Shared Genetic Architecture between Asthma and Allergic Diseases: A Genome-Wide Cross Trait Analysis of 112,000 Individuals from UK Biobank

Zhu, Zhiliang; Ph, Lee; Chaffin, Mark; Chung, Wonil; P, Loh; Lu, Quanming; Dc, Christiani; Liang, Liming

doi:10.1101/133322

Cited by 3 publications

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References 83 publications

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“…We found nine significant associations for imputed PTVs (BY-adjusted p<0.05, Table S2) including rs74315329 in MYOC and glaucoma (MAF=0.0012, p=1.8x10 -30 , OR=4.71, 95% CI: 3.61-6.14) 26 , a well-known risk variant for glaucoma 27 , and D2HGDH and asthma (MAF=0.445, p=1.6x10 -12 , OR=0.95, 95% CI: 0.94-0.96) and hay fever (coded hayfever/allergic rhinitis) (p=8.4x10 -9 , OR=0.94, 95% CI: 0.92-0.96). The D2HGDH PTV is in partial LD with an intronic variant rs34290285 in D2HGDH (r 2 =0.366, LDlink) that has been associated with asthma and allergic disease 28,29 . We also identified an association between the PTV rs754512 in MAPT and Parkinson's disease (MAF=0.23, p=1.1x10 -6 ; OR=0.94, 95% CI: 0.92-0.97) 30 .…”

Section: Figure 2 Identification Of Risk and Protective Alleles For mentioning

confidence: 99%

Medical relevance of protein-truncating variants across 337,208 individuals in the UK Biobank study

DeBoever

Tanigawa

McInnes

et al. 2017

Preprint

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Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. We characterized the effect of 18,228 proteintruncating variants across 135 phenotypes from the UK Biobank and found 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We performed phenome-wide analyses and directly measured the effect of homozygous carriers, commonly referred to as "human knockouts," across medical phenotypes for genes implicated to be protective against disease or associated with at least one phenotype in our study and found several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.Protein-truncating variants (PTVs), genetic variants predicted to shorten the coding sequence of genes, are a promising set of variants for drug discovery since identification of PTVs that protect against human disease provides in vivo validation of therapeutic targets 1,2,3,4 . Although tens of thousands of standing germline PTVs have been identified 5,6 , their medical relevance across a broad range of phenotypes has not been characterized. Because most PTVs are present at low frequency, assessing the effects of PTVs requires genotype data from a large number of individuals with linked phenotype data for a variety of diseases and physiological measurements. The recent release of genotype and linked clinical and questionnaire data for 488,377 individuals in the UK Biobank provides an unprecedented opportunity to assess the clinical impact of truncating protein-coding genes at a resolution not previously possible.. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/179762 doi: bioRxiv preprint first posted online Aug. 23, 2017; ResultsTo assess the clinical relevance of PTVs, we cataloged predicted PTVs present in the Affymetrix UK Biobank array and their effects on medical phenotypes from 337,208 unrelated individuals in the UK Biobank study 7,8 . We defined PTVs as single-nucleotide variants (SNVs) predicted to introduce a premature stop codon or to disrupt a splice site or small insertions or deletions (indels) predicted to disrupt a transcript's reading frame 5 . We identified 18,228 predicted PTVs in the UK Biobank array that were polymorphic across 8,750 genes after filtering (Methods, Figure S1). Each participant had 95 predicted PTVs with minor allele frequency (MAF) less than 1% on average, and 778 genes were predicted to be homozygous or compound heterozygous for PTVs with MAF less than 1% in at least one individual. The observed number of PTVs per individual is consistent with the ~100 loss-of-function variants observed in the 1000 Genomes project 9 . In contrast...

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Section: Figure 2 Identification Of Risk and Protective Alleles For mentioning

confidence: 99%

Medical relevance of protein-truncating variants across 337,208 individuals in the UK Biobank study

DeBoever

Tanigawa

McInnes

et al. 2017

Preprint

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Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study

et al. 2018

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Statistical power and utility of meta-analysis methods for cross-phenotype genome-wide association studies

et al. 2018

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Advances in recent genome wide association studies (GWAS) suggest that pleiotropic effects on human complex traits are widespread. A number of classic and recent meta-analysis methods have been used to identify genetic loci with pleiotropic effects, but the overall performance of these methods is not well understood. In this work, we use extensive simulations and case studies of GWAS datasets to investigate the power and type-I error rates of ten meta-analysis methods. We specifically focus on three conditions commonly encountered in the studies of multiple traits: (1) extensive heterogeneity of genetic effects; (2) characterization of trait-specific association; and (3) inflated correlation of GWAS due to overlapping samples. Although the statistical power is highly variable under distinct study conditions, we found the superior power of several methods under diverse heterogeneity. In particular, classic fixed-effects model showed surprisingly good performance when a variant is associated with more than a half of study traits. As the number of traits with null effects increases, ASSET performed the best along with competitive specificity and sensitivity. With opposite directional effects, CPASSOC featured the first-rate power. However, caution is advised when using CPASSOC for studying genetically correlated traits with overlapping samples. We conclude with a discussion of unresolved issues and directions for future research.

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Shared Genetic Architecture between Asthma and Allergic Diseases: A Genome-Wide Cross Trait Analysis of 112,000 Individuals from UK Biobank

Cited by 3 publications

References 83 publications

Medical relevance of protein-truncating variants across 337,208 individuals in the UK Biobank study

Medical relevance of protein-truncating variants across 337,208 individuals in the UK Biobank study

Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study

Statistical power and utility of meta-analysis methods for cross-phenotype genome-wide association studies

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