F Graeme Frost, Marie Morimoto, Prashant Sharma, Lyse Ruaud, Newell Belnap, Daniel G Calame, Yuri Uchiyama, Naomichi Matsumoto, Machteld M Oud, Elise A Ferreira, Vinodh Narayanan, Sampath Rangasamy, Matt Huentelman, Lisa T Emrick, Ikuko Sato-Shirai, Satoko Kumada, Nicole I Wolf, Peter J Steinbach, Yan Huang, Barbara N Pusey, Sandrine Passemard, Jonathan Levy, Séverine Drunat, Marie Vincent, Agnès Guet, Emanuele Agolini, Antonio Novelli, Maria Cristina Digilio, Jill A Rosenfeld, Jennifer L Murphy, James R Lupski, Gilbert Vezina, Ellen F Macnamara, David R Adams, Maria T Acosta, Cynthia J Tifft, William A Gahl, May Christine V Malicdan
The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants...
March 22, 2023: American Journal of Human Genetics
Zhaotong Lin, Haoran Xue, Wei Pan
Mendelian randomization (MR) is a powerful tool for causal inference with observational genome-wide association study (GWAS) summary data. Compared to the more commonly used univariable MR (UVMR), multivariable MR (MVMR) not only is more robust to the notorious problem of genetic (horizontal) pleiotropy but also estimates the direct effect of each exposure on the outcome after accounting for possible mediating effects of other exposures. Despite promising applications, there is a lack of studies on MVMR's theoretical properties and robustness in applications...
March 16, 2023: American Journal of Human Genetics
Nai-Ning Wang, Yan Zhang, Feng Jiang, Dong-Li Zhu, Chen-Xi Di, Shou-Ye Hu, Xiao-Feng Chen, Li-Qiang Zhi, Yu Rong, Xin Ke, Yuan-Yuan Duan, Shan-Shan Dong, Tie-Lin Yang, Zhi Yang, Yan Guo
Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs)...
March 13, 2023: American Journal of Human Genetics
Rebecca Truty, Susan Rojahn, Karen Ouyang, Curtis Kautzer, Michael Kennemer, Daniel Pineda-Alvarez, Britt Johnson, Amanda Stafford, Lina Basel-Salmon, Sulagna Saitta, Anne Slavotinek, Settara C Chandrasekharappa, Carlos Jose Suarez, Leslie Burnett, Robert L Nussbaum, Swaroop Aradhya
DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset. Using high-depth sequencing, we studied results from one million unrelated individuals referred to for genetic testing for almost 1,900 disease-related genes...
March 10, 2023: American Journal of Human Genetics
Ming-Liang Ji, Zhuang Li, Xin Yue Hu, Wei Tuo Zhang, Hai Xiang Zhang, Jun Lu
Epigenetic reprogramming plays a critical role in chondrocyte senescence during osteoarthritis (OA) pathology, but the underlying molecular mechanisms remain to be elucidated. Here, using large-scale individual datasets and genetically engineered (Col2a1-CreERT2 ;Eldrflox/flox and Col2a1-CreERT2 ;ROSA26-LSL-Eldr+/+ knockin) mouse models, we show that a novel transcript of long noncoding RNA ELDR is essential for the development of chondrocyte senescence. ELDR is highly expressed in chondrocytes and cartilage tissues of OA...
February 24, 2023: American Journal of Human Genetics
Fergus Hamilton, Alexander J Mentzer, Tom Parks, J Kenneth Baillie, George Davey Smith, Peter Ghazal, Nicholas J Timpson
ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity...
February 21, 2023: American Journal of Human Genetics
Abhishek Nag, Ryan S Dhindsa, Lawrence Middleton, Xiao Jiang, Dimitrios Vitsios, Eleanor Wigmore, Erik L Allman, Anna Reznichenko, Keren Carss, Katherine R Smith, Quanli Wang, Benjamin Challis, Dirk S Paul, Andrew R Harper, Slavé Petrovski
Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB...
February 10, 2023: American Journal of Human Genetics
Olivia W Lee, Calvin Rodrigues, Shu-Hong Lin, Wen Luo, Kristine Jones, Derek W Brown, Weiyin Zhou, Eric Karlins, Sairah M Khan, Sylvain Baulande, Virginie Raynal, Didier Surdez, Stephanie Reynaud, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetête, Stelly Ballet, Eve Lapouble, Valérie Laurence, Gaelle Pierron, Nathalie Gaspar, Nadège Corradini, Perrine Marec-Bérard, Nathaniel Rothman, Casey L Dagnall, Laurie Burdett, Michelle Manning, Kathleen Wyatt, Meredith Yeager, Raj Chari, Wendy M Leisenring, Andreas E Kulozik, Jennifer Kriebel, Thomas Meitinger, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lisa Mirabello, Margaret A Tucker, Franck Tirode, Gregory T Armstrong, Smita Bhatia, Leslie L Robison, Yutaka Yasui, Laura Romero-Pérez, Wolfgang Hartmann, Markus Metzler, W Ryan Diver, Adriana Lori, Neal D Freedman, Robert N Hoover, Lindsay M Morton, Stephen J Chanock, Thomas G P Grünewald, Olivier Delattre, Mitchell J Machiela
Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding...
February 8, 2023: American Journal of Human Genetics
Niko Välimäki, Vilja Jokinen, Tatiana Cajuso, Heli Kuisma, Aurora Taira, Olivia Dagnaud, Sini Ilves, Jaana Kaukomaa, Annukka Pasanen, Kimmo Palin, Oskari Heikinheimo, Ralf Bützow, Lauri A Aaltonen, Auli Karhu
Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively...
February 8, 2023: American Journal of Human Genetics
Malú 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
While extensively studied in clinical cohorts, the phenotypic consequences of 22q11.2 copy-number variants (CNVs) in the general population remain understudied. To address this gap, we performed a phenome-wide association scan in 405,324 unrelated UK Biobank (UKBB) participants by using CNV calls from genotyping array. We mapped 236 Human Phenotype Ontology terms linked to any of the 90 genes encompassed by the region to 170 UKBB traits and assessed the association between these traits and the copy-number state of 504 genotyping array probes in the region...
January 24, 2023: American Journal of Human Genetics
Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M R Taylor, Jennifer A Sullivan, Ayat N Asleh, Jaba Mitra, Mohamad A Dar, Amy McNamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R Roeder, Rebecca Okashah Littlejohn, Harpreet K Dibra, Philip J Byrd, Grant S Stewart, Bilgen B Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey-Anne Evans, Gabrielle Lemire, Grace E VanNoy, Anne O'Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F Buckley, Christel Thauvin, George K Essien Umanah, Lionel Van Maldergem, James R Lupski, Tony Roscioli, Valina L Dawson, Ted M Dawson, Stylianos E Antonarakis
Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2)...
January 23, 2023: American Journal of Human Genetics
Md Moksedul Momin, Soohyun Lee, Naomi R Wray, S Hong Lee
The coefficient of determination (R2 ) is a well-established measure to indicate the predictive ability of polygenic scores (PGSs). However, the sampling variance of R2 is rarely considered so that 95% confidence intervals (CI) are not usually reported. Moreover, when comparisons are made between PGSs based on different discovery samples, the sampling covariance of R2 is required to test the difference between them. Here, we show how to estimate the variance and covariance of R2 values to assess the 95% CI and p value of the R2 difference...
January 18, 2023: American Journal of Human Genetics
Jordy Dekker, Rachel Schot, Michiel Bongaerts, Walter G de Valk, Monique M van Veghel-Plandsoen, Kathryn Monfils, Hannie Douben, Peter Elfferich, Esmee Kasteleijn, Leontine M A van Unen, Geert Geeven, Jasper J Saris, Yvette van Ierland, Frans W Verheijen, Marianne L T van der Sterre, Farah Sadeghi Niaraki, Daphne J Smits, Hidde H Huidekoper, Monique Williams, Martina Wilke, Virginie J M Verhoeven, Marieke Joosten, Anneke J A Kievit, Ingrid M B H van de Laar, Lies H Hoefsloot, Marianne Hoogeveen-Westerveld, Mark Nellist, Grazia M S Mancini, Tjakko J van Ham
For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers...
January 17, 2023: American Journal of Human Genetics
Renee C Geck, Nicholas R Powell, Maitreya J Dunham
Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Toward this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases...
January 13, 2023: American Journal of Human Genetics
Xiao Chen, John Harting, Emily Farrow, Isabelle Thiffault, Dalia Kasperaviciute, Alexander Hoischen, Christian Gilissen, Tomi Pastinen, Michael A Eberle
Spinal muscular atrophy, a leading cause of early infant death, is caused by bi-allelic mutations of SMN1. Sequence analysis of SMN1 is challenging due to high sequence similarity with its paralog SMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it is currently not possible to identify silent carriers (2+0) with two copies of SMN1 on one chromosome and zero copies on the other. We developed Paraphase, an informatics method that identifies full-length SMN1 and SMN2 haplotypes, determines the gene copy numbers, and calls phased variants using long-read PacBio HiFi data...
January 12, 2023: American Journal of Human Genetics
Whitney L Do, Dianjianyi Sun, Karlijn Meeks, Pierre-Antoine Dugué, Ellen Demerath, Weihua Guan, Shengxu Li, Wei Chen, Roger Milne, Abedowale Adeyemo, Charles Agyemang, Rami Nassir, JoAnn E Manson, Aladdin H Shadyab, Lifang Hou, Steve Horvath, Themistocles L Assimes, Parveen Bhatti, Kristina M Jordahl, Andrea A Baccarelli, Alicia K Smith, Lisa R Staimez, Aryeh D Stein, Eric A Whitsel, K M Venkat Narayan, Karen N Conneely
This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0...
January 9, 2023: American Journal of Human Genetics
Seyoon Ko, Benjamin B Chu, Daniel Peterson, Chidera Okenwa, Jeanette C Papp, David H Alexander, Eric M Sobel, Hua Zhou, Kenneth L Lange
Admixture estimation plays a crucial role in ancestry inference and genome-wide association studies (GWASs). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105 to 106 samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry-informative SNP markers (AIMs) that exhibit substantially different frequencies across populations...
January 2, 2023: American Journal of Human Genetics
Maimuna S Paul, Anna R Duncan, Casie A Genetti, Hongling Pan, Adam Jackson, Patricia E Grant, Jiahai Shi, Michele Pinelli, Nicola Brunetti-Pierri, Alexandra Garza-Flores, Dave Shahani, Russell P Saneto, Giuseppe Zampino, Chiara Leoni, Emanuele Agolini, Antonio Novelli, Ulrike Blümlein Tobias B Haack, Wolfram Heinritz, Eva Matzker, Bader Alhaddad, Rami Abou Jamra, Tobias Bartolomaeus, Saber AlHamdan, Raphael Carapito, Bertrand Isidor, Seiamak Bahram, Alyssa Ritter, Kosuke Izumi, Ben Pode Shakked, Ortal Barel, Bruria Ben Zeev, Amber Begtrup, Deanna Alexis Carere, Sureni V Mullegama, Timothy Blake Palculict, Daniel G Calame, Katharina Schwan, Alicia R P Aycinena, Rasa Traberg, Sofia Douzgou, Harrison Pirt, Naila Ismayilova, Siddharth Banka, Hsiao-Tuan Chao, Pankaj B Agrawal
No abstract text is available yet for this article.
March 2, 2023: American Journal of Human Genetics
Zornitza Stark, Tiffany Boughtwood, Matilda Haas, Jeffrey Braithwaite, Clara L Gaff, Ilias Goranitis, Amanda B Spurdle, David P Hansen, Oliver Hofmann, Nigel Laing, Sylvia Metcalfe, Ainsley J Newson, Hamish S Scott, Natalie Thorne, Robyn L Ward, Marcel E Dinger, Stephanie Best, Janet C Long, Sean M Grimmond, John Pearson, Nicola Waddell, Christopher P Barnett, Matthew Cook, Michael Field, David Fielding, Stephen B Fox, Jozef Gecz, Adam Jaffe, Richard J Leventer, Paul J Lockhart, Sebastian Lunke, Andrew J Mallett, Julie McGaughran, Linda Mileshkin, Katia Nones, Tony Roscioli, Ingrid E Scheffer, Christopher Semsarian, Cas Simons, David M Thomas, David R Thorburn, Richard Tothill, Deborah White, Sally Dunwoodie, Peter T Simpson, Peta Phillips, Marie-Jo Brion, Keri Finlay, Michael Cj Quinn, Tessa Mattiske, Emma Tudini, Kirsten Boggs, Sean Murray, Kathy Wells, John Cannings, Andrew H Sinclair, John Christodoulou, Kathryn N North
Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests...
March 2, 2023: American Journal of Human Genetics
David L Nelson
This article is based on the address given by the author at the 2022 meeting of The American Society of Human Genetics (ASHG) in Los Angeles, CA. The video of the original address can be found at the ASHG website.
March 2, 2023: American Journal of Human Genetics
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