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.

This month in The Journal
Genomic medicine programs of various sizes have been developed with the aim of identifying individuals with elevated genetic risk for multiple diseases. In this issue, O ’Brien et al. introduce and report the initial results of the Healthy Oregon Project (HOP), a statewide genomic medicine program focused on hereditary cancer and hypercholesterolemia. The authors discuss several practical aspects of developing and implementing a low-cost, yet highly effective, pr ogram, including sample collection protocol, development of a custom gene panel, laboratory innovations, quality control, and return of results. (Source: The A...
Source: The American Journal of Human Genetics - August 3, 2023 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes
We systematically identified 876 functional SNPs associated with insulin resistance-relevant phenotypes and prioritized 102 candidate target genes by multi-omics analyses. Specifically, we decrypted the genetic regulatory mechanism underlying IRS1 locus. Based on the STARR-seq data, we predicted the regulatory activities of over 200,000 noncoding SNPs and developed an open resource. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 27, 2023 Category: Genetics & Stem Cells Authors: Yuan-Yuan Duan, Xiao-Feng Chen, Ren-Jie Zhu, Ying-Ying Jia, Xiao-Ting Huang, Meng Zhang, Ning Yang, Shan-Shan Dong, Mengqi Zeng, Zhihui Feng, Dong-Li Zhu, Hao Wu, Feng Jiang, Wei Shi, Wei-Xin Hu, Xin Ke, Hao Chen, Yunlong Liu, Rui-Hua Jing, Yan Guo, Meng Tags: Article Source Type: research

Population screening shows risk of inherited cancer and familial hypercholesterolemia in Oregon
This report describes our design, experience, and initial findings in a large population screening project, the Healthy Oregon Project. Details include the steps taken to scale up for a large-scale population screening program and an in-depth discussion of the overall lessons learned. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 27, 2023 Category: Genetics & Stem Cells Authors: Timothy D. O ’Brien, Amiee B. Potter, Catherine C. Driscoll, Gregory Goh, John H. Letaw, Sarah McCabe, Jane Thanner, Arpita Kulkarni, Rossana Wong, Samuel Medica, Tiana Week, Jacob Buitrago, Aaron Larson, Katie Johnson Camacho, Kim Brown, Rachel Crist, Tags: Article Source Type: research

An allelic-series rare-variant association test for candidate-gene discovery
Allelic series are collections of variants that lead to a gradation of possible phenotypes. We introduce COAST (Coding-Variant Allelic-Series Test), a test that identifies genes where increasingly deleterious mutations have increasing phenotypic effects. We apply COAST to uncover genes harboring allelic series for lipid and cell-count traits in the UK Biobank. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 25, 2023 Category: Genetics & Stem Cells Authors: Zachary R. McCaw, Colm O ’Dushlaine, Hari Somineni, Michael Bereket, Christoph Klein, Theofanis Karaletsos, Francesco Paolo Casale, Daphne Koller, Thomas W. Soare Tags: Article Source Type: research

A form of inherited hyperferritinemia associated with bi-allelic pathogenic variants of STAB1
Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and flow cytometry assays were performed on liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 24, 2023 Category: Genetics & Stem Cells Authors: Edoardo Monfrini, Sara Pelucchi, Maija Hollm én, Miro Viitala, Raffaella Mariani, Francesca Bertola, Silvia Majore, Alessio Di Fonzo, Alberto Piperno Tags: Report Source Type: research

Genotype error due to low-coverage sequencing induces uncertainty in polygenic scoring
Petter et  al. investigate the impact of genotyping error on the accuracy of polygenic scores (PGSs). The study takes a probabilistic approach to create individual PGS credible intervals accounting for the genotype errors and explores the use of such credible intervals for enhanced PGS-based risk stratificat ion. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 24, 2023 Category: Genetics & Stem Cells Authors: Ella Petter, Yi Ding, Kangcheng Hou, Arjun Bhattacharya, Alexander Gusev, Noah Zaitlen, Bogdan Pasaniuc Tags: Article Source Type: research

Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease
Calame et  al. describe 20 individuals with monoallelic rare damaging DHX9 variants and neurologic phenotypes ranging from severe neurodevelopmental disorders to adult-onset Charcot-Marie-Tooth disease. Functional studies show that DHX9 variants disrupt DHX9 cellular localization and helicase activity and in crease R-loops and double-stranded DNA breaks. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 18, 2023 Category: Genetics & Stem Cells Authors: Daniel G. Calame, Tianyu Guo, Chen Wang, Lillian Garrett, Angad Jolly, Moez Dawood, Alina Kurolap, Noa Zunz Henig, Jawid M. Fatih, Isabella Herman, Haowei Du, Tadahiro Mitani, Lore Becker, Birgit Rathkolb, Raffaele Gerlini, Claudia Seisenberger, Susan Mar Tags: Article Source Type: research

De novo missense variants in phosphatidylinositol kinase PIP5KI γ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling
We describe a neurodevelopmental disorder associated with de novo gain-of-function variants in PIP5KI γ kinase. The variants cause perturbed endosomal function resulting from increased production of phosphatidylinositol 4,5 bisphosphate and enhanced association of F-actin at endosomes. Moreover, mutant zebrafish larvae recapitulate the phenotypes observed in affected individuals from our cohort. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 13, 2023 Category: Genetics & Stem Cells Authors: Manuela Morleo, Rossella Venditti, Evangelos Theodorou, Lauren C. Briere, Marion Rosello, Alfonsina Tirozzi, Roberta Tammaro, Nour Al-Badri, Frances A. High, Jiahai Shi, Undiagnosed Diseases Network, Telethon Undiagnosed Diseases Program, Elena Putti, Lui Tags: Article Source Type: research

Genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis
Multimorbidity is a rising public health challenge. Here, we study the genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis and provide insights into its biological basis. The approach can be applied to any pair of co-occurring diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 10, 2023 Category: Genetics & Stem Cells Authors: Ana Luiza Arruda, April Hartley, Georgia Katsoula, George Davey Smith, Andrew P. Morris, Eleftheria Zeggini Tags: Article Source Type: research

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration
Combining in silico evaluation, in  vitro electrophysiology and Ca2+ imaging, and in vivo modeling in Drosophila, Vetro et al. demonstrate that gain-of-function variants of the stretch-activated ion channel TMEM63B cause a severe neurodevelopmental disorder with early-onset epilepsy and progressive brain damage associated with hem atological abnormalities in most individuals. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 7, 2023 Category: Genetics & Stem Cells Authors: Annalisa Vetro, Cristiana Pelorosso, Simona Balestrini, Alessio Masi, Sophie Hambleton, Emanuela Argilli, Valerio Conti, Simone Giubbolini, Rebekah Barrick, Gaber Bergant, Karin Writzl, Emilia K. Bijlsma, Theresa Brunet, Pilar Cacheiro, Davide Mei, Anita Tags: Article Source Type: research

Response to Li and Hopper
To the Editor: We are thankful for and appreciate the interest shown by Li and Hopper toward our study.1 Our main aim was to answer with systematic evaluations the question frequently encountered with translational research of polygenic risk scores (PRSs): why do we need PRSs if we have information on family history? Surveying family history has been a part of clinical risk estimation in many diseases for decades, making the question highly relevant as genetic profiling data becomes commonly available. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2023 Category: Genetics & Stem Cells Authors: Nina Mars, Joni V. Lindbohm, Pietro della Briotta Parolo, Elisabeth Wid én, Jaakko Kaprio, Aarno Palotie, FinnGen, Samuli Ripatti Tags: Letter to the Editor Source Type: research

Implications of family history and polygenic risk scores for causation
To the Editor: Mars and colleagues1 investigated the risk associations of having a family history, and of a genome-wide polygenic risk score (PRS), for 24 common diseases using the extraordinary FinnGen resource. They first estimated the marginal associations and then the conditional associations by fitting both family history and PRS together. Creatively, they did this separately for family history defined by first- and by second-degree relatives, and the results differed. We believe that their analyses have important implications for understanding both the causes of familial aggregation and the causes of the diseases the...
Source: The American Journal of Human Genetics - July 6, 2023 Category: Genetics & Stem Cells Authors: Shuai Li, John L. Hopper Tags: Letter to the editor Source Type: research

Response to Bassett et  al.
To the Editor: We thank Dr. Bassett and colleagues for their interest in our work. While they raise several pertinent points to nuance our findings, most comments are based on misunderstandings of the presented analyses highlighted below. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2023 Category: Genetics & Stem Cells Authors: Mal ú Zamariolli, Chiara Auwerx, Marie C. Sadler, Adriaan van der Graaf, Kaido Lepik, Tabea Schoeler, Mariana Moysés-Oliveira, Anelisa G. Dantas, Maria Isabel Melaragno, Zoltán Kutalik Tags: Letter to the Editor Source Type: research

Approaches to studying the impact of 22q11.2 copy number variants
To the Editor: We read with interest the recent article “The impact of 22q11.2 copy-number variants on human traits in the general population” by Zamariolli et al.,1 given the importance of copy number variations (CNVs) within this complex region, and in research that could further our understanding of the effects of 22q11.2 CNVs. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2023 Category: Genetics & Stem Cells Authors: Anne S. Bassett, Donna M. McDonald-McGinn, Erik Boot, S ólveig Óskarsdóttir, Ryan K.C. Yuen Tags: Letter to the Editor Source Type: research

Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes
We present multi-response MR (MR2), an MR method specifically designed for multiple outcomes to identify exposures that cause multiple responses or, conversely, exposures that exert their effect on distinct responses. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 6, 2023 Category: Genetics & Stem Cells Authors: Verena Zuber, Alex Lewin, Michael G. Levin, Alexander Haglund, Soumaya Ben-Aicha, Costanza Emanueli, Scott Damrauer, Stephen Burgess, Dipender Gill, Leonardo Bottolo Tags: Article Source Type: research