Read by QxMD icon Read


Yair Field, Evan A Boyle, Natalie Telis, Ziyue Gao, Kyle J Gaulton, David Golan, Loic Yengo, Ghislain Rocheleau, Philippe Froguel, Mark I McCarthy, Jonathan K Pritchard
Detection of recent natural selection is a challenging problem in population genetics. Here we introduce the Singleton Density Score (SDS), a method to infer very recent changes in allele frequencies from contemporary genome sequences. Applied to data from the UK10K Project, SDS reflects allele frequency changes in the ancestors of modern Britons during the past ~2,000-3,000 years. We see strong signals of selection at lactase and the MHC, and in favor of blond hair and blue eyes. For polygenic adaptation we find that recent selection for increased height has driven allele frequency shifts across most of the genome...
October 13, 2016: Science
J Vijayakrishnan, R Kumar, M Y R Henrion, A V Moorman, P S Rachakonda, I Hosen, M I da Silva Filho, A Holroyd, S E Dobbins, R Koehler, H Thomsen, J A Irving, J M Allan, T Lightfoot, E Roman, S E Kinsey, E Sheridan, P D Thompson, P Hoffmann, M M Nöthen, S Heilmann-Heimbach, J Karl-Heinz, M Greaves, C J Harrison, C R Bartram, M Schrappe, M Stanulla, K Hemminki, R S Houlston
Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWAS with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls we identify new susceptibility loci for BCP-ALL mapping to 10q26...
October 3, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Valentina Iotchkova, Jie Huang, John A Morris, Deepti Jain, Caterina Barbieri, Klaudia Walter, Josine L Min, Lu Chen, William Astle, Massimilian Cocca, Patrick Deelen, Heather Elding, Aliki-Eleni Farmaki, Christopher S Franklin, Mattias Franberg, Tom R Gaunt, Albert Hofman, Tao Jiang, Marcus E Kleber, Genevieve Lachance, Jian'an Luan, Giovanni Malerba, Angela Matchan, Daniel Mead, Yasin Memari, Ioanna Ntalla, Kalliope Panoutsopoulou, Raha Pazoki, John R B Perry, Fernando Rivadeneira, Maria Sabater-Lleal, Bengt Sennblad, So-Youn Shin, Lorraine Southam, Michela Traglia, Freerk van Dijk, Elisabeth M van Leeuwen, Gianluigi Zaza, Weihua Zhang, Najaf Amin, Adam Butterworth, John C Chambers, George Dedoussis, Abbas Dehghan, Oscar H Franco, Lude Franke, Mattia Frontini, Giovanni Gambaro, Paolo Gasparini, Anders Hamsten, Aaron Issacs, Jaspal S Kooner, Charles Kooperberg, Claudia Langenberg, Winfried Marz, Robert A Scott, Morris A Swertz, Daniela Toniolo, Andre G Uitterlinden, Cornelia M van Duijn, Hugh Watkins, Eleftheria Zeggini, Mathew T Maurano, Nicholas J Timpson, Alexander P Reiner, Paul L Auer, Nicole Soranzo
Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol...
September 26, 2016: Nature Genetics
Kedar Tatwawadi, Mikel Hernaez, Idoia Ochoa, Tsachy Weissman
MOTIVATION: The dramatic decrease in the cost of sequencing has resulted in the generation of huge amounts of genomic data, as evidenced by projects such as the UK10K and the Million Veteran Project, with the number of sequenced genomes ranging in the order of 10 K to 1 M. Due to the large redundancies among genomic sequences of individuals from the same species, most of the medical research deals with the variants in the sequences as compared with a reference sequence, rather than with the complete genomic sequences...
September 1, 2016: Bioinformatics
Tom G Richardson, Nicholas J Timpson, Colin Campbell, Tom R Gaunt
Current endeavours in rare variant analysis are typically underpowered when investigating association signals from individual genes. We undertook an approach to rare variant analysis which utilises biological pathway information to analyse functionally relevant genes together. Conventional filtering approaches for rare variant analysis are based on variant consequence and are therefore confined to coding regions of the genome. Therefore, we undertook a novel approach to this process by obtaining functional annotations from the Combined Annotation Dependent Depletion (CADD) tool, which allowed potentially deleterious variants from intronic regions of genes to be incorporated into analyses...
August 31, 2016: European Journal of Human Genetics: EJHG
Alejandro Sifrim, Marc-Phillip Hitz, Anna Wilsdon, Jeroen Breckpot, Saeed H Al Turki, Bernard Thienpont, Jeremy McRae, Tomas W Fitzgerald, Tarjinder Singh, Ganesh Jawahar Swaminathan, Elena Prigmore, Diana Rajan, Hashim Abdul-Khaliq, Siddharth Banka, Ulrike M M Bauer, Jamie Bentham, Felix Berger, Shoumo Bhattacharya, Frances Bu'Lock, Natalie Canham, Irina-Gabriela Colgiu, Catherine Cosgrove, Helen Cox, Ingo Daehnert, Allan Daly, John Danesh, Alan Fryer, Marc Gewillig, Emma Hobson, Kirstin Hoff, Tessa Homfray, Anne-Karin Kahlert, Ami Ketley, Hans-Heiner Kramer, Katherine Lachlan, Anne Katrin Lampe, Jacoba J Louw, Ashok Kumar Manickara, Dorin Manase, Karen P McCarthy, Kay Metcalfe, Carmel Moore, Ruth Newbury-Ecob, Seham Osman Omer, Willem H Ouwehand, Soo-Mi Park, Michael J Parker, Thomas Pickardt, Martin O Pollard, Leema Robert, David J Roberts, Jennifer Sambrook, Kerry Setchfield, Brigitte Stiller, Chris Thornborough, Okan Toka, Hugh Watkins, Denise Williams, Michael Wright, Seema Mital, Piers E F Daubeney, Bernard Keavney, Judith Goodship, Riyadh Mahdi Abu-Sulaiman, Sabine Klaassen, Caroline F Wright, Helen V Firth, Jeffrey C Barrett, Koenraad Devriendt, David R FitzPatrick, J David Brook, Matthew E Hurles
Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281)...
September 2016: Nature Genetics
S Riazuddin, M Hussain, A Razzaq, Z Iqbal, M Shahzad, D L Polla, Y Song, E van Beusekom, A A Khan, L Tomas-Roca, M Rashid, M Y Zahoor, W M Wissink-Lindhout, M A R Basra, M Ansar, Z Agha, K van Heeswijk, F Rasheed, M Van de Vorst, J A Veltman, C Gilissen, J Akram, T Kleefstra, M Z Assir, D Grozeva, K Carss, F L Raymond, T D O'Connor, S A Riazuddin, S N Khan, Z M Ahmed, A P M de Brouwer, H van Bokhoven, S Riazuddin
Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes...
July 26, 2016: Molecular Psychiatry
Yu-Fang Pei, Wen-Zhu Hu, Rong Hai, Xiu-Yan Wang, Shu Ran, Yong Lin, Hui Shen, Qing Tian, Shu-Feng Lei, Yong-Hong Zhang, Christopher J Papasian, Hong-Wen Deng, Lei Zhang
Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p=1...
October 2016: Bone
Jack A Kosmicki, Claire L Churchhouse, Manuel A Rivas, Benjamin M Neale
With the rise of sequencing technologies, it is now feasible to assess the role rare variants play in the genetic contribution to complex trait variation. While some of the earlier targeted sequencing studies successfully identified rare variants of large effect, unbiased gene discovery using exome sequencing has experienced limited success for complex traits. Nevertheless, rare variant association studies have demonstrated that rare variants do contribute to phenotypic variability, but sample sizes will likely have to be even larger than those of common variant association studies to be powered for the detection of genes and loci...
June 2016: Human Genetics
Karsten Boldt, Jeroen van Reeuwijk, Qianhao Lu, Konstantinos Koutroumpas, Thanh-Minh T Nguyen, Yves Texier, Sylvia E C van Beersum, Nicola Horn, Jason R Willer, Dorus A Mans, Gerard Dougherty, Ideke J C Lamers, Karlien L M Coene, Heleen H Arts, Matthew J Betts, Tina Beyer, Emine Bolat, Christian Johannes Gloeckner, Khatera Haidari, Lisette Hetterschijt, Daniela Iaconis, Dagan Jenkins, Franziska Klose, Barbara Knapp, Brooke Latour, Stef J F Letteboer, Carlo L Marcelis, Dragana Mitic, Manuela Morleo, Machteld M Oud, Moniek Riemersma, Susan Rix, Paulien A Terhal, Grischa Toedt, Teunis J P van Dam, Erik de Vrieze, Yasmin Wissinger, Ka Man Wu, Gordana Apic, Philip L Beales, Oliver E Blacque, Toby J Gibson, Martijn A Huynen, Nicholas Katsanis, Hannie Kremer, Heymut Omran, Erwin van Wijk, Uwe Wolfrum, François Kepes, Erica E Davis, Brunella Franco, Rachel H Giles, Marius Ueffing, Robert B Russell, Ronald Roepman
Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis...
2016: Nature Communications
Kevin Sharp, Warren Kretzschmar, Olivier Delaneau, Jonathan Marchini
MOTIVATION: There is growing recognition that estimating haplotypes from high coverage sequencing of single samples in clinical settings is an important problem. At the same time very large datasets consisting of tens and hundreds of thousands of high-coverage sequenced samples will soon be available. We describe a method that takes advantage of these huge human genetic variation resources and rare variant sharing patterns to estimate haplotypes on single sequenced samples. Sharing rare variants between two individuals is more likely to arise from a recent common ancestor and, hence, also more likely to indicate similar shared haplotypes over a substantial flanking region of sequence...
July 1, 2016: Bioinformatics
Yi-Juan Hu, Peizhou Liao, H Richard Johnston, Andrew S Allen, Glen A Satten
Next-generation sequencing of DNA provides an unprecedented opportunity to discover rare genetic variants associated with complex diseases and traits. However, the common practice of first calling underlying genotypes and then treating the called values as known is prone to false positive findings, especially when genotyping errors are systematically different between cases and controls. This happens whenever cases and controls are sequenced at different depths, on different platforms, or in different batches...
May 2016: PLoS Genetics
Tom G Richardson, Colin Campbell, Nicholas J Timpson, Tom R Gaunt
BACKGROUND: The success of collapsing methods which investigate the combined effect of rare variants on complex traits has so far been limited. The manner in which variants within a gene are selected prior to analysis has a crucial impact on this success, which has resulted in analyses conventionally filtering variants according to their consequence. This study investigates whether an alternative approach to filtering, using annotations from recently developed bioinformatics tools, can aid these types of analyses in comparison to conventional approaches...
2016: PloS One
Tom G Richardson, Hashem A Shihab, Manuel A Rivas, Mark I McCarthy, Colin Campbell, Nicholas J Timpson, Tom R Gaunt
BACKGROUND: It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit. METHODS: Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1%) together in three different ways 1) variants within single genomic regions which map to individual protein domains 2) variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3) all variants within combined regions from multiple genes responsible for coding the same protein domain (i...
2016: PloS One
Ana Jeroncic, Yasin Memari, Graham Rs Ritchie, Audrey E Hendricks, Anja Kolb-Kokocinski, Angela Matchan, Veronique Vitart, Caroline Hayward, Ivana Kolcic, Dominik Glodzik, Alan F Wright, Igor Rudan, Harry Campbell, Richard Durbin, Ozren Polašek, Eleftheria Zeggini, Vesna Boraska Perica
We have whole-exome sequenced 176 individuals from the isolated population of the island of Vis in Croatia in order to describe exonic variation architecture. We found 290 577 single nucleotide variants (SNVs), 65% of which are singletons, low frequency or rare variants. A total of 25 430 (9%) SNVs are novel, previously not catalogued in NHLBI GO Exome Sequencing Project, UK10K-Generation Scotland, 1000Genomes Project, ExAC or NCBI Reference Assembly dbSNP. The majority of these variants (76%) are singletons...
October 2016: European Journal of Human Genetics: EJHG
Chunqiao Liu, Sonya A Widen, Kathleen A Williamson, Rinki Ratnapriya, Christina Gerth-Kahlert, Joe Rainger, Ramakrishna P Alur, Erin Strachan, Souparnika H Manjunath, Archana Balakrishnan, James A Floyd, Tiansen Li, Andrew Waskiewicz, Brian P Brooks, Ordan J Lehmann, David R FitzPatrick, Anand Swaroop
Ocular coloboma is a common eye malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma...
April 1, 2016: Human Molecular Genetics
Jianping Sun, Karim Oualkacha, Vincenzo Forgetta, Hou-Feng Zheng, J Brent Richards, Antonio Ciampi, Celia Mt Greenwood
For region-based sequencing data, power to detect genetic associations can be improved through analysis of multiple related phenotypes. With this motivation, we propose a novel test to detect association simultaneously between a set of rare variants, such as those obtained by sequencing in a small genomic region, and multiple continuous phenotypes. We allow arbitrary correlations among the phenotypes and build on a linear mixed model by assuming the effects of the variants follow a multivariate normal distribution with a zero mean and a specific covariance matrix structure...
August 2016: European Journal of Human Genetics: EJHG
Jörg Hakenberg, Wei-Yi Cheng, Philippe Thomas, Ying-Chih Wang, Andrew V Uzilov, Rong Chen
BACKGROUND: Data from a plethora of high-throughput sequencing studies is readily available to researchers, providing genetic variants detected in a variety of healthy and disease populations. While each individual cohort helps gain insights into polymorphic and disease-associated variants, a joint perspective can be more powerful in identifying polymorphisms, rare variants, disease-associations, genetic burden, somatic variants, and disease mechanisms. DESCRIPTION: We have set up a Reference Variant Store (RVS) containing variants observed in a number of large-scale sequencing efforts, such as 1000 Genomes, ExAC, Scripps Wellderly, UK10K; various genotyping studies; and disease association databases...
2016: BMC Bioinformatics
Raheleh Rahbari, Arthur Wuster, Sarah J Lindsay, Robert J Hardwick, Ludmil B Alexandrov, Saeed Al Turki, Anna Dominiczak, Andrew Morris, David Porteous, Blair Smith, Michael R Stratton, Matthew E Hurles
Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages...
February 2016: Nature Genetics
Xiaoming Liu, Chunlei Wu, Chang Li, Eric Boerwinkle
The purpose of the dbNSFP is to provide a one-stop resource for functional predictions and annotations for human nonsynonymous single-nucleotide variants (nsSNVs) and splice-site variants (ssSNVs), and to facilitate the steps of filtering and prioritizing SNVs from a large list of SNVs discovered in an exome-sequencing study. A list of all potential nsSNVs and ssSNVs based on the human reference sequence were created and functional predictions and annotations were curated and compiled for each SNV. Here, we report a recent major update of the database to version 3...
March 2016: Human Mutation
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"