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PPP CT-LDSC (PGC 2022, Schizophrenia)

I applied Cross Trait Linkage Disequilibrium Score Regression (CT-LDSC)1 to estimate genetic correlation between the 2022 PGC GWAS of schizophrenia2 and the Olink proteomic 3 GWAS from 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

ICAM5 is the only Bonferroni-significant protein. The NCBI description of ICAM5 says that "This protein is expressed on the surface of telencephalic neurons and displays two types of adhesion activity, homophilic binding between neurons and heterophilic binding between neurons and leukocytes. It may be a critical component in neuron-microglial cell interactions in the course of normal development or as part of neurodegenerative diseases". Thus, at a high level, it is at least plausible that ICAM5 should play a role in schizophrenia, a disease of the central nervous system. It is unclear, however, how increased levels of ICAM5 in the plasma would relate to pathological processes in the central nervous system, given that in theory the blood-brain barrier should separate the CNS from the plasma.

  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. Vassily Trubetskoy, Antonio F Pardiñas, Ting Qi, Georgia Panagiotaropoulou, Swapnil Awasthi, Tim B Bigdeli, Julien Bryois, Chia-Yen Chen, Charlotte A Dennison, Lynsey S Hall, and others. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604(7906):502–508, 2022. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC9392466/. ↩

  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. ↩