scholarly journals No statistical evidence for an effect of CCR5-∆32 on lifespan in the UK Biobank cohort

2019 ◽  
Author(s):  
Robert Maier ◽  
Ali Akbari ◽  
Xinzhu Wei ◽  
Nick Patterson ◽  
Rasmus Nielsen ◽  
...  
Keyword(s):  
Joint Analysis ◽  
Uk Biobank ◽  
Sequencing Data ◽  
Weinberg Equilibrium ◽  
Whole Exome ◽  
Base Pair Deletion ◽  
Whole Exome Sequencing Data ◽  
Hardy Weinberg Equilibrium ◽  
Elevated Rate ◽  
The Uk

AbstractA recent study reported that a 32-base-pair deletion in the CCR5 gene (CCR5-∆32) is deleterious in the homozygous state in humans. Evidence for this came from a survival analysis in the UK Biobank cohort, and from deviations from Hardy-Weinberg equilibrium at a polymorphism tagging the deletion (rs62625034). Here, we carry out a joint analysis of whole-genome genotyping data and whole-exome sequencing data from the UK Biobank, which reveals that technical artifacts are a more plausible cause for deviations from Hardy-Weinberg equilibrium at this polymorphism. Specifically, we find that individuals homozygous for the deletion in the sequencing data are underrepresented in the genotyping data due to an elevated rate of missing data at rs62625034, possibly because the probe for this SNP overlaps with the ∆32 deletion. Another variant which has a higher concordance with the deletion in the sequencing data shows no associations with mortality. A phenome-wide scan for effects of variants tagging this deletion shows an overall inflation of association p-values, but identifies only one trait at p < 5×10−8, and no mediators for an effect on mortality. These analyses show that the original reports of a recessive deleterious effect of CCR5-∆32 are affected by a technical artifact, and that a closer investigation of the same data provides no positive evidence for an effect on lifespan.

scholarly journals CCR5-del32 is not deleterious in the homozygous state in humans

2019 ◽  
Author(s):  
Daniel Gudbjartsson ◽  
Patric Sulem ◽  
Kári Stefansson ◽  
Nina Mars ◽  
Juha Karjalainen ◽  
...  
Keyword(s):  
Health Data ◽  
Uk Biobank ◽  
Homozygous State ◽  
Weinberg Equilibrium ◽  
All Cause Mortality ◽  
Hardy Weinberg Equilibrium ◽  
The Uk ◽  
Protective Variant ◽  
Increase In Risk

Recently, Wei and Nielsen1 reported an analysis of UK Biobank data which suggested that the well-known HIV-protective variant CCR5-del32 is associated with a 21% increase in all-cause mortality. We demonstrate, using two well-powered population samples in Iceland and Finland with extensive health data and death information, neither an effect on mortality nor increase in risk of any disease. Further reexamination of the UK Biobank (UKBB) data suggests that the very modest association was with a SNP of poor genotyping quality – at a nearby proxy SNP, no statistically significant impact on mortality nor deviation from Hardy-Weinberg equilibrium exists in the UKBB sample. We thus find no evidence of any meaningful risk of increased mortality from homozygosity of CCR5-del32.

scholarly journals Deviations from Hardy Weinberg Equilibrium at CCR5-Δ32 in Large Sequencing Data Sets

2019 ◽  
Author(s):  
Xinzhu Wei ◽  
Rasmus Nielsen
Keyword(s):  
Mortality Rate ◽  
Deleterious Effect ◽  
Data Sets ◽  
Sequencing Data ◽  
Genotyping Array ◽  
Array Data ◽  
Weinberg Equilibrium ◽  
Show Evidence ◽  
Hardy Weinberg Equilibrium ◽  
The Uk

AbstractPrevious analyses of the UK Biobank (UKB) genotyping array data in the CCR5-Δ32 locus show evidence for deviations from Hardy-Weinberg Equilibrium (HWE) and an increased mortality rate of homozygous individuals, consistent with a recessive deleterious effect of the deletion mutation. We here examine if similar deviations from HWE can be observed in the newly released UKB Whole Exome Sequencing (WES) data and in the sequencing data of the Genome Aggregation Database (gnomAD). We also examine the reliability of the genotype calls in the UKB array data. The UKB genotyping array probe targeting CCR5-Δ32 (rs62625034) and the WES of Δ32 are strongly correlated (r2 = 0.97). This contrasts to tag SNPs of CCR5-Δ32 in the UKB which have high missing data rates and imputation errors rates. We also show that, while different data sets are subject to different biases, both the UKB-WES and the gnomAD data have a deficiency of homozygous CCR5-Δ32 individuals compared to the HWE expectation (combined P-value < 0.01), consistent with an increased mortality rate in homozygotes. Finally, we perform a survival analysis on data from parents of UKB volunteers, that, while underpowered, is also consistent with the original report of a deleterious effect of CCR5-Δ32 in the homozygous state.

scholarly journals Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

BMJ ◽  
2021 ◽  
pp. n214
Author(s):  
Weedon MN ◽  
Jackson L ◽  
Harrison JW ◽  
Ruth KS ◽  
Tyrrell J ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Predictive Value ◽  
Population Based ◽  
Genome Project ◽  
Personal Genome ◽  
Uk Biobank ◽  
Sequencing Data ◽  
Snp Chip ◽  
Pathogenic Variants ◽  
The Uk

Abstract Objective To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. Design Retrospective, population based diagnostic evaluation. Participants 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. Main outcome measures Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

scholarly journals Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Jong Seop Kim ◽  
Hyoungseok Jeon ◽  
Hyeran Lee ◽  
Jung Min Ko ◽  
Yonghwan Kim ◽  
...  
Keyword(s):  
Hip Dysplasia ◽  
Large Deletion ◽  
Compound Heterozygous ◽  
Radial Head Dislocation ◽  
Sequencing Data ◽  
Novel Mutations ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Carpal Coalition

AbstractAn 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome. Scrutinizing the trio whole-exome sequencing data revealed novel compound heterozygous mutations of COL27A1 (c.[4229_4233dup]; [3718_5436del], p.[Gly1412Argfs*157];[Gly1240_Lys1812del]) in the proband, which were inherited from heterozygous parents. The maternal mutation was a large deletion encompassing exons 38–60, which was challenging to detect.

scholarly journals Long runs of homozygosity are associated with Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Moreno-Grau ◽  
◽  
Maria Victoria Fernández ◽  
Itziar de Rojas ◽  
Pablo Garcia-González ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
European Ancestry ◽  
Runs Of Homozygosity ◽  
Sequencing Data ◽  
Outbred Population ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Outbred Populations ◽  
Recessive Effects

AbstractLong runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; βFROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10−16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10−4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

scholarly journals A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Jennifer D. Hintzsche ◽  
William A. Robinson ◽  
Aik Choon Tan
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sequencing Data ◽  
Disease Treatment ◽  
Computational Tools ◽  
Whole Exome ◽  
Data Production ◽  
Whole Exome Sequencing Data ◽  
Computationally Intensive ◽  
Generation Technology

Whole Exome Sequencing (WES) is the application of the next-generation technology to determine the variations in the exome and is becoming a standard approach in studying genetic variants in diseases. Understanding the exomes of individuals at single base resolution allows the identification of actionable mutations for disease treatment and management. WES technologies have shifted the bottleneck in experimental data production to computationally intensive informatics-based data analysis. Novel computational tools and methods have been developed to analyze and interpret WES data. Here, we review some of the current tools that are being used to analyze WES data. These tools range from the alignment of raw sequencing reads all the way to linking variants to actionable therapeutics. Strengths and weaknesses of each tool are discussed for the purpose of helping researchers make more informative decisions on selecting the best tools to analyze their WES data.

scholarly journals EthSEQ: ethnicity annotation from whole exome sequencing data

2017 ◽  
Vol 33 (15) ◽  
pp. 2402-2404 ◽  
Author(s):  
Alessandro Romanel ◽  
Tuo Zhang ◽  
Olivier Elemento ◽  
Francesca Demichelis
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data
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