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PPP CT-LDSC (Han et al 2020, Asthma)

I applied Cross Trait Linkage Disequilibrium Score Regression (CT-LDSC)1 to estimate genetic correlation between the Han et al.2 GWAS of Asthma and the Olink proteomic 3 GWAS of the European discovery cohort of the UK Biobank Pharma Proteomics Project (UKBB PPP)4.

Results

As is standard for LDSC analysis, I restricted the summary statistics to Hapmap 3 variants, and excluded the MHC region. I used the standard thousand genomes linkage disequilibrium scores provided by the authors of LDSC. To focus on trans effects, I excluded the cis regions from the proteomic GWAS.

The results are below:

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Columns: oid: Olink assay ID; gene: name of gene/protein under study; rg: CT-LDSC genetic correlation estimate; rg_se: jackknife standard error of CT-LDSC genetic correlation estimate; rg_p: p value of test that rg is not zero; gcov: estimated genetic covariance; inter: intercept term in CT-LDSC regression; h2_trait: trait heritability estimate; h2_prot: protein heritability estimate; n_snps: number of hapmap3 variants included; spr: for cases in which multiple rows corresponding to distinct Olink assays of the same protein have been merged into a single row, this gives the maximum spread between the rg values of the merged rows; s_bh: True if the null hypothesis is rejected under the Benjamini-Hochberg procedure at an FDR of 0.05; s_bon: True if the null hypothesis is rejected under the Bonferroni correction at a significance level of 0.05.

Interpretation

  • The top most-significant protein is CLC (Charcot-Leyden Crystal Galectin). Given that CLC is known to be expressed on eosinophils, and eosinophils are known to be important to allergy and asthma, one can make argument for the plausibility of the genetic correlation between asthma and plasma CLC.

  1. Brendan Bulik-Sullivan, Hilary K Finucane, Verneri Anttila, Alexander Gusev, Felix R Day, Po-Ru Loh, ReproGen Consortium, Psychiatric Genomics Consortium, Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3, Laramie Duncan, and others. An atlas of genetic correlations across human diseases and traits. Nature Genetics, 47(11):1236–1241, 2015. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC4797329/. ↩

  2. Yi Han, Qiong Jia, Pedram Shafiei Jahani, Benjamin P Hurrell, Calvin Pan, Pin Huang, Janet Gukasyan, Nicholas C Woodward, Eleazar Eskin, Frank D Gilliland, and others. Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma. Nature Communications, 11(1):1776, 2020. URL: https://www.nature.com/articles/s41467-020-15649-3. ↩

  3. Lotta Wik, Niklas Nordberg, John Broberg, Johan Björkesten, Erika Assarsson, Sara Henriksson, Ida Grundberg, Erik Pettersson, Christina Westerberg, Elin Liljeroth, and others. Proximity extension assay in combination with next-generation sequencing for high-throughput proteome-wide analysis. Molecular & Cellular Proteomics, 20:100168, 2021. URL: https://www.sciencedirect.com/science/article/pii/S1535947621001407. ↩

  4. Benjamin B Sun, Joshua Chiou, Matthew Traylor, Christian Benner, Yi-Hsiang Hsu, Tom G Richardson, Praveen Surendran, Anubha Mahajan, Chloe Robins, Steven G Vasquez-Grinnell, and others. Plasma proteomic associations with genetics and health in the UK Biobank. Nature, 622(7982):329–338, 2023. URL: https://www.nature.com/articles/s41586-023-06592-6. ↩