Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses

Barton, Alison R.; Sherman, Maxwell A.; Mukamel, Ronen E.; Loh, Po−Ru

doi:10.1038/s41588-021-00892-1

Cited by 174 publications

(132 citation statements)

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“…c. Associations between whole-gene deletions and quantitative traits in targeted analyses of 41 gene-trait pairs for which we previously identified likely trait-altering PTVs 23 and for which the HI-CNV call set contained at least two whole-gene deletions. Effect sizes and 95% confidence intervals are shown in red for 16 genes for which whole-gene deletions exhibited nominally significant associations (P < 0.05); effect sizes for SNP or indel PTVs 23 are shown in black. d. Observing 16 nominally significant associations was consistent with whole-gene deletions having the same effects as PTVs.…”

Section: Discussionmentioning

confidence: 99%

“…These traits included anthropometric traits, blood pressure, measures of lung function, bone mineral density, blood cell indices, and serum biomarkers (Supplementary Data 1). Quality control and normalization of the quantitative traits was previously described 22,23 .…”

Section: Uk Biobank Genetic and Phenotypic Datamentioning

confidence: 99%

“…We conducted association tests using BOLT-LMM 21,22 (--lmmForceNonInf) with assessment center, genotyping array, sex, age, age squared and 20 genetic principal components included as covariates. We fit the mixed model on directly genotyped autosomal variants with MAF > 10 -4 and missingness < 0.1 and computed association test statistics for CNVs in the three categories defined above; a similar pipeline produced association test statistics for SNP and indel variants imputed by UK Biobank (the imp_v3 release) and variants we previously imputed from the first tranche of exome-sequencing of 49,960 participants 23 . We included all participants with non-missing phenotypes in the European-ancestry HI-CNV call set described above.…”

Section: Association Testing and Statistical Fine-mappingmentioning

confidence: 99%

“…To filter significant associations to a set of likely-causal associations, we used a pipeline we previously developed 23 to eliminate associations that could be explained by linkage disequilibrium (LD) with nearby variants (here, either SNP or indel variants from the UK Biobank imp_v3 release or variants we had imputed from WES 23 ). This filter required CNVs to remain significant after conditioning on any other more strongly associated variant nearby.…”

Section: Association Testing and Statistical Fine-mappingmentioning

confidence: 99%

“…We defined likely-causal associations as those with the property that 𝜒 $|% ( ≥ 29.7168 (P < 5 x 10 -8 ) for all variants j more strongly associated with the trait than CNV i. We previously observed that this pairwise LDbased filter was effective for fine-mapping rare variant associations 23 .…”

Section: Association Testing and Statistical Fine-mappingmentioning

confidence: 99%

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Influences of rare copy number variation on human complex traits

Hujoel

Sherman

Barton

et al. 2021

Preprint

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The human genome contains hundreds of thousands of regions exhibiting copy number variation (CNV). However, the phenotypic effects of most such polymorphisms are unknown because only larger CNVs (spanning tens of kilobases) have been ascertainable from the SNP-array data generated by large biobanks. We developed a new computational approach that leverages abundant haplotype-sharing in biobank cohorts to more sensitively detect CNVs co-inherited within extended SNP haplotypes. Applied to UK Biobank, this approach achieved 6-fold increased CNV detection sensitivity compared to previous analyses, accounting for approximately half of all rare gene inactivation events produced by genomic structural variation. This extensive CNV call set enabled the most comprehensive analysis to date of associations between CNVs and 56 quantitative traits, identifying 269 independent associations (P < 5 x 10-8) - involving 97 loci - that rigorous statistical fine-mapping analyses indicated were likely to be causally driven by CNVs. Putative target genes were identifiable for nearly half of the loci, enabling new insights into dosage-sensitivity of these genes and implicating several novel gene-trait relationships. CNVs at several loci created extended allelic series including deletions or duplications of distal enhancers that associated with much stronger phenotypic effects than SNPs within these regulatory elements. These results demonstrate the ability of haplotype-informed analysis to empower structural variant detection and provide insights into the genetic basis of human complex traits.

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Section: Discussionmentioning

confidence: 99%

Section: Uk Biobank Genetic and Phenotypic Datamentioning

confidence: 99%

Section: Association Testing and Statistical Fine-mappingmentioning

confidence: 99%

Section: Association Testing and Statistical Fine-mappingmentioning

confidence: 99%

Section: Association Testing and Statistical Fine-mappingmentioning

confidence: 99%

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Influences of rare copy number variation on human complex traits

Hujoel

Sherman

Barton

et al. 2021

Preprint

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At What Age Does Age-Related Macular Degeneration Start?

2021

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Patients presenting to an ophthalmologist with macular drusen at a young age is not an uncommon scenario in medical retina clinics. These young patients want to be informed regarding their future visual prognosis, possible impact on occupation or activities of daily living, and most importantly, any prospect of treatment. What criteria could contribute to an ophthalmologist's confidence in diagnosing early-onset age-related macular degeneration (AMD) as opposed to the early features of an inherited macular dystrophy, such as Doyne retinal dystrophy/Malattia Leventinese or Sorsby fundus dystrophy? In this issue of JAMA Ophthalmology, de Breuk et al 1 report the findings of a genotype-phenotype study in patients with early-onset macular drusen. The authors have used the term early-onset drusen maculopathy (EODM) to describe younger (≤55 years) patients with macular drusen and compared 89 patients with EODM with 91 patients diagnosed with AMD who were 65 years or older.Strikingly, the study shows that approximately 45% of these patients with EODM developed geographic atrophy or choroidal neovascularization in at least 1 eye by the mean age of 56.4 years, with associated visual impairment. Approximately 30% of patients in the EODM cohort carried a rare complement factor H (CFH) genetic variant, compared with approximately 8% of patients with AMD. Patients with EODM tended to carry fewer common variants that are known to predispose to maculopathy in patients with AMD. 2 However, these patients showed a considerable enrichment in genetic risk attributable to rare genetic variation. Rare genetic variants, particularly located in protein-coding regions of genes, tend to have very large effects, inversely proportional with their allele frequency. 3 The presence of rarer risk variants located within the same genes in patients with EODM intriguingly may suggest an explanation for the early onset of symptoms compared with the AMD cohort.This study demonstrates a shared genetic and phenotypic profile between EOMD and AMD. Therefore, is EOMD a separate disease from AMD or does it suggest that AMD exists in individuals younger than 55 years? The findings described here 1 suggest that patients presenting with an AMD phenotype who are younger than 55 years have a similar genetic basis for the disease, albeit with more rare variants, and as such, have an early-onset form of AMD.A lower genetic risk score for common AMD genetic risk variants was observed in the EOMD cohort. While the genes involved are the same for both the EOMD and AMD cohorts, the differences in phenotypic expression probably represent a reflection of the genetic architecture, ie, individuals with a

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Molecular mechanisms of perilipin protein function in lipid droplet metabolism

Griseti,

Bello,

Bieth

et al. 2024

FEBS Letters

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Perilipins are abundant lipid droplet (LD) proteins present in all metazoans and also in Amoebozoa and fungi. Humans express five perilipins, which share a similar domain organization: an amino‐terminal PAT domain and an 11‐mer repeat region, which can fold into amphipathic helices that interact with LDs, followed by a structured carboxy‐terminal domain. Variations of this organization that arose during vertebrate evolution allow for functional specialization between perilipins in relation to the metabolic needs of different tissues. We discuss how different features of perilipins influence their interaction with LDs and their cellular targeting. PLIN1 and PLIN5 play a direct role in lipolysis by regulating the recruitment of lipases to LDs and LD interaction with mitochondria. Other perilipins, particularly PLIN2, appear to protect LDs from lipolysis, but the molecular mechanism is not clear. PLIN4 stands out with its long repetitive region, whereas PLIN3 is most widely expressed and is used as a nascent LD marker. Finally, we discuss the genetic variability in perilipins in connection with metabolic disease, prominent for PLIN1 and PLIN4, underlying the importance of understanding the molecular function of perilipins.

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Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses

Cited by 174 publications

References 61 publications

Influences of rare copy number variation on human complex traits

Influences of rare copy number variation on human complex traits

At What Age Does Age-Related Macular Degeneration Start?

Molecular mechanisms of perilipin protein function in lipid droplet metabolism

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