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A RAG Chatbot for Precision Medicine of Multiple Myeloma medRxiv. Genet. Genom. Med. Pub Date : 2024-03-18 Mujahid Ali Quidwai, Alessandro Lagana
The advent of precision medicine has revolutionized cancer treatment by integrating individual genetic, lifestyle, and environmental factors to tailor patient care (Huang et al., 2020; Ginsburg and Phillips, 2018). However, the complexity and heterogeneity of diseases like Multiple Myeloma (MM) pose significant challenges in leveraging the vast amounts of genomic data and biomedical literature available
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Location of ryanodine receptor type 2 mutation predicts age of onset of sudden death in catecholaminergic polymorphic ventricular tachycardia. A systematic review and meta analysis of case based literature medRxiv. Genet. Genom. Med. Pub Date : 2024-03-16 Halil Beqaj, Leah Sittenfeld, Alexander Chang, Marco Miotto, Haikel dridi, Gloria Willson, Carolyn Martinez Jorge, Jaan Altosaar Li, Steven Reiken, Yang Liu, Zonglin Dai, Andrew R Marks
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia caused by mutations in the ryanodine receptor type 2 (RyR2). Diagnosis of CPVT often occurs after a major cardiac event, thus posing a severe threat to the patient's health. Methods: Publication databases, including PubMed, Scopus, and Embase, were searched for articles on patients with RyR2-CPVT
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A framework for conducting time-varying genome-wide association studies: An application to body mass index across childhood in six multiethnic cohorts medRxiv. Genet. Genom. Med. Pub Date : 2024-03-16 Kimberley Burrows, Anni Heiskala, Jonathan P Bradfield, Zhanna Balkhiyarova, Lijiao Ning, Mathilde Boissel, Yee-Ming Chan, Philippe Froguel, Amelie Bonnefond, Hakon Hakonarson, Alessander Couto Alves, Deborah A Lawlor, Marika Kaakinen, Marjo-Riitta Jarvelin, Struan F.A. Grant, Kate Tilling, Inga Prokopenko, Sylvain Sebert, Mickael Canouil, Nicole M Warrington
Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an
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Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Jessica Gold, Colleen M Kripke, Regeneron Genetics Center, Penn Medicine BioBank, Theodore G Drivas
Numerous studies have underscored the diagnostic and therapeutic potential of exome or genome sequencing in critically ill pediatric populations. However, an equivalent investigation in critically ill adults remains conspicuously absent. We retrospectively analyzed whole exome sequencing (WES) data available through the PennMedicine Biobank (PMBB) from all 365 young adult patients, aged 18-40 years
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Pan-UK Biobank GWAS improves discovery, analysis of genetic architecture, and resolution into ancestry-enriched effects medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Konrad J Karczewski, Rahul Gupta, Masahiro Kanai, Wenhan Lu, Kristin Tsuo, Ying Wang, Raymond K Walters, Patrick Turley, Shawneequa Callier, Nikolas Baya, Duncan S Palmer, Jacqueline I Goldstein, Gopal Sarma, Matthew Solomonson, Nathan Cheng, Sam Bryant, Claire Churchhouse, Caroline M Cusick, Timothy Poterba, John Compitello, Daniel King, Wei Zhou, Cotton Seed, Hilary K Finucane, Mark J Daly, Benjamin
Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse genetic ancestry groups are often excluded from association analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses
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Refining the scope of genetic influences on alcohol misuse through environmental stratification and gene-environment interaction medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Jeanne E Savage, Christiaan A de Leeuw, Josefin Werme, Spit for Science Working Group, Danielle M Dick, Danielle Posthuma, Sophie van der Sluis
Background: Gene-environment interaction (GxE) is likely an important influence shaping individual differences in alcohol misuse (AM), yet it has not been extensively studied in molecular genetic research. In this study, we utilize a series of genome-wide gene-environment interaction (GWEIS) and in silico annotation methods with the aim of improving gene identification and biological understanding
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Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal cell DNA of individuals with spinocerebellar ataxia type 3 medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G. Monckton
Spinocerebellar ataxia type 3 (SCA3), a currently untreatable disorder, is caused by the expansion of a genetically unstable polyglutamine-encoding complex CAG repeat in the ATXN3 gene. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease
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A retrospective case-control study for Clinical Validation of mutated ZNF208 as a novel biomarker of fatal blast crisis in Chronic Myeloid Leukemia medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Nawaf Alanzazi, Amer Mahmood, Masood A Shammas, Salman Basit, Aamer Aleem, Sarah Al-Mukhaylid, Zafar Iqbal
The hallmark of Chronic Myeloid Leukemia (CML) is Philadelphia chromosome t(9:22), which leads to formation of BCR-ABL1 fusion oncogene. BCR-ABL1 induces genetic instability, causing the progression of chronic myeloid leukemia (CML) from the manageable Chronic Phase (CP-CML) to the accelerated phase (AP-CML) and ultimately to the lethal blast crisis (BC-CML). The precise mechanism responsible for CML
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Enhanced Data Pre-processing for the Identification of Alzheimer's Disease-Associated SNPs medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Juliana Ferreira Alves, Ricardo Cerri, Eduardo Costa, Luiz Fernando Brito, Alencar Xavier
Alzheimer's Disease (AD) is a complex neurodegenerative disorder that has gained significant attention in scientific research, particularly since the Human Genome Project. Based on twin studies that utilize the resemblance of Alzheimer's disease risk between pairs of twins, it has been found that the overall heritability of the disease is estimated at 0.58. When shared environmental factors are taken
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Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Marco Matejcic, Jamie K Teer, Hannah J Hoehn, Diana B Diaz, Kritika Shankar, Jun Gong, Nathalie T Nguyen, Nicole Lorona, Domenico Coppola, Clifton Fulmer, Ozlen Saglam, Kun Jiang, Douglas Cress, Teresita Munoz-Antonia, Idhaliz Flores, Edna Gordian, Jose A Oliveras Torres, Seth I Felter, Julian A Sanchez, Jason Fleming, Erin M Siegel, Jennifer A Freedman, Julie Dutil, Mariana C Stern, Brooke L Fridley
Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry
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Sparse haplotype-based fine-scale local ancestry inference at scale reveals recent selection on immune responses medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Yaoling Yang, Richard Durbin, Astrid K.N. Iversen, Daniel John Lawson
Increasingly efficient methods for inferring the ancestral origin of genome regions are needed to gain new insights into genetic function and history as biobanks grow in scale. Here we describe two near-linear time algorithms to learn ancestry harnessing the strengths of a Positional Burrows-Wheeler Transform (PBWT). SparsePainter is a faster, sparse replacement of previous model-based `chromosome
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SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Randy L. Parrish, Aron S. Buchman, Shinya Tasaki, Yanling Wang, Denis Avey, Jishu Xu, Philip L. De Jager, David A. Bennett, Michael P. Epstein, Jingjing Yang
Multiple reference panels of a given tissue or multiple tissues often exist, and multiple regression methods could be used for training gene expression imputation models for TWAS. To leverage expression imputation models (i.e., base models) trained with multiple reference panels, regression methods, and tissues, we develop a Stacked Regression based TWAS (SR-TWAS) tool which can obtain optimal linear
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Understanding monogenic Parkinson's disease at a global scale medRxiv. Genet. Genom. Med. Pub Date : 2024-03-15 Johanna Junker, Lara M. Lange, Eva-Juliane Vollstedt, Karisha Roopnarain, Maria Leila M. Doquenia, Azlina Ahmad-Annuar, Micol Avenali, Soraya Bardien, Natascha Bahr, Melina Ellis, Caterina Galandra, Thomas Gasser, Peter Heutink, Anastasia Illarionova, Yuliia Kanana, Ignacio J. Keller Sarmiento, Kishore R. Kumar, Shen-Yang Lim, Harutyun Madoev, Ignacio Mata, Niccolo E. Mencacci, Mike A. Nalls, Shalini
Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at global scale. The first systematic approach to embrace monogenic PD worldwide, the Michael J. Fox Foundation Global Monogenic PD (MJFF GMPD) Project, contacted authors of publications reporting
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Characterization of the common genetic variation in the Spanish population of Navarre medRxiv. Genet. Genom. Med. Pub Date : 2024-03-14 Alberto Maillo, Estefania Huergo, Maria Apellaniz-Ruiz, Edurne Urrutia, Maria Miranda, Josefa Salgado, Sara Pasalodos-Sanchez, Luna Delgado-Mora, Oscar Teijido, Ibai Goicoechea, Rosario Carmona, Javier Perez-Florido, Virginia Aquino, Daniel Lopez-Lopez, Maria Pena-Chilet, Sergi Beltran, Joaquin Dopazo, Inigo Lasa, Juan Jose Beloqui, Angel Alonso, David Gomez-Cabrero
Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals
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Potential associations of selected polymorphic genetic variants with COVID-19 disease susceptibility and severity medRxiv. Genet. Genom. Med. Pub Date : 2024-03-14 Orsolya Mozner, Edit Szabo, Anna Kulin, Gyorgy Varady, Judit Moldvay, Vivien Vass, Andrea Szentesi, Agoston Janosi, Peter Hegyi, Balazs Sarkadi
In this study, we analyzed the potential associations of selected laboratory and anamnestic parameters, as well as 12 genetic polymorphisms (SNPs), with clinical COVID-19 occurrence and severity in 869 hospitalized patients. The SNPs analyzed by qPCR were selected based on population-wide genetic (GWAS) data previously indicating association with the severity of COVID-19. We confirmed the associations
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Medically relevant tandem repeats in nanopore sequencing of control cohorts medRxiv. Genet. Genom. Med. Pub Date : 2024-03-14 Wouter De Coster, Ida Hoijer, Inge Bruggeman, Svenn D'Hert, Malin Melin, Adam Ameur, Rosa Rademakers
Research and diagnostics for medically relevant tandem repeats and repeat expansions are hampered by the lack of population-scale databases. We attempt to fill this gap using our pathSTR web tool, which leverages long-read sequencing of large cohorts to determine repeat length and sequence composition in the general population. The current version includes 878 individuals of the 1000 Genomes Project
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Unlocking the Treatment of Facioscapulohumeral Muscular Dystrophy Type 2: The Bisphenol Connection medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Saed Sayad, Mark Hiatt, Hazem Mustafa
Background. Facioscapulohumeral muscular dystrophy type 2 (FSHD2) poses a significant challenge within the domain of neuromuscular disorders, marked by a progressive decline in muscle strength accompanied by tissue wasting. FSHD2 results from chromosomal deletions triggering the activation of a dormant gene known as DUX4. While DUX4 typically regulates early embryonic development, its activation in
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Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Nora I. Strom, Zachary F Gerring, Marco Galimberti, Dongmei Yu, Matthew W Halvorsen, Abdel Abdellaoui, Cristina Rodriguez-Fontenla, Julia M Sealock, Tim Bigdeli, Jonathan R. I. Coleman, Behrang Mahjani, Jackson G Thorp, Katharina Bey, Christie L Burton, Jurjen J Luykx, Gwyneth Zai, Silvia Alemany, Christine Andre, Kathleen D Askland, Nerisa Banaj, Cristina Barlassina, Judith Becker Nissen, O. Joseph
Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent
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Leveraging cancer mutation data to predict the pathogenicity of germline missense variants medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Bushra Haque, David Cheerie, Amy Pan, Meredith Curtis, Thomas Nalpathamkalam, Jimmy Nguyen, Celine Salhab, Bhooma Thiruvahindrapura, Jade Zhang, Madeline Couse, Taila Hartley, Michelle M Morrow, E Magda Price, Susan Walker, David Malkin, Frederick P Roth, Gregory Costain
Background: Innovative and easy-to-implement strategies are needed to improve the pathogenicity assessment of rare germline missense variants. Somatic cancer driver mutations identified through large-scale tumor sequencing studies often impact genes that are also associated with rare Mendelian disorders. The use of cancer mutation data to aid in the interpretation of germline missense variants, regardless
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Characterizing genetic profiles for high triglyceride levels in U.S. patients of African ancestry medRxiv. Genet. Genom. Med. Pub Date : 2024-03-13 Lan Jiang, Srushti Gangireddy, Alyson Dickson, Vivian Kawai, Nancy J Cox, Macrae Linton, Wei-Qi Wei, C. Michael Stein, QiPing Feng
Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated circulating triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry (EA). However, relatively little is known about the contribution of genetic variation to HTG in people of AA, potentially constraining research
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Pre-diagnosis blood DNA methylation profiling of twin pairs discordant for breast cancer points to the importance of environmental risk medRxiv. Genet. Genom. Med. Pub Date : 2024-03-12 Hannes F Bode, Liang He, Jacob Hjelmborg, Jaakko Kaprio, Miina Ollikainen
Background: Assessment of breast cancer (BC) risk generally relies on mammography, family history, reproductive history, and genotyping of major mutations. However, assessing the impact of environmental factors, such as lifestyle, health related behavior or external exposures, is still challenging. DNA methylation (DNAm), capturing both genetic and environmental effects, presents a promising opportunity
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Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics medRxiv. Genet. Genom. Med. Pub Date : 2024-03-11 R. Taylor Sundby, Jeffrey J. Szymanski, Alexander Pan, Paul A. Jones, Sana Z. Mahmood, Olivia H. Reid, Divya Srihari, Amy E Armstrong, Stacey Chamberlain, Sanita Burgic, Kara Weekley, Béga Murray, Sneh Patel, Faridi Qaium, Andrea N. Lucas, Margaret Fagan, Anne Dufek, Christian F. Meyer, Natalie B. Collins, Christine A. Pratilas, Eva Dombi, Andrea M. Gross, AeRang Kim, John S.A Chrisinger, Carina A
Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 121 NF1 patients and 21 healthy controls
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Systematic Review and Meta-Analysis: Research Using the Autism Polygenic Score medRxiv. Genet. Genom. Med. Pub Date : 2024-03-09 Melanie M. de Wit, Morgan J. Morgan, Ilan Libedinsky, Chloe Austerberry, Sander Begeer, Abdel Abdellaoui, Angelica Ronald, Tinca J.C. Polderman
Objective: Genetic factors play a substantial role in the etiology of autism and its co-occurrence with other conditions and traits. The autism polygenic score, derived from the latest autism case-control meta-genome-wide association studies, captures some of the accumulated influence of common genetic variants on autism. We reviewed and meta-analyzed published studies that assessed the relationship
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Genome-wide association study identifies new loci associated with OCD medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Nora I Strom, Matthew W Halvorsen, Chao Tian, Christian Rück, Gerd Kvale, Bjarne Hansen, Jonas Bybjerg-Grauholm, Jakob Grove, Julia Boberg, Judith Becker Nissen, Thomas Damm Als, Thomas Werge, Elles de Schipper, Bengt Fundin, Christina Hultman, Kira D Höffler, Nancy Pedersen, Sven Sandin, Cynthia Bulik, Mikael Landén, Elinor Karlsson, Kristen Hagen, Kerstin Lindblad-Toh, Nordic OCD and Related Disorders
To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28\% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS
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Locus-specific stratification and prioritization unveil high risk genes underlying hyperuricemia medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Jing Zhang, Yue Guo, Luyu Gong, Limei Xia, Qiaoqiao Liu, Kangchun Wang, Qi Wang, Zhaojun Liu, Zhaohui Qin, Shaolin Shi, Jingping Yang
The development of alternative medications for urate-lowering therapies is imperative for patients that are intolerant to current treatments. Despite GWAS have identified hundreds of loci associated with serum urate levels, the mechanistic understanding and discovery of drug targets remain difficult. This difficulty arises from the multiple-independent-associations challenge in the genomic studies
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A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Pavithra Nagarajan, Thomas W Winkler, Amy R Bentley, Clint L Miller, Aldi T Kraja, Karen Schwander, Songmi Lee, Wenyi Wang, Michael R Brown, John L Morrison, Ayush Giri, Jeffrey R O'Connell, Traci M Bartz, Lisa de las Fuentes, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Zhijie Huang, Mart Kals, Minjung Kho, Christophe Lefevre, Jian'an Luan, Leo-Pekka Lyytikainen, Massimo Mangino, Yuri Milaneschi
Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811
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GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases medRxiv. Genet. Genom. Med. Pub Date : 2024-03-08 Hellen Lesmann, Alexander Hustinx, Shahida Moosa, Elaine Marchi, Pilar Caro, Ibrahim M. Abdelrazek, Jean Tori Pantel, Hannah Klinkhammer, Merle ten Hagen, Tom Kamphans, Wolfgang Meiswinkel, Jing-Mei Li, Behnam Javanmardi, Alexej Knaus, Annette Uwineza, Cordula Knopp, Tinatin Tkemaladze, Miriam Elbracht, Larissa Mattern, Rami Abou Jamra, Clara Velmans, Vincent Strehlow, Himanshu Goel, Beatriz Carvalho
Dysmorphologists sometimes encounter challenges in recognizing disorders due to phenotypic variability influenced by factors such as age and ethnicity. Moreover, the performance of Next Generation Phenotyping Tools such as GestaltMatcher is dependent on the diversity of the training set. Therefore, we developed GestaltMatcher Database (GMDB) - a global reference for the phenotypic variability of rare
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Nanopore sequencing of 1000 Genomes Project samples to build a comprehensive catalog of human genetic variation medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Jonas A Gustafson, Sophia B Gibson, Nikhita Damaraju, Miranda PG Zalusky, Kendra Hoekzema, David Twesigomwe, Lei Yang, Anthony A Snead, Phillip A Richmond, Wouter De Coster, Nathan D Olson, Andrea Guarracino, Qiuhui Li, Angela L Miller, Joy Goffena, Zachery Anderson, Sophie HR Storz, Sydney A Ward, Maisha Sinha, Claudia Gonzaga-Jauregui, Wayne E Clarke, Anna O Basile, Andre Corvelo, Catherine E Reeves
Less than half of individuals with a suspected Mendelian condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control datasets for variant filtering and prioritization has made tertiary analysis of LRS
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The performance of AlphaMissense to identify genes causing disease medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Yiheng Chen, Guillaume Butler-Laporte, Kevin Y.H. Liang, Yann Ilboudo, Summaira Yasmeen, Takayoshi Sasako, Claudia Langenberg, Celia MT Greenwood, J Brent Richards
A novel algorithm, AlphaMissense, has been shown to have an improved ability to predict the pathogenicity of rare missense genetic variants. However, it is not known whether AlphaMissense improves the ability of gene-based testing to identify disease-causing genes. Using whole-exome sequencing data from the UK Biobank, we compared gene-based association analysis strategies including sets of deleterious
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Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Sarah L Stenton, Vikas Pejaver, Timothy Bergquist, Leslie G Biesecker, Alicia B Byrne, Emily Nadeau, Marc S Greenblatt, Steven Harrison, Sean Tavtigian, Predrag Radivojac, Steven E Brenner, Anne O'Donnell-Luria, ClinGen Sequence Variant Interpretation Working Group
Purpose: To investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the calibrated PP3/BP4 computational recommendations. Methods: Missense variants from the genome sequences of 300 probands from the Rare Genomes Project with suspected rare disease were analyzed using computational prediction tools able to reach PP3_Strong
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GENOTYPIC SPECTRUM OF ALBINISM IN MALI medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Diallo Modibo, Ousmane Sylla, Mohamed K Sidibe, Claudio Plaisant, Elina Mercier, Angele Sequeira, Sophie Javerzat, Aziz Hadid, Eulalie Lasseaux, Vincent Michaud, Benoit Arveiler
Albinism is a phenotypically and genetically heterogeneous condition characterized by a variable degree of hypopigmentation and by ocular features leading to reduced visual acuity. Whereas numerous genotypic studies have been conducted throughout the world, very little is known about the genotypic spectrum of albinism in Africa and especially in Sub-Saharan Western Africa. Here we report the analysis
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An integrative multi-context Mendelian randomization method for identifying risk genes across human tissues medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Yihao Lu, Ke Xu, Bowei Kang, Brandon L Pierce, Fan Yang, Lin Chen
Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often
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Structural characterization of a complex repeat at the CACNA1C pan-psychiatric locus medRxiv. Genet. Genom. Med. Pub Date : 2024-03-07 Raquel Moya, Xiaohan Wang, Richard W Tsien, Matthew T Maurano
Genetic variation within intron 3 of CACNA1C surrounding a variable-number tandem repeat (VNTR) is associated with schizophrenia and bipolar disorder, but the causal variant(s) and their effects remain unclear. We fine-mapped the association at CACNA1C including this VNTR using sequences from 155 long-read genome assemblies. Across global populations, we found 7 alleles (called Types) of the CACNA1C
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ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favorable outcomes medRxiv. Genet. Genom. Med. Pub Date : 2024-03-06 Ming-Feng He, Li-Hong Liu, Sheng Luo, Juan Wang, Jia-Jun Guo, Peng-Yu Wang, Qiong-Xiang Zhai, Su-Li He, Dongfang Zou, Xiao-Rong Liu, Bing-Mei Li, Hai-Yan Ma, Jing-Da Qiao, Peng Zhou, Na He, Yong-Hong Yi, Weiping Liao
Background The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation, and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. Methods Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3
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The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup medRxiv. Genet. Genom. Med. Pub Date : 2024-03-06 Yu-Jyun Huang, Nuzulul Kurniansyah, Matthew O Goodman, Brian W Spitzer, Jiongming Wang, Adrienne M Stilp, Cecelia Laurie, Paul S de Vries, Han Chen, Yuan-I Min, Mario Sims, Gina M Peloso, Xiuqing Guo, Joshua C Bis, Jennifer A Brody, Laura M Raffield, Jennifer A Smith, Wei Zhao, Jerome I Rotter, Stephen S Rich, Susan Redline, Myriam Fornage, Robert Kaplan, Nora Franceschini, Daniel Levy, Alanna C Morrison
Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called expected PRS (ePRS), the expected value of a PRS based on the global or local admixture patterns of an individual. We
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Evaluation of Bayesian Classification Framework on the Variant Classification of Hereditary Cancer Predisposition Genes medRxiv. Genet. Genom. Med. Pub Date : 2024-03-06 Mohammad K. Eldomery, Jamie L. Maciaszek, Taylor Cain, Victor Pastor Loyola, Suraj Sarvode Mothi, David A. Wheeler, Li Tang, Lu Wang, Jeffery M. Klco, Patrick R. Blackburn
Purpose: To assess the differences in the variants classifications using the ACMG/AMP 2015 guidelines and the Bayesian point-based classification system (here referred to as point system) in 115 hereditary cancer predisposition genes and explore the utility of the point system in variant reanalysis. Methods: Germline variant classifications from 721 pediatric patients were evaluated using the two scoring
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Dissecting the contribution of common variants to risk of rare neurodevelopmental conditions medRxiv. Genet. Genom. Med. Pub Date : 2024-03-06 Qin Qin Huang, Emilie M Wigdor, Patrick Campbell, Daniel S Malawsky, Kaitlin E Samocha, V Kartik Chundru, Petr Danecek, Sarah Lindsay, Thomas Marchant, Mahmoud Koko Musa, Sana Amanat, Davide Bonifanti, Eamonn Sheridan, Elizabeth J Radford, Jeffrey C Barrett, Caroline F Wright, Helen V Firth, Varun Warrier, Alexander Strudwick Young, Matthew Hurles, Hilary C Martin
Although rare neurodevelopmental conditions have a large Mendelian component, common genetic variants also contribute to risk. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents, its interplay with rare variants, and whether parents' polygenic background contributes to their children's risk beyond the direct effect of variants
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Leveraging molecular-QTL co-association to predict novel disease-associated genetic loci using a graph convolutional neural network medRxiv. Genet. Genom. Med. Pub Date : 2024-03-05 Julian Ng-Kee-Kwong, Andrew David Bretherick
Genome-wide association studies (GWAS) have successfully uncovered numerous associations between genetic variants and disease traits to date. Yet, identifying significantly associated loci remains a considerable challenge due to the concomitant multiple-testing burden of performing such analyses genome-wide. Here, we leverage the genetic associations of molecular traits — DNA CpG-site methylation status
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Investigating the Relationship Between Rare Genetic Variants and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease medRxiv. Genet. Genom. Med. Pub Date : 2024-03-04 Julia Wattacheril, Sarah E Kleinstein, Patrick R Shea, Laura A Wilson, G Mani Subramanian, Robert P Myers, Jay Lefkowitch, Cynthia Behling, Stavra A Xanthakos, David B Goldstein, NASH Clinical Research Network
Background and Aims: Nonalcoholic Fatty Liver Disease (NAFLD) is a complex human disease. Common genetic variation in the patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been associated with an increased risk of developing NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis in adults. The role of rare genetic variants in the
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High Probability of Lynch Syndrome among colorectal cancer patients in Indonesia is associated with higher occurrence of KRAS and PIK3CA mutations medRxiv. Genet. Genom. Med. Pub Date : 2024-03-04 Didik Setyo Heriyanto, Naomi Yoshuantari, Gilang Akbariani, Vincent Lau, Hanifa Hanini, Zulfa Hidayati, Muhammad Zulfikar Arief, Andrew Nobiantoro Gunawan, Asep Muhamad Ridwanuloh, Wien Kusharyoto, Adeodatus Yuda Handaya, Mohammad Ilyas, Johan Kurnianda, Susanna Hilda Hutajulu, Susanti Susanti
Background: In Indonesia, early-onset colorectal cancer (EOCRC) rates are higher in patients <50 years old compared to western populations, possibly due to a higher frequency of Lynch Syndrome (LS) in CRC patients. We aim to examine the association of KRAS and PIK3CA mutation with LS. Methods: In this cross-sectional study, the PCR-HRM-based test was used for screening of MSI mononucleotide markers
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Multi-omics Integration Identifies Genes Influencing Traits Associated with Cardiovascular Risks: The Long Life Family Study medRxiv. Genet. Genom. Med. Pub Date : 2024-03-04 Sandeep Acharya, Shu Liao, Wooseok J Jung, Yu Sung Kang, Vaha A. Moghaddam, Mary Feitosa, Mary Wojczynski, Shiow Lin, Jason A. Anema, Karen Schwander, Jeff O Connell, Mike Province, Michael Richard Brent
The Long Life Family Study (LLFS) enrolled 4,953 participants in 539 pedigrees displaying exceptional longevity. To identify genetic mechanisms that affect cardiovascular risks in the LLFS population, we developed a multi-omics integration pipeline and applied it to 11 traits associated with cardiovascular risks. Using our pipeline, we aggregated gene-level statistics from rare-variant analysis, GWAS
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Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk medRxiv. Genet. Genom. Med. Pub Date : 2024-03-04 Daniel R. Barnes, Jonathan P. Tyrer, Joe Dennis, Goska Leslie, Manjeet K. Bolla, Michael Lush, Amber M. Aeilts, Kristiina Aittomaki, Nadine Andrieu, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Banu K. Arun, Judith Balmana, Elisa V. Bandera, Rosa B. Barkardottir, Lieke P.V. Berger, Amy Berrington de Gonzalez, Pascaline Berthet, Katarzyna Bialkowska, Line Bjorge, Amie M. Blanco, Marinus J
Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238
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Ethnic variation and structure-function analysis of tauopathy-associated PERK alleles. medRxiv. Genet. Genom. Med. Pub Date : 2024-03-04 Goonho Park, Angela Galdamez, Masako Le, Keon-Hyoung Song, Kyle Kim, Jonathan H Lin
EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic
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Meta-Analysis of Breast Cancer Risk for Individuals with PALB2 Pathogenic Variants medRxiv. Genet. Genom. Med. Pub Date : 2024-03-04 Thanthirige Lakshika M. Ruberu, Danielle Braun, Giovanni Parmigiani, Swati Biswas
Background: Pathogenic variants in cancer susceptibility genes can now be tested efficiently and economically with the wide availability of multi-gene panel testing. This has resulted in an unprecedented rate of identifying individuals carrying pathogenic variants. These carriers need to be counselled about their future cancer risk conferred by the specific gene mutation. An important cancer susceptibility
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Analytical and clinical validation of a targeted-enhanced whole genome sequencing-based comprehensive genomic profiling test. medRxiv. Genet. Genom. Med. Pub Date : 2024-03-03 Stephanie Ferguson, Shruthi Sriram, Jeonghoon Lee, Jonathan Kyle Wallace, Jung-Ah Kim, Yoonsuh Lee, Brian Baek-Lok Oh, Won Chul Lee, Sangmoon Lee, Erin C Connolly-Strong
Evaluation of the test performance of the targeted enhanced whole-genome sequencing (TE-WGS) assay for comprehensive oncology genomic profiling. The analytical validation of the assay included sensitivity and specificity for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), revealing a revealed a sensitivity of 99.8% for SNVs and 99.2% for indels. The
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The contribution of de novo coding mutations to meningomyelocele medRxiv. Genet. Genom. Med. Pub Date : 2024-03-02 Yoo-Jin Ha, Joseph G Gleeson
Meningomyelocele (MM) is considered a genetically complex disease resulting from failure of neural tube closure (NTD). Patients display neuromotor disability and frequent hydrocephalus requiring ventricular shunting. A few proposed genes contribute to disease susceptibility, but most risk remains unexplained. We postulated that de novo mutations (DNMs) under purifying selection contribute to MM risk
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Enhancer RNA transcriptome-wide association study reveals an atlas of pan-cancer susceptibility eRNAs medRxiv. Genet. Genom. Med. Pub Date : 2024-03-02 Wenyan Chen, Zeyang Wang, Jianxiang Lin, Shuxin Chen, Hui Chen, Xuelian Ma, Xudong Zou, Xing Li, Yinuo Wang, Yangmei Qin, Xixian Ma, Yunbo Qiao, Lei Li
Many cancer risk variants are located within enhancer regions and lack sufficient molecular interpretation. Here, we constructed the first comprehensive atlas of enhancer RNA (eRNA)-mediated genetic effects from 28,033 RNA sequencing samples across 11,606 individuals, identifying 11,757 eRNA quantitative trait loci (eRNA-QTLs) significantly associated with eRNA expression. Mechanistically, eRNA-QTLs
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Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder medRxiv. Genet. Genom. Med. Pub Date : 2024-03-02 Khemika K Sudnawa, Wenxing Li, Sean Calamia, Cara H. Kanner, Jennifer M Bain, Aliaa H Abdelhakim, Alexa Geltzeiler, Caroline M Mebane, Frank A Provenzano, Tristan T Sands, Robert J Fee, Jacqueline Montes, Yufeng Shen, Wendy K Chung
Purpose: Pathogenic variants in Kinesin Family Member 1A (KIF1A) are associated with KIF1A-associated neurological disorder (KAND). We report the clinical phenotypes and correlate genotypes of individuals with KAND. Methods: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic and cognitive assessments. Results: We collected
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Copy number variants differ in frequency across genetic ancestry groups medRxiv. Genet. Genom. Med. Pub Date : 2024-03-02 Laura M. Schultz, Alexys Knighton, Guillaume Huguet, Zohra Saci, Martineau Jean-Louis, Josephine Mollon, Emma E.M. Knowles, David C. Glahn, Sébastien Jacquemont, Laura Almasy
Copy number variants (CNVs), which are duplicated or deleted genomic segments larger than 1000 base pairs, have been implicated in a variety of neuropsychiatric and cognitive phenotypes. In the first large-scale of examination of genome-wide CNV frequencies across ancestry groups, we found that deleterious CNVs are less prevalent in non-European ancestry groups than they are in European ancestry groups
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Machine Learning for Predicting Therapeutic Outcomes in Acute Myeloid Leukemia Patients medRxiv. Genet. Genom. Med. Pub Date : 2024-03-02 Nestoras Karathanasis, Panayiota Papasavva, Anastasis Oulas, George M Spyrou
Background and Objective: The standard of care in Acute Myeloid Leukemia patients has remained essentially unchanged for nearly 40 years. Due to the complicated mutational patterns within and between individual patients and a lack of targeted agents for most mutational events, implementing individualized treatment for AML has proven difficult. We reanalysed the BeatAML dataset employing Machine Learning
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Multi-trait genetic analysis identifies novel pleiotropic loci for depression and schizophrenia in East Asians medRxiv. Genet. Genom. Med. Pub Date : 2024-03-01 Yingchao Song, Linzehao Li, Yue Jiang, Bichen Peng, Hengxuan Jiang, Zhen Chao, Xiao Chang
While genetic correlations, pleiotropic loci, and shared genetic mechanisms of psychiatric disorders have been extensively studied in European populations, the investigation of these factors in East Asian populations has been relatively limited. To identify novel pleiotropic risk loci for depression and schizophrenia (SCZ) in East Asians. We harnessed the most comprehensive dataset available for East
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RFC1 repeat expansion analysis from whole genome sequencing data simplifies screening and increases diagnostic rates medRxiv. Genet. Genom. Med. Pub Date : 2024-02-29 Roisin Sullivan, Sai Chen, Christopher T Saunders, Wai Yan Yau, Yee Yen Goh, Emer O'Connor, Natalia Dominik, Valentina Galassi Deforie, Heba Morsy, Andrea Cortese, Henry Houlden, Michael A Eberle, Jana Vandrovcova
Biallelic expansions and a motif change in RFC1 are a common cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Molecular diagnosis relies on a complicated combination of repeat primed PCR and Southern blotting. We developed a whole genome sequencing based method for RFC1 repeat detection. The combination of sequence motifs and allele length analysis in 29,478 individuals showed
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Epigenetic timing effects on child developmental outcomes: A longitudinal meta-regression of findings from the Pregnancy And Childhood Epigenetics Consortium medRxiv. Genet. Genom. Med. Pub Date : 2024-02-29 Alexander Neumann, Sara Sammallahti, Marta Cosin-Tomas, Sarah E Reese, Matthew Suderman, Silvia Alemany, Catarina Almqvist, Sandra Andrusaityte, Syed H Arshad, Marian J Bakermans-Kranenburg, Lawrence Beilin, Carrie Breton, Mariona Bustamante, Darina Czamara, Dana Dabelea, Celeste Eng, Brenda Eskenazi, Bernard F Fuemmeler, Frank D Gilliland, Regina Grazuleviciene, Siri E Håberg, Gunda Herberth, Nina
DNA methylation (DNAm) is a developmentally dynamic epigenetic process, yet we still know little about how epigenetic effects on health outcomes vary over time; whether DNAm alterations during certain periods of development are more informative than others; and whether epigenetic timing effects differ by outcome. To address these questions, we applied longitudinal meta-regression to published meta-analyses
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APOL1 variants G1, G2 and N264K affect APOL1 plasma protein concentration: a UK Biobank study medRxiv. Genet. Genom. Med. Pub Date : 2024-02-29 Walt E Adamson, Harry Noyes, John Ogunsola, Rulan S Parekh, Anneli Cooper, Annette MacLeod
Background APOL1 variants G1 and G2 are common in populations with recent sub-Saharan African ancestry. They are known to influence health conditions: most notably being associated with protection from human African trypanosomiasis and increased risk of susceptibility to chronic kidney disease. Association studies have often considered G1 and G2 as equivalent, however we recently presented evidence
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Antiandrogen Flutamide-Induced Restoration of miR-449 Expression Mitigates Functional Biomarkers Associated with Ovarian Cancer Risk medRxiv. Genet. Genom. Med. Pub Date : 2024-02-29 xia wang, Ho-Hyung Woo, Michele Wei, Steven Gibson, Mitzi Miranda, Demaretta Rush, Janiel Cragun, Wenxin Zheng, Guang Yao, Setsuko K Chambers
Background: The involvement of the androgen and androgen receptor (AR) pathway in the development of epithelial ovarian cancer is increasingly recognized. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. We examined the effects of flutamide on the miRNA expression profile found in women at high risk (HR)
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Proteomic Networks and Related Genetic Variants Associated with Smoking and Chronic Obstructive Pulmonary Disease medRxiv. Genet. Genom. Med. Pub Date : 2024-02-28 Iain R Konigsberg, Thao Vu, Weixuan Liu, Elizabeth M Litkowski, Katherine A. Pratte, Luciana B Vargas, Niles Gilmore, Mohamed Abdel-Hafiz, Ani W. Manichaikul, Michael Cho, Craig Hersh, Dawn DeMeo, Farnoush Banaei-Kashani, Russell Paul Bowler, Leslie Lange, Katerina Kechris
Background Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features. Methods Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW)
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Curating genomic disease-gene relationships with Gene2Phenotype medRxiv. Genet. Genom. Med. Pub Date : 2024-02-28 Thabo Michael Yates, Morad Ansari, Louise Thompson, Sarah E Hunt, Elena Cibrian Uhalte, Rachel J Hobson, Joseph A Marsh, Caroline F Wright, Helen V Firth
Genetically determined disorders are highly heterogenous in clinical presentation and underlying molecular mechanism. The evidence underpinning these conditions in the peer-reviewed literature is variable and requires robust critical evaluation for diagnostic use. Here, we present a structured curation process for the Gene2Phenotype (G2P) project. This draws on multiple lines of clinical, bioinformatic
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Partitioning the Genomic Components of Behavioral Disinhibition and Substance Use (Disorder) Using Genomic Structural Equation Modeling medRxiv. Genet. Genom. Med. Pub Date : 2024-02-27 Tanya B. Horwitz, Katerina Zorina-Lichtenwalter, Daniel E. Gustavson, Andrew D. Grotzinger, Michael C. Stallings
Externalizing behaviors encompass manifestations of risk-taking, self-regulation, aggression, sensation-/reward-seeking, and impulsivity. Externalizing research often includes substance use (SU), substance use disorder (SUD), and other (non-SU/SUD) "behavioral disinhibition" (BD) traits. Genome-wide and twin research have pointed to overlapping genetic architecture within and across SUB, SUD, and BD
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Blood-based DNA methylation study of alcohol consumption medRxiv. Genet. Genom. Med. Pub Date : 2024-02-27 Elena Bernabeu, Aleksandra Chybowska, Jacob K Kresovich, Matthew Suderman, Daniel L. McCartney, Robert F Hillary, Janie Corley, Maria Del Carmen Valdes Hernandez, Susana Munoz Maniega, Mark E Bastin, Joanna M Wardlaw, Zongli Xu, Dale P. Sandler, Archie Campbell, Sarah E Harris, Andrew M McIntosh, Jack Taylor, Paul Darius Yousefi, Simon R Cox, Kathryn L Evans, Matthew Richard Robinson, Catalina A Vallejos
Alcohol consumption is an important risk factor for multiple diseases. It is typically assessed via self-report, which is open to measurement error and bias. Instead, molecular data such as blood-based DNA methylation (DNAm) could be used to derive a more objective measure of alcohol consumption by incorporating information from cytosine-phosphate-guanine (CpG) sites known to be linked to the trait
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Multi-omics clustering analysis carries out the molecular specific subtypes of thyroid carcinoma: implicating for the precise treatment strategies medRxiv. Genet. Genom. Med. Pub Date : 2024-02-27 Zhenglin Wang, Qiju Han, Xianyu Hu, Xu Wang, Rui Sun, Siwei Huang, Wei Chen
Background Thyroid cancer is the most prevalent endocrine malignancy, Recent classifications highlight the importance of molecular characteristics in TC, including BRAF, TERT, and RET fusion gene mutations, which are crucial for diagnosis, prognosis, and targeted therapy. This study aims to explore molecular subtypes of TC to identify new biomarkers and improve patient selection for targeted therapies