Genetics
Abstract
BACKGROUND. Most genome wide association studies (GWAS) of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry enriched protein quantitative loci (pQTL). METHODS. We conducted a discovery GWAS of ~3,000 plasma proteins measured by the antibody based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS), and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs were further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome wide association study (PheWAS) across two large multi-ethnic electronic health record (EHR) systems in All of Us and BioMe. RESULTS. We identified 1002 pQTLs for 925 proteins. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for Cathepsin L (CTSL) and Siglec-9 that were linked with sarcoidosis and non-Hodgkin’s lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, white blood cell count, and multiple sclerosis. CONCLUSIONS. Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.
Authors
Usman A. Tahir, Jacob L. Barber, Daniel E. Cruz, Meltem Ece Kars, Shuliang Deng, Bjoernar Tuftin, Madeline G. Gillman, Mark D. Benson, Jeremy M. Robbins, Zsu-Zsu Chen, Prashant Rao, Daniel H. Katz, Laurie Farrell, Tamar Sofer, Michael E. Hall, Lynette Ekunwe, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Thomas J. Wang, Alex P. Reiner, Pradeep Natarajan, Yuval Itan, Stephen S. Rich, Jerome I. Rotter, James G. Wilson, Laura M. Raffield, Robert E. Gerszten
Abstract
A hexanucleotide GGGGCC repeat expansion in the non-coding region of C9orf72 gene is the most common genetic mutation identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The resulting repeat RNA and dipeptide repeat proteins from non-conventional repeat translation have been recognized as important markers associated with the diseases. CRISPR-Cas13d, a powerful RNA targeting tool, has faced challenges in effectively targeting RNA with stable secondary structures. Here we report that CRISPR-Cas13d can be optimized to specifically target GGGGCC repeat RNA. Our results demonstrate that the CRISPR-Cas13d system can be harnessed to significantly diminish the translation of poly-dipeptides originating from the GGGGCC repeat RNA. This efficacy has been validated in various cell types, including induced pluripotent stem cells and differentiated motor neurons originating from C9orf72-ALS patients, as well as in C9orf72 repeat transgenic mice. These findings demonstrate the application of CRISPR-Cas13d in targeting RNA with intricate higher-order structures and suggest a potential therapeutic approach for ALS and FTD.
Authors
Honghe Liu, Xiao-Feng Zhao, Yu-Ning Lu, Lindsey R. Hayes, Jiou Wang
Abstract
BACKGROUND It is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODS Three cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTS Monogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (–3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (–2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONS Monogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATION NA.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
Authors
Mark D. Elliott, Natalie Vena, Maddalena Marasa, Enrico Cocchi, Shiraz Bheda, Kelsie Bogyo, Ning Shang, Francesca Zanoni, Miguel Verbitsky, Chen Wang, Victoria Kolupaeva, Gina Jin, Maayan Sofer, Rafael Gras Pena, Pietro A. Canetta, Andrew S. Bomback, Lisa M. Guay-Woodford, Jean Hou, Brenda W. Gillespie, Bruce M. Robinson, Jon B. Klein, Michelle N. Rheault, William E. Smoyer, Larry A. Greenbaum, Larry B. Holzman, Ronald J. Falk, Afshin Parsa, Simone Sanna-Cherchi, Laura H. Mariani, Matthias Kretzler, Krzysztof Kiryluk, Ali G. Gharavi, CureGN Consortium
Abstract
Background Cystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases. Methods Using whole genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies. Results In 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with novel statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK BioBank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations but suggested this category of variation contributes 3-9% to the heritability of CyKD across European ancestries. Conclusion By providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counselling in the clinic. Keywords: genomics, cystic kidney disease, renal, ADPKD, WGS
Authors
Omid Sadeghi-Alavijeh, Melanie MY. Chan, Gabriel T. Doctor, Catalin D. Voinescu, Alexander Stuckey, Athanasios Kousathanas, Alexander T. Ho, Horia C. Stanescu, Detlef Bockenhauer, Richard N. Sandford, Adam P. Levine, Daniel P. Gale
Abstract
Authors
Benjamin J. Landis, Benjamin M. Helm, Matthew D. Durbin, Lindsey R. Helvaty, Jeremy L. Herrmann, Michael Johansen, Gabrielle C. Geddes, Stephanie M. Ware
Abstract
Authors
Dan Wang, Ania Baghoomian, Zhengyi Zhang, Ya Cui, Emily C. Whang, Xiang Li, Josue Fraga, Rachel Spellman, Tien S. Dong, We Li, Arpana Gupta, Jihane N. Benhammou, Tamer Sallam
Abstract
Authors
Vicente Quiroz, Laura Planas-Serra, Abigail Sveden, Amy Tam, Hyo M. Kim, Umar Zubair, Dario Resch, Afshin Saffari, Matt C. Danzi, Stephan Züchner, Maya Chopra, Luca Schierbaum, Aurora Pujol, Erik A. Eklund, Darius Ebrahimi-Fakhari
Abstract
Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.
Authors
Yang Li, Ke Ma, Zhujun Dong, Shijuan Gao, Jing Zhang, Shan Huang, Jie Yang, Guangming Fang, Yujie Li, Xiaowei Li, Carrie Welch, Emily L. Griffin, Prema Ramaswamy, Zaheer Valivullah, Xiuying Liu, Jianzeng Dong, Dao Wen Wang, Jie Du, Wendy K. Chung, Yulin Li
Abstract
Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes in addition to bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in IFITM5. Here, we generated a conditional Rosa26 knock-in mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in OI type V patients. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with increase in the skeletal progenitor population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 showed decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupts early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.
Authors
Ronit Marom, I-Wen Song, Emily C. Busse, Megan E. Washington, Ava S. Berrier, Vittoria C. Rossi, Laura Ortinau, Youngjae Jeong, Ming-Ming Jiang, Brian C. Dawson, Mary Adeyeye, Carolina Leynes, Caressa D. Lietman, Bridget M. Stroup, Dominyka Batkovskyte, Mahim Jain, Yuqing Chen, Racel Cela, Alexis Castellon, Alyssa A. Tran, Isabel Lorenzo, D. Nicole Meyers, Shixia Huang, Alicia Turner, Vinitha Shenava, Maegen Wallace, Eric Orwoll, Dongsu Park, Catherine G. Ambrose, Sandesh C.S. Nagamani, Jason D. Heaney, Brendan H. Lee
Abstract
GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G-protein Gαo. Of >80 pathogenic mutations, most are single amino acid substitutions spreading across Gαo sequence. We perform extensive characterization of Gαo mutants showing abnormal GTP uptake and hydrolysis, and deficiencies to bind Gβγ and RGS19. Plasma membrane localization of Gαo is decreased for a subset of mutations that leads to epilepsy; dominant interactions with GPCRs also emerge for the more severe mutants. Pathogenic mutants massively gain interaction with Ric8A and, surprisingly, Ric8B proteins, delocalizing them from cytoplasm to Golgi. Of these two mandatory Gα-subunit chaperones, Ric8A is normally responsible for the Gαi/o, Gαq, and Gα12/13 subfamilies, and Ric8B solely for Gαs/olf. Ric8A/B mediate the disease dominance when engaging in neomorphic interactions with pathogenic Gαo through disbalancing the neuronal G protein signaling networks. As the strength of Gαo-Ric8B interactions correlates with disease severity, our study further identifies an efficient biomarker and predictor for clinical manifestations in GNAO1 encephalopathies. Our work discovers the neomorphic molecular mechanism of mutations underlying pediatric encephalopathies and offers insights to other maladies caused by G protein misfunctioning and further genetic diseases.
Authors
Gonzalo P. Solis, Alexey Koval, Jana Valnohova, Arghavan Kazemzadeh, Mikhail Savitsky, Vladimir L. Katanaev
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)