Rhiannon B Werder, Kayleigh A Berthiaume, Carly Merritt, Marissa Gallagher, Carlos Villacorta-Martin, Feiya Wang, Pushpinder Bawa, Vidhi Malik, Shawn M Lyons, Maria C Basil, Edward E Morrisey, Darrell N Kotton, Xiaobo Zhou, Michael H Cho, Andrew A Wilson
Emphysema and chronic obstructive pulmonary disease (COPD) most commonly result from the effects of environmental exposures in genetically susceptible individuals. Genome-wide association studies have implicated ADGRG6 in COPD and reduced lung function, and a limited number of studies have examined the role of ADGRG6 in cells representative of the airway. However, the ADGRG6 locus is also associated with DLCO/VA, an indicator of gas exchange efficiency and alveolar function. Here, we sought to evaluate the mechanistic contributions of ADGRG6 to homeostatic function and disease in type 2 alveolar epithelial cells...
September 12, 2023: American Journal of Human Genetics
Warren van Loggerenberg, Shahin Sowlati-Hashjin, Jochen Weile, Rayna Hamilton, Aditya Chawla, Dayag Sheykhkarimli, Marinella Gebbia, Nishka Kishore, Laure Frésard, Sami Mustajoki, Elena Pischik, Elena Di Pierro, Michela Barbaro, Ylva Floderus, Caroline Schmitt, Laurent Gouya, Alexandre Colavin, Robert Nussbaum, Edith C H Friesema, Raili Kauppinen, Jordi To-Figueras, Aasne K Aarsand, Robert J Desnick, Michael Garton, Frederick P Roth
Defects in hydroxymethylbilane synthase (HMBS) can cause acute intermittent porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ∼⅓ of clinical HMBS variants are missense variants, and most clinically reported HMBS missense variants are designated as "variants of uncertain significance" (VUSs). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino acid substitutions...
September 12, 2023: American Journal of Human Genetics
Santiago G Medina-Muñoz, Diego Ortega-Del Vecchyo, Luis Pablo Cruz-Hervert, Leticia Ferreyra-Reyes, Lourdes García-García, Andrés Moreno-Estrada, Aaron P Ragsdale
Demographic models of Latin American populations often fail to fully capture their complex evolutionary history, which has been shaped by both recent admixture and deeper-in-time demographic events. To address this gap, we used high-coverage whole-genome data from Indigenous American ancestries in present-day Mexico and existing genomes from across Latin America to infer multiple demographic models that capture the impact of different timescales on genetic diversity. Our approach, which combines analyses of allele frequencies and ancestry tract length distributions, represents a significant improvement over current models in predicting patterns of genetic variation in admixed Latin American populations...
September 11, 2023: American Journal of Human Genetics
Chang Xu, Santhi K Ganesh, Xiang Zhou
Accurate polygenic scores (PGSs) facilitate the genetic prediction of complex traits and aid in the development of personalized medicine. Here, we develop a statistical method called multi-trait assisted PGS (mtPGS), which can construct accurate PGSs for a target trait of interest by leveraging multiple traits relevant to the target trait. Specifically, mtPGS borrows SNP effect size similarity information between the target trait and its relevant traits to improve the effect size estimation on the target trait, thus achieving accurate PGSs...
September 7, 2023: American Journal of Human Genetics
Stefan van Duijvenboden, Julia Ramírez, William J Young, Kaya J Olczak, Farah Ahmed, Mohammed J A Y Alhammadi, Christopher G Bell, Andrew P Morris, Patricia B Munroe
Genome-wide association studies of blood pressure (BP) have identified >1,000 loci, but the effector genes and biological pathways at these loci are mostly unknown. Using published association summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation and colocalization to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with ≥2 BP traits and 84 with all three...
September 1, 2023: American Journal of Human Genetics
Wenlong Carl Chen, Jean-Tristan Brandenburg, Ananyo Choudhury, Mahtaab Hayat, Dhriti Sengupta, Yaniv Swiel, Chantal Babb de Villiers, Lucien Ferndale, Colleen Aldous, Cassandra C Soo, Sang Lee, Charles Curtis, Rob Newton, Tim Waterboer, Freddy Sitas, Debbie Bradshaw, Christian C Abnet, Michele Ramsay, M Iqbal Parker, Elvira Singh, Cathryn M Lewis, Christopher G Mathew
Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4...
August 29, 2023: American Journal of Human Genetics
Gaia Andreoletti, Oriana Romano, Hsin-Jung Chou, Mahjoubeh J Sefid-Dashti, Andrea Grilli, Clarice Chen, Neema Lakshman, Pravin Purushothaman, Fatbardha Varfaj, Fulvio Mavilio, Silvio Bicciato, Fabrizia Urbinati
X-linked myotubular myopathy (XLMTM) is a severe congenital disease characterized by profound muscle weakness, respiratory failure, and early death. No approved therapy for XLMTM is currently available. Adeno-associated virus (AAV)-mediated gene replacement therapy has shown promise as an investigational therapeutic strategy. We aimed to characterize the transcriptomic changes in muscle biopsies of individuals with XLMTM who received resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) in the ASPIRO clinical trial and to identify potential biomarkers that correlate with therapeutic outcome...
August 29, 2023: American Journal of Human Genetics
Kathryn A McGurk, Xiaolei Zhang, Pantazis Theotokis, Kate Thomson, Andrew Harper, Rachel J Buchan, Erica Mazaika, Elizabeth Ormondroyd, William T Wright, Daniela Macaya, Chee Jian Pua, Birgit Funke, Daniel G MacArthur, Sanjay K Prasad, Stuart A Cook, Mona Allouba, Yasmine Aguib, Magdi H Yacoub, Declan P O'Regan, Paul J R Barton, Hugh Watkins, Leonardo Bottolo, James S Ware
Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD)...
August 28, 2023: American Journal of Human Genetics
Lin Miao, Lin Jiang, Bin Tang, Pak Chung Sham, Miaoxin Li
Despite extensive research on global heritability estimation for complex traits, few methods accurately dissect local heritability. A precise local heritability estimate is crucial for high-resolution mapping in genetics. Here, we report the effective heritability estimator (EHE) that can use p values from genome-wide association studies (GWASs) for local heritability estimation by directly converting marginal heritability estimates of SNPs to a non-redundant heritability estimate of a gene or a small genomic region...
August 25, 2023: American Journal of Human Genetics
Cong Zhang, Konstantin Shestopaloff, Benjamin Hollis, Chun Hei Kwok, Claudia Hon, Nicole Hartmann, Chengeng Tian, Magdalena Wozniak, Luis Santos, Dominique West, Stephen Gardiner, Ann-Marie Mallon, Aimee Readie, Ruvie Martin, Thomas Nichols, Michael T Beste, Jonas Zierer, Enrico Ferrero, Marc Vandemeulebroecke, Luke Jostins-Dean
Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials across four indications (psoriatic arthritis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis), we tested whether genetics predicted response to secukinumab...
August 24, 2023: American Journal of Human Genetics
Alesha A Hatton, Robert F Hillary, Elena Bernabeu, Daniel L McCartney, Riccardo E Marioni, Allan F McRae
The recent increase in obesity levels across many countries is likely to be driven by nongenetic factors. The epigenetic modification DNA methylation (DNAm) may help to explore this, as it is sensitive to both genetic and environmental exposures. While the relationship between DNAm and body-fat traits has been extensively studied, there is limited literature on the shared associations of DNAm variation across such traits. Akin to genetic correlation estimates, here, we introduce an approach to evaluate the similarities in DNAm associations between traits: DNAm correlations...
August 23, 2023: American Journal of Human Genetics
Moriel Singer-Berk, Sanna Gudmundsson, Samantha Baxter, Eleanor G Seaby, Eleina England, Jordan C Wood, Rachel G Son, Nicholas A Watts, Konrad J Karczewski, Steven M Harrison, Daniel G MacArthur, Heidi L Rehm, Anne O'Donnell-Luria
Predicted loss of function (pLoF) variants are often highly deleterious and play an important role in disease biology, but many pLoF variants may not result in loss of function (LoF). Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines' PVS1 criterion...
August 22, 2023: American Journal of Human Genetics
Danyue Dong, Haoyu Shen, Zhenguo Wang, Jiaqi Liu, Zhe Li, Xin Li
Understanding dosage sensitivity or why Mendelian diseases have dominant vs. recessive modes of inheritance is crucial for uncovering the etiology of human disease. Previous knowledge of dosage sensitivity is mainly based on observations of rare loss-of-function mutations or copy number changes, which are underpowered due to ultra rareness of such variants. Thus, the functional underpinnings of dosage constraint remain elusive. In this study, we aim to systematically quantify dosage perturbations from cis-regulatory variants in the general population to yield a tissue-specific dosage constraint map of genes and further explore their underlying functional logic...
August 17, 2023: American Journal of Human Genetics
Lisa Bastarache, Sarah Delozier, Anita Pandit, Jing He, Adam Lewis, Aubrey C Annis, Jonathon LeFaive, Joshua C Denny, Robert J Carroll, Russ B Altman, Jacob J Hughey, Matthew Zawistowski, Josh F Peterson
Population-scale biobanks linked to electronic health record data provide vast opportunities to extend our knowledge of human genetics and discover new phenotype-genotype associations. Given their dense phenotype data, biobanks can also facilitate replication studies on a phenome-wide scale. Here, we introduce the phenotype-genotype reference map (PGRM), a set of 5,879 genetic associations from 523 GWAS publications that can be used for high-throughput replication experiments. PGRM phenotypes are standardized as phecodes, ensuring interoperability between biobanks...
August 16, 2023: American Journal of Human Genetics
Chelsea Lowther, Elise Valkanas, Jessica L Giordano, Harold Z Wang, Benjamin B Currall, Kathryn O'Keefe, Emma Pierce-Hoffman, Nehir E Kurtas, Christopher W Whelan, Stephanie P Hao, Ben Weisburd, Vahid Jalili, Jack Fu, Isaac Wong, Ryan L Collins, Xuefang Zhao, Christina A Austin-Tse, Emily Evangelista, Gabrielle Lemire, Vimla S Aggarwal, Diane Lucente, Laura D Gauthier, Charlotte Tolonen, Nareh Sahakian, Christine Stevens, Joon-Yong An, Shan Dong, Mary E Norton, Tippi C MacKenzie, Bernie Devlin, Kelly Gilmore, Bradford C Powell, Alicia Brandt, Francesco Vetrini, Michelle DiVito, Stephan J Sanders, Daniel G MacArthur, Jennelle C Hodge, Anne O'Donnell-Luria, Heidi L Rehm, Neeta L Vora, Brynn Levy, Harrison Brand, Ronald J Wapner, Michael E Talkowski
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families...
August 16, 2023: American Journal of Human Genetics
Menno Ter Huurne, Benjamin L Parker, Ning Qing Liu, Elizabeth Ling Qian, Celine Vivien, Kathy Karavendzas, Richard J Mills, Jennifer T Saville, Dad Abu-Bonsrah, Andrea F Wise, James E Hudson, Andrew S Talbot, Patrick F Finn, Paolo G V Martini, Maria Fuller, Sharon D Ricardo, Kevin I Watt, Kathy M Nicholls, Enzo R Porrello, David A Elliott
Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate...
August 12, 2023: American Journal of Human Genetics
Paulien Terhal, Anton J Venhuizen, Davor Lessel, Wen-Hann Tan, Abdulrahman Alswaid, Regina Grün, Hamad I Alzaidan, Simon von Kroge, Nada Ragab, Maja Hempel, Christian Kubisch, Eduardo Novais, Alba Cristobal, Kornelia Tripolszki, Peter Bauer, Björn Fischer-Zirnsak, Rutger A J Nievelstein, Atty van Dijk, Peter Nikkels, Ralf Oheim, Heidi Hahn, Aida Bertoli-Avella, Madelon M Maurice, Uwe Kornak
Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity...
August 9, 2023: American Journal of Human Genetics
Yuzhuo Wang, Yue Ding, Su Liu, Cheng Wang, Erbao Zhang, Congcong Chen, Meng Zhu, Jing Zhang, Chen Zhu, Mengmeng Ji, Juncheng Dai, Guangfu Jin, Zhibin Hu, Hongbing Shen, Hongxia Ma
Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs...
August 3, 2023: American Journal of Human Genetics
Sven E Ojavee, Liza Darrous, Marion Patxot, Kristi Läll, Krista Fischer, Reedik Mägi, Zoltan Kutalik, Matthew R Robinson
There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modeling framework, which determines the time dependency of DNA-variant age-at-onset associations without a significant multiple-testing burden...
August 1, 2023: American Journal of Human Genetics
Éadaoin Harney, Kendra Sirak, Jakob Sedig, Steven Micheletti, Roslyn Curry, Samantha Ancona Esselmann, David Reich
Ancient DNA studies have begun to explore the possibility of identifying identical DNA segments shared between historical and living people. This research requires access to large genetic datasets to maximize the likelihood of identifying previously unknown, close genetic connections. Direct-to-consumer genetic testing companies, such as 23andMe, Inc., manage by far the largest and most diverse genetic databases that can be used for this purpose. It is therefore important to think carefully about guidelines for carrying out collaborations between researchers and such companies...
July 26, 2023: American Journal of Human Genetics
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