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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 62,933 bioRxiv papers from 279,142 authors.

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in category genetics

3,496 results found. For more information, click each entry to expand.

21: Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation
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Posted to bioRxiv 20 Apr 2016

Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation
6,924 downloads genetics

Jeremy F McRae, Stephen Clayton, Tomas W Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, AlejandroW Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M Barrett, Tanya Bayzetinova, Philip Jones, Wendy D Jones, Daniel King, Netravathi Krishnappa, Laura E Mason, Tarjinder Singh, Adrian R Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D'Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, AndrewW Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V.K Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O'Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellaker

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 x 10-7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.

22: Analysis of shared heritability in common disorders of the brain
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Posted to bioRxiv 16 Apr 2016

Analysis of shared heritability in common disorders of the brain
6,835 downloads genetics

V Anttila, B Bulik-Sullivan, H Finucane, R Walters, J Bras, L Duncan, V Escott-Price, G Falcone, P Gormley, R Malik, N Patsopoulos, S Ripke, Z Wei, D Yu, PH Lee, P Turley, IGAP consortium, IHGC consortium, ILAE Consortium on Complex Epilepsies, IMSGC consortium, IPDGC consortium, METASTROKE and Intracerebral Hemorrhage Studies of the International Stroke Genetics Consortium, Attention-Deficit Hyperactivity Disorder Working Group of the Psychiatric Genomics Consortium, Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, Bipolar Disorders Working Group of the Psychiatric Genomics Consortium, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, G Breen, C Churchhouse, C Bulik, M Daly, M Dichgans, SV Faraone, R Guerreiro, P Holmans, K Kendler, B Koeleman, CA Mathews, AL Price, JM Scharf, P Sklar, J Williams, N Wood, C Cotsapas, A Palotie, JW Smoller, P Sullivan, J Rosand, A Corvin, BM Neale, on behalf of the Brainstorm consortium

Disorders of the brain exhibit considerable epidemiological comorbidity and frequently share symptoms, provoking debate about the extent of their etiologic overlap. We quantified the genetic sharing of 25 brain disorders based on summary statistics from genome-wide association studies of 215,683 patients and 657,164 controls, and their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders show substantial sharing of common variant risk, while neurological disorders appear more distinct from one another. We observe limited evidence of sharing between neurological and psychiatric disorders, but do identify robust sharing between disorders and several cognitive measures, as well as disorders and personality types. We also performed extensive simulations to explore how power, diagnostic misclassification and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a source of risk for brain disorders and the value of heritability-based methods in understanding their etiology.

23: Reprogramming human T cell function and specificity with non-viral genome targeting
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Posted to bioRxiv 31 Aug 2017

Reprogramming human T cell function and specificity with non-viral genome targeting
6,832 downloads genetics

Theodore L. Roth, Cristina Puig-Saus, Ruby Yu, Eric Shifrut, Julia Carnevale, Joseph Hiatt, Justin Saco, Han Li, Jonathan Li, Victoria Tobin, David Nguyen, Andrea M. Ferris, Jeff Chen, Jean-Nicolas Schickel, Laurence Pellerin, David Carmody, Gorka Alkorta-Aranburu, Daniela Del Gaudio, Hiroyuki Matsumoto, Montse Morell, Ying Mao, Rolen Quadros, Channabasavaiah Gurumurthy, Baz Smith, Michael Haugwitz, Stephen H. Hughes, Jonathan Weissman, Kathrin Schumann, Andrew P May, Alan Ashworth, Gary Kupfer, Siri Greeley, Rosa Bacchetta, Eric Meffre, Maria Grazia Roncarolo, Neil Romberg, Kevan C. Herold, Antoni Ribas, Manuel D. Leonetti, Alexander Marson

Human T cells are central to physiological immune homeostasis, which protects us from pathogens without collateral autoimmune inflammation. They are also the main effectors in most current cancer immunotherapy strategies. Several decades of work have aimed to genetically reprogram T cells for therapeutic purposes, but as human T cells are resistant to most standard methods of large DNA insertion these approaches have relied on recombinant viral vectors, which do not target transgenes to specific genomic sites. In addition, the need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells through homology-directed repair (HDR), but to date in human T cells this still requires viral transduction. Here, we developed a non-viral, CRISPR-Cas9 genome targeting system that permits the rapid and efficient insertion of individual or multiplexed large (>1 kilobase) DNA sequences at specific sites in the genomes of primary human T cells while preserving cell viability and function. We successfully tested the potential therapeutic use of this approach in two settings. First, we corrected a pathogenic IL2RA mutation in primary T cells from multiple family members with monogenic autoimmune disease and demonstrated enhanced signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR redirecting T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized the tumour antigen, with concomitant cytokine release and tumour cell killing. Taken together, these studies provide preclinical evidence that non-viral genome targeting will enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

24: New mutations, old statistical challenges
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Posted to bioRxiv 12 Mar 2017

New mutations, old statistical challenges
6,775 downloads genetics

Jeffrey C Barrett, Joseph D. Buxbaum, David J. Cutler, Mark J. Daly, Bernie Devlin, Jacob Gratten, Matthew E Hurles, Jack A. Kosmicki, Eric S Lander, Daniel G. MacArthur, Benjamin M Neale, Kathryn Roeder, Peter M. Visscher, Naomi R. Wray

Based on targeted sequencing of 208 genes in 11,730 neurodevelopmental disorder cases, Stessman et al. report the identification of 91 genes associated (at a False Discovery Rate [FDR] of 0.1) with autism spectrum disorders (ASD), intellectual disability (ID), and developmental delay (DD)-including what they characterize as 38 novel genes, not previously reported as connected with these diseases. If true, this would represent a substantial step forward. Unfortunately, each of the two discovery analyses (1. De novo mutation analysis and, 2. a comparison of private mutations with public control data) contain critical statistical flaws. When one accounts for these problems, fewer than half of the genes-and very few, if any, of the novel findings-survive. These errors have implications for how future analyses should be conducted, for understanding the genetic basis of these disorders, and for genomic medicine. We discuss the two main analyses in turn and provide more detailed treatment of the issues in a supplementary technical note.

25: Activity-by-Contact model of enhancer specificity from thousands of CRISPR perturbations
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Posted to bioRxiv 26 Jan 2019

Activity-by-Contact model of enhancer specificity from thousands of CRISPR perturbations
6,733 downloads genetics

Charles P Fulco, Joseph Nasser, Thouis R Jones, Glen Munson, Drew T Bergman, Vidya Subramanian, Sharon R Grossman, Rockwell Anyoha, Tejal A Patwardhan, Tung H Nguyen, Michael Kane, Benjamin Doughty, Elizabeth M. Perez, Neva C. Durand, Elena K Stamenova, Erez Lieberman Aiden, Eric S Lander, Jesse M Engreitz

Mammalian genomes harbor millions of noncoding elements called enhancers that quantitatively regulate gene expression, but it remains unclear which enhancers regulate which genes. Here we describe an experimental approach, based on CRISPR interference, RNA FISH, and flow cytometry (CRISPRi-FlowFISH), to perturb enhancers in the genome, and apply it to test >3,000 potential regulatory enhancer-gene connections across multiple genomic loci. A simple equation based on a mechanistic model for enhancer function performed remarkably well at predicting the complex patterns of regulatory connections we observe in our CRISPR dataset. This Activity-by-Contact (ABC) model involves multiplying measures of enhancer activity and enhancer-promoter 3D contacts, and can predict enhancer-gene connections in a given cell type based on chromatin state maps. Together, CRISPRi-FlowFISH and the ABC model provide a systematic approach to map and predict which enhancers regulate which genes, and will help to interpret the functions of the thousands of disease risk variants in the noncoding genome.

26: Partitioning heritability by functional category using GWAS summary statistics
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Posted to bioRxiv 23 Jan 2015

Partitioning heritability by functional category using GWAS summary statistics
6,730 downloads genetics

Hilary K Finucane, Brendan Bulik-Sullivan, Alexander Gusev, Gosia Trynka, Yakir Reshef, Po-Ru Loh, Verneri Anttilla, Han Xu, Chongzhi Zang, Kyle Farh, Stephan Ripke, Felix Day, ReproGen Consortium, Schizophrenia Working Group of the Psychiatric Genetics Consortium, The RACI Consortium, Shaun Purcell, Eli Stahl, Sara Lindstrom, John RB Perry, Yukinori Okada, Soumya Raychaudhuri, Mark Daly, Nick Patterson, Benjamin M Neale, Alkes L. Price

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.

27: Expanding Parkinson's disease genetics: novel risk loci, genomic context, causal insights and heritable risk.
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Posted to bioRxiv 09 Aug 2018

Expanding Parkinson's disease genetics: novel risk loci, genomic context, causal insights and heritable risk.
6,719 downloads genetics

Mike A Nalls, Cornelis Blauwendraat, Costanza L. Vallerga, Karl Heilbron, Sara Bandres-Ciga, Diana Chang, Manuela Tan, Demis A Kia, Alastair J. Noyce, Angli Xue, Jose Bras, Emily Young, Rainer von Coelln, Javier Simón-Sánchez, Claudia Schulte, Manu Sharma, Lynne Krohn, Lasse Pihlstrom, Ari Siitonen, Hirotaka Iwaki, Hampton Leonard, Faraz Faghri, J. Raphael Gibbs, Dena G. Hernandez, Sonja W Scholz, Juan A Botia, Maria Martinez, Jean-Christophe Corvol, Suzanne Lesage, Joseph Jankovic, Lisa M. Shulman, The 23andMe Research Team, System Genomics of Parkinson’s Disease (SGPD) Consortium, Margaret Sutherland, Pentti Tienari, Kari Majamaa, Mathias Toft, Ole A Andreassen, Tushar Bangale, Alexis Brice, Jian Yang, Ziv Gan-Or, Thomas Gasser, Peter Heutink, Joshua M Shulman, Nicolas Wood, David A. Hinds, John A. Hardy, Huw R Morris, Jacob Gratten, Peter M. Visscher, Robert R Graham, Andrew B. Singleton, for the International Parkinson’s Disease Genomics Consortium

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

28: Reconstructing Genetic History of Siberian and Northeastern European Populations
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Posted to bioRxiv 18 Oct 2015

Reconstructing Genetic History of Siberian and Northeastern European Populations
6,414 downloads genetics

Emily H.M. Wong, Andrey Khrunin, Larissa Nichols, Dmitry Pushkarev, Denis Khokhrin, Dmitry Verbenko, Oleg Evgrafov, James Knowles, John Novembre, Svetlana Limborska, Anton Valouev

Siberia and Western Russia are home to over 40 culturally and linguistically diverse indigenous ethnic groups. Yet, genetic variation of peoples from this region is largely uncharacterized. We present whole-genome sequencing data from 28 individuals belonging to 14 distinct indigenous populations from that region. We combine these datasets with additional 32 modern-day and 15 ancient human genomes to build and compare autosomal, Y-DNA and mtDNA trees. Our results provide new links between modern and ancient inhabitants of Eurasia. Siberians share 38% of ancestry with descendants of the 45,000-year-old Ust-Ishim people, who were previously believed to have no modern-day descendants. Western Siberians trace 57% of their ancestry to the Ancient North Eurasians, represented by the 24,000-year-old Siberian Malta boy. In addition, Siberians admixtures are present in lineages represented by Eastern European hunter-gatherers from Samara, Karelia, Hungary and Sweden (from 8,000-6,600 years ago), as well as Yamnaya culture people (5,300-4,700 years ago) and modern-day northeastern Europeans. These results provide new evidence of ancient gene flow from Siberia into Europe.

29: Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
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Posted to bioRxiv 30 Nov 2018

Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
6,234 downloads genetics

F. Kyle Satterstrom, Jack A. Kosmicki, Jiebiao Wang, Michael S. Breen, Silvia De Rubeis, Joon-Yong An, Minshi Peng, Ryan Collins, Jakob Grove, Lambertus Klei, Christine Stevens, Jennifer Reichert, Maureen S. Mulhern, Mykyta Artomov, Sherif Gerges, Brooke Sheppard, Xinyi Xu, Aparna Bhaduri, Utku Norman, Harrison Brand, Grace Schwartz, Rachel Nguyen, Elizabeth E. Guerrero, Caroline Dias, Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H. Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Currò, Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier González-Peñas, Stephen Guter, Danielle Halpern, Emily Hansen-Kiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M Hougaard, Christina M Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtimäki, Elaine T Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fátima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda Montenegro M. de Souza, Danielle Moreira, Eric M Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L Santangelo, Gerry Schellenberg, Stephen W Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela Maya W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pål Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher Walsh, Lauren A. Weiss, Thomas Werge, Donna Werling, Emilie M. Wigdor, Emma Wilkinson, Jeremy A Willsey, Tim Yu, Mullin H.C. Yu, Ryan Yuen, Elaine Zachi, iPSYCH consortium, Catalina Betancur, Edwin H. Cook, Louise Gallagher, Michael Gill, James S Sutcliffe, Audrey Thurm, Michael E. Zwick, Anders D. Børglum, Matthew W State, A. Ercument Cicek, Michael E. Talkowski, David J. Cutler, Bernie Devlin, Stephan Sanders, Kathryn Roeder, Mark J. Daly, Joseph D. Buxbaum

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

30: SABER enables highly multiplexed and amplified detection of DNA and RNA in cells and tissues
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Posted to bioRxiv 27 Aug 2018

SABER enables highly multiplexed and amplified detection of DNA and RNA in cells and tissues
6,203 downloads genetics

Jocelyn Y. Kishi, Brian J. Beliveau, Sylvain W Lapan, Emma R. West, Allen Zhu, Hiroshi M. Sasaki, Sinem K. Saka, Yu Wang, Constance L Cepko, Peng Yin

Fluorescent in situ hybridization (FISH) reveals the abundance and positioning of nucleic acid sequences in fixed samples and can be combined with cell segmentation to produce a powerful single cell gene expression assay. However, it remains difficult to label more than a few targets and to visualize nucleic acids in environments such as thick tissue samples using conventional FISH technologies. Recently, methods have been developed for multiplexed amplification of FISH signals, yet it remains challenging to achieve high levels of simultaneous multiplexing combined with high sampling efficiency and simple workflows. Here, we introduce signal amplification by exchange reaction (SABER), which endows oligo-based FISH probes with long, single-stranded DNA concatemers that serve as targets for sensitive fluorescent detection. We establish that SABER effectively amplifies the signal of probes targeting nucleic acids in fixed cells and tissues, can be deployed against at least 17 targets simultaneously, and detects mRNAs with high efficiency. As a demonstration of the utility of SABER in assays involving genetic manipulations, we apply multiplexed FISH of reporters and cell type markers to the identification of enhancers with cell type-specific activity in the mouse retina. SABER represents a simple and versatile molecular toolkit to allow rapid and cost effective multiplexed imaging.

31: Genetic Consequences of Social Stratification in Great Britain
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Posted to bioRxiv 30 Oct 2018

Genetic Consequences of Social Stratification in Great Britain
6,194 downloads genetics

Abdel Abdellaoui, David Hugh-Jones, Kathryn E. Kemper, Yan Holtz, Michel G. Nivard, Laura Veul, Loic Yengo, Brendan P. Zietsch, Timothy M Frayling, Naomi Wray, Jian Yang, Karin J.H. Verweij, Peter M. Visscher

Human DNA varies across geographic regions, with most variation observed so far reflecting distant ancestry differences. Here, we investigate the geographic clustering of genetic variants that influence complex traits and disease risk in a sample of ~450,000 individuals from Great Britain. Out of 30 traits analyzed, 16 show significant geographic clustering at the genetic level after controlling for ancestry, likely reflecting recent migration driven by socio-economic status (SES). Alleles associated with educational attainment (EA) show most clustering, with EA-decreasing alleles clustering in lower SES areas such as coal mining areas. Individuals that leave coal mining areas carry more EA-increasing alleles on average than the rest of Great Britain. In addition, we leveraged the geographic clustering of complex trait variation to further disentangle regional differences in socio-economic and cultural outcomes through genome-wide association studies on publicly available regional measures, namely coal mining, religiousness, 1970/2015 general election outcomes, and Brexit referendum results.

32: Genomewide association study identifies 30 loci associated with bipolar disorder
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Posted to bioRxiv 07 Aug 2017

Genomewide association study identifies 30 loci associated with bipolar disorder
6,099 downloads genetics

Eli Ayumi Stahl, Gerome Breen, Andreas Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R. I. Coleman, Héléna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H. Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J. Raymond DePaulo, Srdjan Djurovic, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, JoséGuzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Stéphane Jamain, Jessica S Johnson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A. Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W. Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P. S. Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B. Potash, Shaun M. Purcell, Eline J Regeer, Andreas Reif, Céline S Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W Weickert, Stephanie H. Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D. Børglum, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Tõnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, RenéS Kahn, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B. Vincent, Thomas Werge, John I Nurnberger, Naomi R. Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J. Scott, Ole A Andreassen, John Kelsoe, Pamela Sklar

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P<1x10-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

33: Y-chromosome haplogroups from Hun, Avar and conquering Hungarian period nomadic people of the Carpathian Basin
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Posted to bioRxiv 03 Apr 2019

Y-chromosome haplogroups from Hun, Avar and conquering Hungarian period nomadic people of the Carpathian Basin
6,078 downloads genetics

Endre Neparaczki, Zoltán Maróti, Tibor Kalmár, Kitti Maár, István Nagy, Dóra Latinovics, Ágnes Kustár, György Pálfi, Erika Molnár, Antónia Marcsik, Csilla Balogh, Gábor Lőrinczy, Szilárd Sándor Gál, Péter Tomka, Bernadett Kovacsóczy, László Kovács, István Raskó, Tibor Török

Hun, Avar and conquering Hungarian nomadic groups arrived into the Carpathian Basin from the Eurasian Steppes and significantly influenced its political and ethnical landscape. In order to shed light on the genetic affinity of above groups we have determined Y chromosomal haplogroups and autosomal loci, from 49 individuals, supposed to represent military leaders. Haplogroups from the Hun-age are consistent with Xiongnu ancestry of European Huns. Most of the Avar-age individuals carry east Eurasian Y haplogroups typical for modern north-eastern Siberian and Buryat populations and their autosomal loci indicate mostly unmixed Asian characteristics. In contrast the conquering Hungarians seem to be a recently assembled population incorporating pure European, Asian and admixed components. Their heterogeneous paternal and maternal lineages indicate similar phylogeographic origin of males and females, derived from Central-Inner Asian and European Pontic Steppe sources. Composition of conquering Hungarian paternal lineages is very similar to that of Baskhirs, supporting historical sources that report identity of the two groups.

34: The genetic architecture of the human cerebral cortex
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Posted to bioRxiv 03 Sep 2018

The genetic architecture of the human cerebral cortex
6,050 downloads genetics

Katrina L. Grasby, Neda Jahanshad, Jodie N Painter, Lucía Colodro-Conde, Janita Bralten, Derrek P Hibar, Penelope A Lind, Fabrizio Pizzagalli, Christopher R.K. Ching, Mary AB McMahon, Natalia Shatokhina, Leo C.P. Zsembik, Ingrid Agartz, Saud Alhusaini, Marcio AA Almeida, Dag Alnæs, Inge K Amlien, Micael Andersson, Tyler Ard, Nicola J. Armstrong, Allison Ashley-Koch, Joshua R Atkins, Manon Bernard, Rachel M. Brouwer, Elizabeth EL Buimer, Robin Bülow, Christian Bürger, Dara M. Cannon, Mallar Chakravarty, Qiang Chen, Joshua W. Cheung, Baptiste Couvy-Duchesne, Anders M Dale, Shareefa Dalvie, Tânia K de Araujo, Greig I. de Zubicaray, Sonja MC de Zwarte, Anouk den Braber, Nhat Trung Doan, Katharina Dohm, Stefan Ehrlich, Hannah-Ruth Engelbrecht, Susanne Erk, Chun Chieh Fan, Iryna O. Fedko, Sonya F Foley, Judith M Ford, Masaki Fukunaga, Melanie E. Garrett, Tian Ge, Sudheer Giddaluru, Aaron L. Goldman, Melissa J Green, Nynke A. Groenewold, Dominik Grotegerd, Tiril P. Gurholt, Boris A. Gutman, Narelle K. Hansell, Mathew A Harris, Marc B Harrison, Courtney C. Haswell, Michael Hauser, Stefan Herms, Dirk J. Heslenfeld, New Fei Ho, David Hoehn, Per Hoffmann, Laurena Holleran, Martine Hoogman, Jouke-Jan Hottenga, Masashi Ikeda, Deborah Janowitz, Iris E Jansen, Tianye Jia, Christiane Jockwitz, Ryota Kanai, Sherif Karama, Dalia Kasperaviciute, Tobias Kaufmann, Sinead Kelly, Masataka Kikuchi, Marieke Klein, Michael Knapp, Annchen R Knodt, Bernd Krämer, Max Lam, Thomas M Lancaster, Phil H. Lee, Tristram A Lett, Lindsay B Lewis, Iscia Lopes-Cendes, Michelle Luciano, Fabio Macciardi, Andre F. Marquand, Samuel R Mathias, Tracy R Melzer, Yuri Milaneschi, Nazanin Mirza-Schreiber, Jose CV Moreira, Thomas W Mühleisen, Bertram Müller-Myhsok, Pablo Najt, Soichiro Nakahara, Kwangsik Nho, Loes M Olde Loohuis, Dimitri Papadopoulos Orfanos, John F Pearson, Toni L Pitcher, Benno Pütz, Yann Quidé, Anjanibhargavi Ragothaman, Faisal M. Rashid, William R Reay, Ronny Redlich, Céline S Reinbold, Jonathan Repple, Geneviève Richard, Brandalyn C Riedel, Shannon L. Risacher, Cristiane S Rocha, Nina Roth Mota, Lauren Salminen, Arvin Saremi, Andrew J. Saykin, Fenja Schlag, Lianne Schmaal, Peter R. Schofield, Rodrigo Secolin, Chin Yang Shapland, Li Shen, Jean Shin, Elena Shumskaya, Ida E Sønderby, Emma Sprooten, Lachlan T. Strike, Katherine E Tansey, Alexander Teumer, Anbupalam Thalamuthu, Sophia I. Thomopoulos, Diana Tordesillas-Gutiérrez, Jessica A. Turner, Anne Uhlmann, Costanza Ludovica Vallerga, Dennis van der Meer, Marjolein MJ van Donkelaar, Liza van Eijk, Theo G.M. van Erp, Neeltje E.M. van Haren, Daan Van Rooij, Marie-José van Tol, Jan H Veldink, Ellen Verhoef, Esther Walton, Mingyuan Wang, Yunpeng Wang, Joanna M Wardlaw, Wei Wen, Lars T. Westlye, Christopher D. Whelan, Stephanie H. Witt, Katharina Wittfeld, Christiane Wolf, Thomas Wolfers, Jing Qin Wu, Clarissa L. Yasuda, Dario Zaremba, Zuo Zhang, Alyssa H Zhu, Marcel P. Zwiers, Eric Artiges, Amelia A. Assareh, Rosa Ayesa-Arriola, Aysenil Belger, Christine L. Brandt, Gregory G Brown, Sven Cichon, Joanne E. Curran, Gareth E. Davies, Franziska Degenhardt, Michelle F Dennis, Bruno Dietsche, Srdjan Djurovic, Colin P. Doherty, Ryan Espiritu, Daniel Garijo, Yolanda Gil, Penny A Gowland, Robert C. Green, Alexander N Häusler, Walter Heindel, Beng-Choon Ho, Wolfgang U Hoffmann, Florian Holsboer, Georg Homuth, Norbert Hosten, Clifford R. Jack, MiHyun Jang, Andreas Jansen, Nathan A Kimbrel, Knut Kolskår, Sanne Koops, Axel Krug, Kelvin O. Lim, Jurjen J. Luykx, Daniel H Mathalon, Karen A. Mather, Venkata S. Mattay, Sarah Matthews, Jaqueline Mayoral Van Son, Sarah C McEwen, Ingrid Melle, Derek W Morris, Bryon A. Mueller, Matthias Nauck, Jan E. Nordvik, Markus M Nöthen, Daniel S O'Leary, Nils Opel, Marie-Laure Paillère Martinot, G B Pike, Adrian Preda, Erin B. Quinlan, Paul E Rasser, Varun Ratnakar, Simone Reppermund, Vidar M. Steen, Paul A Tooney, Fábio R Torres, Dick J. Veltman, James T Voyvodic, Robert Whelan, Tonya White, Hidenaga Yamamori, Hieab HH Adams, Joshua C Bis, Stéphanie Debette, Charles Decarli, Myriam Fornage, Vilmundur Gudnason, Edith Hofer, M. A Ikram, Lenore Launer, W T Longstreth, Oscar L. Lopez, Bernard Mazoyer, Thomas H Mosley, Gennady V Roshchupkin, Claudia L Satizabal, Reinhold Schmidt, Sudha Seshadri, Qiong Yang, The Alzheimer's Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, Mid-Atlantic MIRECC Workgroup, SYS Consortium, The Parkinson's Progression Markers Initiative, Marina KM Alvim, David Ames, Tim J Anderson, Ole A Andreassen, Alejandro Arias-Vasquez, Mark E Bastin, Bernhard T. Baune, John Blangero, Dorret I Boomsma, Henry Brodaty, Han G Brunner, Randy L. Buckner, Jan K Buitelaar, Juan R Bustillo, Wiepke Cahn, Murray J Cairns, Vince Calhoun, Vaughan j Carr, Xavier Caseras, Svenja Caspers, Gianpiero L. Cavalleri, Fernando Cendes, Aiden Corvin, Benedicto Crespo-Facorro, John C Dalrymple-Alford, Udo Dannlowski, Eco J.C. de Geus, Ian J Deary, Norman Delanty, Chantal Depondt, Sylvane Desrivières, Gary Donohoe, Thomas Espeseth, Guillén Fernández, Simon E. Fisher, Herta Flor, Andreas J. Forstner, Clyde Francks, Barbara Franke, David C Glahn, Randy L. Gollub, Hans J Grabe, Oliver Gruber, Asta K Håberg, Ahmad R Hariri, Catharina A. Hartman, Ryota Hashimoto, Andreas Heinz, Frans A Henskens, Manon H.J. Hillegers, Pieter J. Hoekstra, Avram J. Holmes, L E Hong, William D Hopkins, Hilleke E. Hulshoff Pol, Terry L Jernigan, Erik G Jönsson, René S. Kahn, Martin A Kennedy, Tilo TJ Kircher, Peter Kochunov, John BJ Kwok, Stephanie Le Hellard, Carmel M Loughland, Nicholas G Martin, Jean-Luc Martinot, Colm McDonald, Katie L. McMahon, Andreas Meyer-Lindenberg, Patricia T Michie, Rajendra A. Morey, Bryan Mowry, Lars Nyberg, Jaap Oosterlaan, Roel A. Ophoff, Christos Pantelis, Tomáŝ Paus, Zdenka Pausova, Brenda W.J.H. Penninx, Tinca JC Polderman, Danielle Posthuma, Marcella Rietschel, Joshua L. Roffman, Laura M Rowland, Perminder S. Sachdev, Philipp G Sämann, Ulrich Schall, Gunter Schumann, Rodney J. Scott, Kang Sim, Sanjay M. Sisodiya, Jordan W. Smoller, Iris E Sommer, Beate St Pourcain, Dan J. Stein, Arthur W Toga, Julian N. Trollor, Nic JA Van der Wee, Dennis van't Ent, Henry Völzke, Henrik Walter, Bernd Weber, Daniel R Weinberger, Margaret J Wright, Juan Zhou, Jason L Stein, Paul M Thompson, Sarah E Medland

The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci (P ≤ 5 x 10-8); 199 survived multiple testing correction (P ≤ 8.3 x 10-10; 187 surface area; 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression and ADHD. NOTE: K.L.G. and N.J. contributed to this work as co-first authors for this preprint. J.N.P., L.C.-C., J.B., D.P.H., P.A.L., F.P. contributed to this work as co-second authors for this preprint. J.L.S., P.M.T., S.E.M. contributed to this work as co-last authors for this preprint.

35: Genetic compensation is triggered by mutant mRNA degradation
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Posted to bioRxiv 22 May 2018

Genetic compensation is triggered by mutant mRNA degradation
6,041 downloads genetics

Mohamed El-Brolosy, Andrea Rossi, Zacharias Kontarakis, Carsten Kuenne, Stefan Günther, Nana Fukuda, Carter Takacs, Shih-Lei Lai, Ryuichi Fukuda, Claudia Gerri, Khrievono Kikhi, Antonio Giraldez, Didier Y.R. Stainier

Genetic compensation by transcriptional modulation of related gene(s) (also known as transcriptional adaptation) has been reported in numerous systems; however, whether and how such a response can be activated in the absence of protein feedback loops is unknown. Here, we develop and analyze several models of transcriptional adaptation in zebrafish and mouse that we show are not caused by loss of protein function. We find that the increase in transcript levels is due to enhanced transcription, and observe a correlation between the levels of mutant mRNA decay and transcriptional upregulation of related genes. To assess the role of mutant mRNA degradation in triggering transcriptional adaptation, we use genetic and pharmacological approaches and find that mRNA degradation is indeed required for this process. Notably, uncapped RNAs, themselves subjected to rapid degradation, can also induce transcriptional adaptation. Next, we generate alleles that fail to transcribe the mutated gene and find that they do not show transcriptional adaptation, and exhibit more severe phenotypes than those observed in alleles displaying mutant mRNA decay. Transcriptome analysis of these different alleles reveals the upregulation of hundreds of genes with enrichment for those showing sequence similarity with the mutated gene's mRNA, suggesting a model whereby mRNA degradation products induce the response via sequence similarity. These results expand the role of the mRNA surveillance machinery in buffering against mutations by triggering the transcriptional upregulation of related genes. Besides implications for our understanding of disease-causing mutations, our findings will help design mutant alleles with minimal transcriptional adaptation-derived compensation.

36: Variational Inference of Population Structure in Large SNP Datasets
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Posted to bioRxiv 02 Dec 2013

Variational Inference of Population Structure in Large SNP Datasets
5,967 downloads genetics

Anil Raj, Matthew Stephens, Jonathan K Pritchard

Tools for estimating population structure from genetic data are now used in a wide variety of applications in population genetics. However, inferring population structure in large modern data sets imposes severe computational challenges. Here, we develop efficient algorithms for approximate inference of the model underlying the STRUCTURE program using a variational Bayesian framework. Variational methods pose the problem of computing relevant posterior distributions as an optimization problem, allowing us to build on recent advances in optimization theory to develop fast inference tools. In addition, we propose useful heuristic scores to identify the number of populations represented in a dataset and a new hierarchical prior to detect weak population structure in the data. We test the variational algorithms on simulated data, and illustrate using genotype data from the CEPH-Human Genome Diversity Panel. The variational algorithms are almost two orders of magnitude faster than STRUCTURE and achieve accuracies comparable to those of ADMIXTURE. Furthermore, our results show that the heuristic scores for choosing model complexity provide a reasonable range of values for the number of populations represented in the data, with minimal bias towards detecting structure when it is very weak. Our algorithm, fastSTRUCTURE, is freely available online at http://pritchardlab.stanford.edu/structure.html.

37: Common risk variants identified in autism spectrum disorder
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Posted to bioRxiv 25 Nov 2017

Common risk variants identified in autism spectrum disorder
5,933 downloads genetics

Jakob Grove, Stephan Ripke, Thomas D Als, Manuel Mattheisen, Raymond Walters, Hyejung Won, Jonatan Pallesen, Esben Agerbo, Ole A Andreassen, Richard Anney, Rich Belliveau, Francesco Bettella, Joseph D. Buxbaum, Jonas Bybjerg-Grauholm, Marie Bækved-Hansen, Felecia Cerrato, Kimberly Chambert, Jane H Christensen, Claire Churchhouse, Karin Dellenvall, Ditte Demontis, Silvia De Rubeis, Bernie Devlin, Srdjan Djurovic, Ashle Dumont, Jacqueline Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V Hollegaard, Sigrun Hope, Daniel P Howrigan, Hailiang Huang, Christina Hultman, Lambertus Klei, Julian Maller, Joanna Martin, Alicia R Martin, Jennifer Moran, Mette Nyegaard, Terje Nærland, Duncan S Palmer, Aarno Palotie, Carsten B Pedersen, Marianne G Pedersen, Timothy Poterba, Jesper B Poulsen, Beate St Pourcain, Per Qvist, Karola Rehnström, Avi Reichenberg, Jennifer Reichert, Elise B Robinson, Kathryn Roeder, Panos Roussos, Evald Saemundsen, Sven Sandin, F. Kyle Satterstrom, George D Smith, Hreinn Stefansson, Kari Stefansson, Stacy Steinberg, Christine Stevens, Patrick F Sullivan, Patrick Turley, G Bragi Walters, Xinyi Xu, Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Daniel Geschwind, Merete Nordentoft, David M Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Benjamin M Neale, Mark J. Daly, Anders D. Børglum

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.

38: Efficient generation of targeted large insertions in mouse embryos using 2C-HR-CRISPR
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Posted to bioRxiv 16 Oct 2017

Efficient generation of targeted large insertions in mouse embryos using 2C-HR-CRISPR
5,889 downloads genetics

Bin Gu, Eszter Posfai, Janet Rossant

Rapid and efficient generation of large fragment targeted knock-in mouse models is still a major hurdle in mouse genetics. Here we developed 2C-HR-CRISPR, a highly efficient gene editing method based on introducing CRISPR reagents into mouse embryos at the 2-cell stage, taking advantage of the likely increase in HR efficiency during the long G2 phase and open chromatin structure of the 2-cell embryo. With 2C-HR-CRISPR and a modified biotin-streptavidin approach to localize repair templates to target sites, we rapidly targeted 20 endogenous genes that are expressed in mouse blastocysts with fluorescent reporters and generated reporter mouse lines. We showcase the first live triple-color blastocyst with all three lineages differentially reported. Additionally, we demonstrated efficient double targeting, enabling rapid assessment of the auxin-inducible degradation system for probing protein function in mouse embryos. These methods open up exciting avenues for exploring cell fate decisions in the blastocyst and later stages of development. We also suggest that 2C-HR-CRISPR can be a better alternative to random transgenesis by ensuring transgene insertions at defined safe harbor sites.

39: Genome-wide association studies of brain structure and function in the UK Biobank
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Posted to bioRxiv 21 Aug 2017

Genome-wide association studies of brain structure and function in the UK Biobank
5,775 downloads genetics

Lloyd T Elliott, Kevin Sharp, Fidel Alfaro-Almagro, Sinan Shi, Karla L. Miller, Gwenaelle Douaud, Jonathan Marchini, Stephen M. Smith

The genetic basis of brain structure and function is largely unknown. We carried out genome-wide association studies of 3,144 distinct functional and structural brain imaging derived phenotypes in UK Biobank (discovery dataset 8,428 subjects). We show that many of these phenotypes are heritable. We identify 148 clusters of SNP-imaging associations with lead SNPs that replicate at p<0.05, when we would expect 21 to replicate by chance. Notable significant and interpretable associations include: iron transport and storage genes, related to changes in T2* in subcortical regions; extracellular matrix and the epidermal growth factor genes, associated with white matter micro-structure and lesion volume; genes regulating mid-line axon guidance development associated with pontine crossing tract organisation; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide new insight into the genetic architecture of the brain with relevance to complex neurological and psychiatric disorders, as well as brain development and aging. The full set of results is available on the interactive Oxford Brain Imaging Genetics (BIG) web browser.

40: LIMIX: genetic analysis of multiple traits
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Posted to bioRxiv 21 May 2014

LIMIX: genetic analysis of multiple traits
5,700 downloads genetics

Christoph Lippert, Franceso Paolo Casale, Barbara Rakitsch, Oliver Stegle

Multi-trait mixed models have emerged as a promising approach for joint analyses of multiple traits. In principle, the mixed model framework is remarkably general. However, current methods implement only a very specific range of tasks to optimize the necessary computations. Here, we present a multi-trait modeling framework that is versatile and fast: LIMIX enables to flexibly adapt mixed models for a broad range of applications with different observed and hidden covariates, and variable study designs. To highlight the novel modeling aspects of LIMIX we performed three vastly different genetic studies: joint GWAS of correlated blood lipid phenotypes, joint analysis of the expression levels of the multiple transcript-isoforms of a gene, and pathway-based modeling of molecular traits across environments. In these applications we show that LIMIX increases GWAS power and phenotype prediction accuracy, in particular when integrating stepwise multi-locus regression into multi-trait models, and when analyzing large numbers of traits. An open source implementation of LIMIX is freely available at: https://github.com/PMBio/limix.

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