Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight adipocyte biology

Tanigawa, Yosuke; Li, Jiehan; Justesen, Johanne Marie; Horn, Heiko; Aguirre, Matthew; DeBoever, Christopher; Chang, Chris; Narasimhan, Balasubramanian; Lage, Kasper; Hastie, Trevor; Park, Chong Y.; Bejerano, Gill; Ingelsson, Erik; Rivas, Manuel A.

doi:10.1038/s41467-019-11953-9

Cited by 59 publications

(93 citation statements)

References 64 publications

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“…Analogous to prior publications in the medical genetics community, we discovered that technical errors and inadequate quality control protocol introduced false-positive findings in Wei and Nielsen and that the deviation from HWE can be explained by poor genotyping performance 6 . 3 ). C) Scatterplot of the genotyping rate (x-axis) versus Hardy-Weinberg Equilibrium deviation p-value (y-axis) for rs62625034.…”

Section: Mainmentioning

confidence: 99%

Reported CCR5-∆32 deviation from Hardy-Weinberg equilibrium is explained by poor genotyping of rs62625034

Tanigawa

Rivas

2019

Preprint

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In the fall of 2018, news broke about a researcher from China who had used CRISPR gene editing to cause human babies to have a deletion in the CCR5 chemokine receptor, making them resistant to HIV infection. One of the numerous ethical concerns about this study is that the deletion may have other effects. Subsequently, Nature Medicine published a Brief Communications from Wei and Nielsen concluding that homozygotes for the CCR5-∆32 deletion have a survival probability to age 76 of 83.5% compared to 86.5% and 86.4% for the heterozygotes and the other homozygote, respectively, and that observed departures from Hardy Weinberg proportions also support selection operating on this allele 1 . In the study, Wei and Nielsen used a proxy variant, rs62625034 in their analysis. Here, we report that the reported CCR5-∆32 deviation from Hardy-Weinberg equilibrium (HWE) inferred by Wei and Nielsen can be explained by poor genotyping of rs62625034, the variant used for their analysis.

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Section: Mainmentioning

confidence: 99%

Reported CCR5-∆32 deviation from Hardy-Weinberg equilibrium is explained by poor genotyping of rs62625034

Tanigawa

Rivas

2019

Preprint

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“…33 Here, we hoped to learn the same sorts of factors by decomposing only summary GWAS data on clinical disease endpoints. Our continuous shrinkage weight learnt across all 13 training datasets appears to enable us to extract disease-relevant structure, with projected traits lying close to their training data counterparts, something achieved with disease-specific hard thresholded weights 14 for only the largest datasets.…”

Section: Discussionmentioning

confidence: 99%

“…12 It has also been used to explore structure in genetic association with multiple traits, either through aggregated signals across SNPs according to physical proximity to genes 13 or using a linkage disequilibrium (LD) independent subset of SNPs. 14 In either case, the reduced dimensional space was used to explore the same datasets as used to define it, with two implications. First, GWAS summary statistics are a composite of biological signal, technical noise, and sampling variation.…”

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confidence: 99%

Informed dimension reduction of clinically-related genome-wide association summary data characterises cross-trait axes of genetic risk

Burren

Reales

Wong

et al. 2020

Preprint

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Genome-wide association studies (GWAS) have uncovered pervasive genetic overlap between common clinically related immune-mediated diseases (IMD). To distinguish axes of IMD risk, and extend genetic knowledge of rare IMDs and subtypes, we developed a Bayesian shrinkage approach to perform a disease-focused decomposition of IMD GWAS summary statistics. We derive 13 components which summarise the multidimensional patterns of IMD genetic risk including those related to raised eosinophil count and serum IP-10. Projection of UK Biobank data demonstrated the IMD-specificity and accuracy of our reduced dimension basis in independent datasets. By projecting 22 rare IMD or IMD subtypes onto the basis we were able to identify disease-discriminating components and suggest novel associations. Requiring only summary level data, our approach allows the genetic architectures across any range of clinically-related traits to be characterised in fewer dimensions, facilitating the analysis of studies with modest sample size, where classical GWAS approaches are challenging.

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“…We identified 146 quantitative phenotypes with at least 3,000 observations among the 337,205 white British subjects in the UK Biobank. As previously described, we took non-NA median of multiple measurements across up to three time points (Tanigawa et al, 2019). We focused on food intake, immune cell measurements, gross body measurements, behavioral phenotypes, and several other phenotypes (Table S1).…”

Section: Genetic Association Analysesmentioning

confidence: 99%

Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

DeBoever

Venkatakrishnan

Paggi

et al. 2019

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G protein-coupled receptors (GPCRs) drive an array of important physiological functions and are the targets of nearly one-third of all FDA approved drugs. Large scale genomic initiatives are mapping the genetic diversity in GPCRs, however, a map of which GPCR genetic variants are associated with phenotypic variation and disease is lacking. Furthermore, the mechanistic basis of how the individual GPCR genetic variants regulate molecular function is also largely unknown. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes using data from 337,205 unrelated white British UK Biobank participants and identified 138 associations at a false discovery rate of 5%. We found a novel association between rs12295710 in MRGPRE, a member of the Mas-related receptor family involved in nociception, and migraine risk. We also identified an association between rs3732378, a missense mutation in the binding pocket of CX3CR1, and hypothyroidism. Five orphan GPCRs had eight genetic associations, highlighting novel biology for these receptors of unknown function. We found several associations between GPCR variants and food intake phenotypes, including an association between the variants in TAS2R38 known to affect the ability to taste phenylthiocarbamide and tea intake as well as a non-additive associations between variants in TAS2R19 and TAS2R31 and coffee and tea intake. Finally, we tested whether genetic variants in ADRB2 associated with immune cell amounts and pulmonary function affect downstream signaling pathways and found that two ADRB2 haplotypes are associated with differential signaling relative to the most common haplotype. Overall, this study provides a map of genetic associations for GPCR coding variants across a wide variety of phenotypes that can inform future drug discovery efforts targeting GPCRs.

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Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight adipocyte biology

Cited by 59 publications

References 64 publications

Reported CCR5-∆32 deviation from Hardy-Weinberg equilibrium is explained by poor genotyping of rs62625034

Reported CCR5-∆32 deviation from Hardy-Weinberg equilibrium is explained by poor genotyping of rs62625034

Informed dimension reduction of clinically-related genome-wide association summary data characterises cross-trait axes of genetic risk

Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

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