Ferkingstad E, Sulem P, Atlason BA, Sveinbjornsson G, Magnusson MI, Styrmisdottir EL, Gunnarsdottir K, Helgason A, Oddsson A, Halldorsson BV, Jensson BO, Zink F, Halldorsson GH, Masson G, Arnadottir GA, Katrinardottir H, Juliusson K, Magnusson MK, Magnusson OT, Fridriksdottir R, Saevarsdottir S, Gudjonsson SA, Stacey SN, Rognvaldsson S, Eiriksdottir T, Olafsdottir TA, Steinthorsdottir V, Tragante V, Ulfarsson MO, Stefansson H, Jonsdottir I, Holm H, Rafnar T, Melsted P, Saemundsdottir J, Norddahl GL, Lund SH, Gudbjartsson DF, Thorsteinsdottir U, Stefansson K. Large-scale integration of the plasma proteome with genetics and disease. Nature Genetics, December 2, 2021

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  1. This study is a massive undertaking, relating genetic variants to protein levels in plasma. Proteomics measured in biofluids provides impelling opportunities to study in great detail how genetic risk factors impact on disease pathogenesis in patients.

    Ferkingstad et al. used this approach and measured in existing blood samples proteomics with the aptamer approach of Somascan in 35,559 individuals, which is almost 15 percent of the total population of Iceland. Note that part of these samples were enriched for cancer as they were acquired in the context of the Icelandic Cancer project.   

    About a quarter of proteins showed cis associations, meaning that a variant in a given gene was related to plasma concentrations of the corresponding protein. The majority of associations were, however, trans, with a given variant influencing concentrations of another protein than it encodes. One of those trans associations was a variant cluster surrounding the MS4A6A and MSA4A genes, which are expressed in microglia. Variants in those genes have been associated with Alzheimer’s disease before, and in this study were associated with lower plasma concentrations of TREM2, replicating another study (Deming et al., 2019).

    TREM2 itself also has known AD risk variants. The authors do not go into detail on those relationships, although they suggest that certain variants may lead to artefactual measures of plasma TREM2 with Somascan. A previous study comparing rare TREM2 variants on plasma TREM2 levels did not find clear associations (Ashton et al., 2019). Together these results further support involvement of microglia in AD disease pathogenesis. However, from the main text it was unclear whether the presence of AD pathology in individuals carrying the variants was assessed, as well as their clinical diagnosis and age.

    In the case of Alzheimer’s disease, it would be of interest to measure plasma p-tau levels as well to further understand which gene-protein concentrations may be related to amyloid pathology in the brain. Finally, it would be interesting to study whether gene-protein associations would be similar for cerebrospinal fluid.

    References:

    Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, Li Z, Del-Aguila JL, Dube U, Farias FG, Bradley J, Budde J, Ibanez L, Fernandez MV, Blennow K, Zetterberg H, Heslegrave A, Johansson PM, Svensson J, Nellgård B, Lleo A, Alcolea D, Clarimon J, Rami L, Molinuevo JL, Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Ewers M, Harari O, Haass C, Brett TJ, Benitez BA, Karch CM, Piccio L, Cruchaga C. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk. Sci Transl Med. 2019 Aug 14;11(505) PubMed.

    Ashton NJ, Suárez-Calvet M, Heslegrave A, Hye A, Razquin C, Pastor P, Sanchez-Valle R, Molinuevo JL, Visser PJ, Blennow K, Hodges AK, Zetterberg H. Plasma levels of soluble TREM2 and neurofilament light chain in TREM2 rare variant carriers. Alzheimers Res Ther. 2019 Nov 28;11(1):94. PubMed.

    View all comments by Pieter Jelle Visser

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  1. Massive Proteomics Study Connects Genes, Proteins, Disease