Thousands of missing variants in the UK Biobank are recoverable by genome realignment

Jia, Tongqiu; Munson, Brenton; Allen, Hana Lango; Ideker, Trey; Majithia, Amit R.

doi:10.1111/ahg.12383

Cited by 22 publications

(12 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next annotated all variants with Variant Effect Predictor (v97) 57 , extracted variants in exclusively X-linked recessive genes, and retained only the most severe consequence in canonical transcripts. We note that none of these X-linked recessive genes are affected by the recently-reported problem with this UKBB exome data release which is related to mapping errors 63 .…”

Section: Methodsmentioning

confidence: 74%

The contribution of X-linked coding variation to severe developmental disorders

Martin

Gardner

Samocha

et al. 2020

Preprint

View full text Add to dashboard Cite

Over 130 X-linked genes have been robustly associated with developmental disorders (DDs), and X-linked causes have been hypothesised to underlie the higher DD rates in males. We evaluated the burden of X-linked coding variation in 11,046 DD patients, and found a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We developed an improved strategy to detect novel X-linked DDs and identified 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known DD-associated genes. Importantly, we estimated that, in male probands, only 13% of inherited rare missense variants in known DD-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

show abstract

Section: Methodsmentioning

confidence: 74%

The contribution of X-linked coding variation to severe developmental disorders

Martin

Gardner

Samocha

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…With the increased adoption of the reference genome version GRCh38, many pipelines currently utilizing older reference genomes will need mechanisms to test their correct functionality in GRCh38 before the transition. Adopting a new reference genome can sometimes have unanticipated side‐effects, as was highlighted with an analysis of missing variant calls from realigning WGS datasets in the UK Biobank (Jia et al, 2020). A diverse set of variant scenarios involving several inheritance models, genic impacts, and mix of novel and known pathogenic variants has utility for testing these continuously updated pipelines, without the challenge of handling sensitive patient data.…”

Section: Discussionmentioning

confidence: 99%

GeneBreaker: Variant simulation to improve the diagnosis of Mendelian rare genetic diseases

et al. 2021

View full text Add to dashboard Cite

Mendelian rare genetic diseases affect 5%–10% of the population, and with over 5300 genes responsible for ∼7000 different diseases, they are challenging to diagnose. The use of whole‐genome sequencing (WGS) has bolstered the diagnosis rate significantly. The effective use of WGS relies on the ability to identify the disrupted gene responsible for disease phenotypes. This process involves genomic variant calling and prioritization, and is the beneficiary of improvements to sequencing technology, variant calling approaches, and increased capacity to prioritize genomic variants with potential pathogenicity. As analysis pipelines continue to improve, careful testing of their efficacy is paramount. However, real‐life cases typically emerge anecdotally, and utilization of clinically sensitive and identifiable data for testing pipeline improvements is regulated and limiting. We identified the need for a gene‐based variant simulation framework that can create mock rare disease scenarios, utilizing known pathogenic variants or through the creation of novel gene‐disrupting variants. To fill this need, we present GeneBreaker, a tool that creates synthetic rare disease cases with utility for benchmarking variant calling approaches, testing the efficacy of variant prioritization, and as an educational mechanism for training diagnostic practitioners in the expanding field of genomic medicine. GeneBreaker is freely available at http://GeneBreaker.cmmt.ubc.ca.

show abstract

“…Second, it has been reported that there was an issue with the UKB functionally equivalent WES calling. 53 This mapping issue may have resulted in under-calling alternative alleles and therefore should not increase false positive findings. Third, we relied on a meta-analysis approach using summary statistics to perform our gene-based testing due to differences in sequencing platforms and genotyping calling within the multiple consortia contributing to the results.…”

Section: Discussionmentioning

confidence: 99%

Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Hindy¹,

Dornbos²,

Chaffin³

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryLarge-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency<1%) predicted damaging coding variation using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

show abstract

Thousands of missing variants in the UK Biobank are recoverable by genome realignment

Cited by 22 publications

References 18 publications

The contribution of X-linked coding variation to severe developmental disorders

The contribution of X-linked coding variation to severe developmental disorders

GeneBreaker: Variant simulation to improve the diagnosis of Mendelian rare genetic diseases

Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Contact Info

Product

Resources

About