Imputation of Behavioral Candidate Gene Repeat Polymorphisms in 486,551 Publicly-Available UK Biobank Individuals

Mapping Intimacies ◽

10.1101/358267 ◽

2018 ◽

Author(s):

Richard Border ◽

Andrew Smolen ◽

Robin P. Corley ◽

Michael C. Stallings ◽

Sandra A. Brown ◽

...

Keyword(s):

Imputation Accuracy ◽

Variable Number Tandem Repeat ◽

Variable Number ◽

Uk Biobank ◽

Out Of Sample ◽

The Subject ◽

Polymorphism Data ◽

The Uk ◽

Broad Interest ◽

Vntr Polymorphisms

AbstractSome of the most widely studied polymorphisms in psychiatric genetics include variable number tandem repeat polymorphisms (VNTRs) in SLC6A3, DRD4, SLC6A4, and MAOA. While initial findings suggested large effects, their importance with respect to psychiatric phenotypes is the subject of much debate with broadly conflicting results. Despite broad interest, these loci remain absent from the largest available samples, such as the UK Biobank, limiting researchers’ ability to test these contentious hypotheses rigorously in large samples. Here, using two independent reference datasets, we report out-of-sample imputation accuracy estimates of >0.96 for all four VNTR polymorphisms and one modifying SNP, depending on the reference and target dataset. We describe the imputation procedures of these candidate polymorphisms in 486,551 UK Biobank individuals, and have made the imputed polymorphism data available to UK Biobank researchers. This resource, provided to the community, will allow the most rigorous tests to-date of the roles of these polymorphisms in behavioral and psychiatric phenotypes.

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A study of the variation in genetic diversity of Haemophilus Influenzae serotype b (Hib) strains in the UK between 1987 and 2010 using multilocus variable-number tandem repeat analysis (MLVA)

Journal of Infection ◽

10.1016/j.jinf.2011.04.169 ◽

2011 ◽

Vol 63 (6) ◽

pp. e100

Author(s):

Sapna Manglani ◽

David Litt ◽

Shona Neal ◽

Mary Slack

Keyword(s):

Genetic Diversity ◽

Haemophilus Influenzae ◽

Tandem Repeat ◽

Variable Number Tandem Repeat ◽

Variable Number ◽

Repeat Analysis ◽

Serotype B ◽

The Uk

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Accurate Genomic Prediction Of Human Height

10.1101/190124 ◽

2017 ◽

Cited By ~ 6

Author(s):

Louis Lello ◽

Steven G. Avery ◽

Laurent Tellier ◽

Ana I. Vazquez ◽

Gustavo de los Campos ◽

...

Keyword(s):

Genetic Architecture ◽

Uk Biobank ◽

Multiple Phenotypes ◽

Human Height ◽

Out Of Sample ◽

Heel Bone ◽

The Common ◽

Actual Height ◽

The Uk ◽

Missing Heritability Problem

AbstractWe construct genomic predictors for heritable and extremely complex human quan-titative traits (height, heel bone density, and educational attainment) using modern methods in high dimensional statistics (i.e., machine learning). Replication tests show that these predictors capture, respectively, ∼40, 20, and 9 percent of total variance for the three traits. For example, predicted heights correlate ∼0.65 with actual height; actual heights of most individuals in validation samples are within a few cm of the prediction. The variance captured for height is comparable to the estimated SNP heritability from GCTA (GREML) analysis, and seems to be close to its asymptotic value (i.e., as sample size goes to infinity), suggesting that we have captured most of the heritability for the SNPs used. Thus, our results resolve the common SNP portion of the “missing heritability” problem – i.e., the gap between prediction R-squared and SNP heritability. The ∼20k activated SNPs in our height predictor reveal the genetic architecture of human height, at least for common SNPs. Our primary dataset is the UK Biobank cohort, comprised of almost 500k individual genotypes with multiple phenotypes. We also use other datasets and SNPs found in earlier GWAS for out-of-sample validation of our results.

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The Association between a MAOB Variable Number Tandem Repeat Polymorphism and Cocaine and Opiate Addictions in Polyconsumers

Brain Sciences ◽

10.3390/brainsci11101265 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1265

Author(s):

César Mateu ◽

Marta Rodríguez-Arias ◽

Isis Gil-Miravet ◽

Ana Benito ◽

José M. Tomás ◽

...

Keyword(s):

Tandem Repeat ◽

Serotonin Receptor ◽

Variable Number Tandem Repeat ◽

Genetic Diagnosis ◽

Variable Number ◽

Repeat Polymorphism ◽

Addictive Disorders ◽

Vntr Polymorphisms ◽

Tandem Repeat Polymorphism

Genetic analysis of the association between alcohol, cocaine, and opiate addiction and variable number tandem repeat (VNTR) polymorphisms in monoamine oxidase B (MAOB) and serotonergic 5-hydroxytryptamine (serotonin) receptor 1B and 2C (HTR1B 21 and HTR2C) pathway genes was performed in a sample of 302 polyconsumers. Our genetic association analysis revealed a significant association between a 184 base pair (bp) VNTR polymorphism in the MAOB gene and addiction to cocaine and opiates. This work highlights new genetic marker associations in cocaine and opiate polyconsumer addictions. These data help to clarify and quantify the complex role of genetics in addictive disorders, as well as their future contribution to the prevention (genetic counselling), diagnosis (genetic diagnosis of vulnerability), and treatment (pharmacogenomics) of these disorders.

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Capsular type K54, clonal group 29 and virulence plasmids: an analysis of K54 and non-K54 closely related isolates of Klebsiella pneumoniae

Epidemiology and Infection ◽

10.1017/s0950268818001826 ◽

2018 ◽

Vol 146 (14) ◽

pp. 1813-1823 ◽

Cited By ~ 4

Author(s):

J. F. Turton ◽

Z. Payne ◽

K. Micah ◽

J. A. Turton

Keyword(s):

Klebsiella Pneumoniae ◽

Variable Number Tandem Repeat ◽

Variable Number ◽

Virulence Plasmid ◽

Reference Laboratory ◽

Capsular Type ◽

Clonal Group ◽

Virulence Plasmids ◽

Repeat Analysis ◽

The Uk

AbstractCapsular type K54 of Klebsiella pneumoniae is associated with hypervirulence and we sought to discover the basis for this among isolates submitted to the UK reference laboratory between 2012 and 2017. Isolates were typed by variable number tandem repeat analysis, and capsular type and virulence elements sought by PCR. The most prevalent type found (15/31 isolates) corresponded to clonal group (CG) 29 and included five representatives carrying rmpA, rmpA2 (regulators of mucoid phenotype), iutA and iroD (from the aerobactin and salmochelin siderophore clusters) associated with virulence plasmids. These included isolate KpvK54, recovered from pus. The remaining isolates did not carry a virulence plasmid. We also noted 11 further related isolates, including NCTC 9159, not of capsular type K54, but nevertheless sometimes associated with sepsis and abscesses. Whole-genome sequencing showed that KpvK54 carried a large virulence plasmid and an ICEKp3-like structure carrying the yersiniabactin cluster, absent in NCTC 9159. Comparative chromosomal analysis with an additional four genomes showed that KpvK54 shared further genes with K1-ST23 hypervirulent isolates, and with LS358, a K54-ST29 isolate from liver abscess puncture fluid. While CG29 isolates displayed varying degrees of virulence, some, especially those with the virulence plasmid (all K54), were clearly associated with hypervirulence.

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Intergenic Variable-Number Tandem-Repeat Polymorphism Upstream ofrocAAlters Toxin Production and Enhances Virulence in Streptococcus pyogenes

Infection and Immunity ◽

10.1128/iai.00258-16 ◽

2016 ◽

Vol 84 (7) ◽

pp. 2086-2093 ◽

Cited By ~ 17

Author(s):

Luchang Zhu ◽

Randall J. Olsen ◽

Nicola Horstmann ◽

Samuel A. Shelburne ◽

Jia Fan ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Tandem Repeat ◽

Variable Number Tandem Repeat ◽

Toxin Production ◽

Variable Number ◽

Altered Level ◽

Content Type ◽

Vntr Polymorphism ◽

New Findings ◽

Vntr Polymorphisms

Variable-number tandem-repeat (VNTR) polymorphisms are ubiquitous in bacteria. However, only a small fraction of them has been functionally studied. Here, we report an intergenic VNTR polymorphism that confers an altered level of toxin production and increased virulence inStreptococcus pyogenes. The nature of the polymorphism is a one-unit deletion in a three-tandem-repeat locus upstream of therocAgene encoding a sensor kinase.S. pyogenesstrains with this type of polymorphism cause human infection and produce significantly larger amounts of the secreted cytotoxinsS. pyogenesNADase (SPN) and streptolysin O (SLO). Using isogenic mutant strains, we demonstrate that deleting one or more units of the tandem repeats abolished RocA production, reduced CovR phosphorylation, derepressed multiple CovR-regulated virulence factors (such as SPN and SLO), and increased virulence in a mouse model of necrotizing fasciitis. The phenotypic effect of the VNTR polymorphism was nearly the same as that of inactivating therocAgene. In summary, we identified and characterized an intergenic VNTR polymorphism inS. pyogenesthat affects toxin production and virulence. These new findings enhance understanding ofrocAbiology and the function of VNTR polymorphisms inS. pyogenes.

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Clusters of genetically similar isolates of Pseudomonas aeruginosa from multiple hospitals in the UK

Journal of Medical Microbiology ◽

10.1099/jmm.0.054841-0 ◽

2013 ◽

Vol 62 (7) ◽

pp. 988-1000 ◽

Cited By ~ 32

Author(s):

Kate Martin ◽

Buket Baddal ◽

Nazim Mustafa ◽

Claire Perry ◽

Anthony Underwood ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Variable Number Tandem Repeat ◽

Variable Number ◽

Reference Laboratory ◽

Clinical Environment ◽

Accessory Gene ◽

Gene Profiles ◽

Typing Methods ◽

The Uk ◽

Generation Sequencing

Variable number tandem repeat (VNTR) analysis at nine loci of isolates of Pseudomonas aeruginosa submitted to the national reference laboratory from UK hospitals, from over 2000 patients, between June 2010 and June 2012 revealed four widely found types that collectively were received from approximately a fifth of patients, including from those with cystic fibrosis. These types were also prevalent among related submissions from the clinical environment and were received from up to 54 (out of 143) hospitals. Multi-locus sequence typing and bla OXA-50-like sequencing confirmed the clonal relationship within each cluster, and representatives from multiple centres clustered within about 70 % by pulsed-field gel electrophoresis. Illumina sequencing of 12 isolates of cluster A of VNTR profile 8, 3, 4, 5, 2, 3, 5, 2, x (where the repeat number at the last, most discriminatory locus is variable) revealed a large number of variably present targets in the accessory genome and seven of these were sought by PCR among a larger set of isolates. Representatives from patients within a single centre mostly had distinct accessory gene profiles, suggesting that these patients acquired the strain independently, while those with clear epidemiological links shared the same profile. Profiles also varied between representatives from different centres. Epidemiological investigations of widely found types such as these require the use of finer-typing methods, which increasingly will be informed by next generation sequencing.

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Fast and accurate long-range phasing in a UK Biobank cohort

10.1101/028282 ◽

2015 ◽

Cited By ~ 5

Author(s):

Po-Ru Loh ◽

Pier Francesco Palamara ◽

Alkes L Price

Keyword(s):

Long Range ◽

Error Rate ◽

Rare Variants ◽

Imputation Accuracy ◽

Computational Cost ◽

Uk Biobank ◽

Identical By Descent ◽

Icelandic Population ◽

Related Individuals ◽

The Uk

Recent work has leveraged the extensive genotyping of the Icelandic population to perform long-range phasing (LRP), enabling accurate imputation and association analysis of rare variants in target samples typed on genotyping arrays. Here, we develop a fast and accurate LRP method, Eagle, that extends this paradigm to populations with much smaller proportions of genotyped samples by harnessing long (>4cM) identical-by-descent (IBD) tracts shared among distantly related individuals. We applied Eagle to N=150K samples (0.2% of the British population) from the UK Biobank, and we determined that it is 1-2 orders of magnitude faster than existing methods while achieving similar or better phasing accuracy (switch error rate ≈0.3%, corresponding to perfect phase in most 10Mb segments). We also observed that when used within an imputation pipeline, Eagle pre-phasing improved downstream imputation accuracy compared to pre-phasing in batches using existing methods (as necessary to achieve comparable computational cost).

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Outbreak ofEscherichia coliO157 Phage Type 32 linked to the consumption of venison products

Epidemiology and Infection ◽

10.1017/s0950268818001784 ◽

2018 ◽

Vol 146 (15) ◽

pp. 1922-1927 ◽

Cited By ~ 1

Author(s):

A. Smith-Palmer ◽

G. Hawkins ◽

L. Browning ◽

L. Allison ◽

M. Hanson ◽

...

Keyword(s):

Escherichia Coli ◽

Tandem Repeat ◽

Shiga Toxin ◽

Phage Type ◽

Variable Number Tandem Repeat ◽

Variable Number ◽

Food History ◽

Repeat Analysis ◽

Asymptomatic Case ◽

The Uk

AbstractIn September 2015, an outbreak ofEscherichia coliPhage Type 32 with an indistinguishable multi locus variable number tandem repeat analysis profile was identified in Scotland. Twelve cases were identified; nine primary cases, two secondary and one asymptomatic case. Extensive food history investigations identified venison products containing wild venison produced by a single food business operator as the most likely source of the outbreak. Of the nine primary cases, eight had consumed venison products, and one case had not eaten venison themselves but had handled and cooked raw venison in the household. This was the first reported outbreak of Shiga toxin-producingEscherichia coli(STEC) linked to venison products in the UK, and was also notable due to the implicated products being commercially produced and widely distributed. In contrast, previous venison outbreaks reported from other countries have tended to be smaller and related to individually prepared carcases. The outbreak has highlighted some important knowledge gaps in relation to STEC in venison that are currently been investigated via a number of research studies.

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