. Katz Tags: Perspective Source Type: research

This month in The Journal
Wilczewski et  al., p. 3 (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 5, 2023 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype
We identified 27 individuals with neurodevelopmental disorders (NDD) with rare variants in ZMYM3, an X chromosome gene encoding a transcriptional regulator. Some variants recurrently affect the same codons, and computational and experimental analyses suggest the variants impair ZMYM3 function. Our data strongly support ZMYM3 as an NDD gene. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 30, 2022 Category: Genetics & Stem Cells Authors: Susan M. Hiatt, Slavica Trajkova, Matteo Rossi Sebastiano, E. Christopher Partridge, Fatima E. Abidi, Ashlyn Anderson, Muhammad Ansar, Stylianos E. Antonarakis, Azadeh Azadi, Ruxandra Bachmann-Gagescu, Andrea Bartuli, Caroline Benech, Jennifer L. Berkowit Tags: Article Source Type: research

Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?
Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. (Source: The A...
Source: The American Journal of Human Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: David A. Mackey, Jue-Sheng Ong, Stuart MacGregor, David C. Whiteman, Jamie E. Craig, M. Isabel G. Lopez Sanchez, Lisa S. Kearns, Sandra E. Staffieri, Linda Clarke, Myra B. McGuinness, Wafaa Meteoukki, Sona Samuel, Jonathan B. Ruddle, Celia Chen, Clare L. Tags: Matters Arising Source Type: research

Low disease risk and penetrance in Leber hereditary optic neuropathy
The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it o...
Source: The American Journal of Human Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Eloise C. Watson, Ryan L. Davis, Shyamsundar Ravishankar, Joseph Copty, Sarah Kummerfeld, Carolyn M. Sue Tags: Matters Arising Source Type: research

De novo mutation hotspots in homologous protein domains identify function-altering mutations in neurodevelopmental disorders
We developed MDHS which utilizes homologous protein domains to identify domain-based variant hotspots. Applying MDHS on de novo mutations from 31,058 patients with neurodevelopmental disorders (NDDs) identified three missense hotspots across 25 genes, of which 19 genes were previously associated with NDD. The identified missense mutations at the hotspots are suggested to alter function. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 22, 2022 Category: Genetics & Stem Cells Authors: Laurens Wiel, Juliet E. Hampstead, Hanka Venselaar, Lisenka E.L.M. Vissers, Han G. Brunner, Rolph Pfundt, Gerrit Vriend, Joris A. Veltman, Christian Gilissen Tags: Article Source Type: research

Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy
15 individuals with mono-allelic or inherited bi-allelic variants in the DEAD-box gene EIF4A2 were identified with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies. In Drosophila melanogaster, mono-allelic variants in EIF4A2 led to variant-specific behavioral and developmental defects, secondary to both loss- and gain-of-function mechanisms. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 16, 2022 Category: Genetics & Stem Cells Authors: Maimuna S. Paul, Anna R. Duncan, Casie A. Genetti, Hongling Pan, Adam Jackson, Patricia E. Grant, Jiahai Shi, Michele Pinelli, Nicola Brunetti-Pierri, Alexandra Garza-Flores, Dave Shahani, Russell P. Saneto, Giuseppe Zampino, Chiara Leoni, Emanuele Agolin Tags: Article Source Type: research

An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14
Pathogenic repeat expansions (RE) cause an array of neurogenetic disorders including cerebellar ataxia. While traditionally difficult to identify, new genomic tools and bioinformatic analyses are enabling rapid RE discovery and diagnosis. Here we characterize SCA50, an adult-onset ataxia caused by a pathogenic GAA repeat expansion within intron one of FGF14. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 8, 2022 Category: Genetics & Stem Cells Authors: Haloom Rafehi, Justin Read, David J. Szmulewicz, Kayli C. Davies, Penny Snell, Liam G. Fearnley, Liam Scott, Mirja Thomsen, Greta Gillies, Kate Pope, Mark F. Bennett, Jacob E. Munro, Kathie J. Ngo, Luke Chen, Mathew J. Wallis, Ernest G. Butler, Kishore R. Tags: Article Source Type: research

Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes
The contribution of copy-number variants to cleft lip with or without cleft palate (CL/P) has been relatively understudied. Using a strategy to identify likely higher effect size microdeletions, we identify COBLL1, RIC1, and ARHGEF38 as genes associated with CL/P that play important roles in vertebrate craniofacial development. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 8, 2022 Category: Genetics & Stem Cells Authors: Lisa A. Lansdon, Amanda Dickinson, Sydney Arlis, Huan Liu, Arman Hlas, Alyssa Hahn, Greg Bonde, Abby Long, Jennifer Standley, Anastasia Tyryshkina, George Wehby, Nanette R. Lee, Sandra Daack-Hirsch, Karen Mohlke, Santhosh Girirajan, Benjamin W. Darbro, Ro Tags: Article Source Type: research

LDAK-GBAT: Fast and powerful gene-based association testing using summary statistics
LDAK-GBAT is a new tool for gene-based association testing using GWAS summary statistics. Applied to 109 phenotypes from large biobanks, LDAK-GBAT finds at least 20% more significant genes than popular tools such as MAGMA and GCTA-FastBAT. Further, LDAK-GBAT is computationally efficient, with good control of type 1 error in simulation studies. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 7, 2022 Category: Genetics & Stem Cells Authors: Takiy-Eddine Berrandou, David Balding, Doug Speed Tags: Article Source Type: research

SDPRX: A statistical method for cross-population prediction of complex traits
We developed a statistical method, SDPRX, to improve the performance of polygenic risk score (PRS) in non-European populations by jointly modeling GWAS summary statistics from European and non-European populations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 1, 2022 Category: Genetics & Stem Cells Authors: Geyu Zhou, Tianqi Chen, Hongyu Zhao Tags: Article Source Type: research