Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer’s Disease Risk Reveal a Potential Role for SIGLEC14
Genome-wide association studies (GWAS) have identified immune-related genes as risk factors for Alzheimer’s disease (AD), including TREM2 and CD33, frequently passing a stringent false-discovery rate. These genes either encode or signal through immunomodulatory tyrosine-phosphorylated inhibitory motifs (ITIMs) or activation motifs (ITAMs) and govern processes critical to AD pathology, such as inflammation and amyloid phagocytosis. To investigate whether additional ITIM and ITAM-containing family members may contribute to AD risk and be overlooked due to the stringent multiple testing in GWAS, we combined protein quantitative trait loci (pQTL) data from a recent plasma proteomics study with AD associations in a recent GWAS. We found that pQTLs for genes encoding ITIM/ITAM family members were more frequently associated with AD than those for non-ITIM/ITAM genes. Further testing of one family member, SIGLEC14 which encodes an ITAM, uncovered substantial copy number variations, identified an SNP as a proxy for gene deletion, and found that gene expression correlates significantly with gene deletion. We also found that SIGLEC14 deletion increases the expression of SIGLEC5, an ITIM. We conclude that many genes in this ITIM/ITAM family likely impact AD risk, and that complex genetics including copy number variation, opposing function of encoded proteins, and coupled gene expression may mask these AD risk associations at the genome-wide level.
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This work was funded by grants R21AG068370 (S.E.), RF1AG059717 (S.E.), RF1AG059717-01S1 (S.E. & B.C.S.), R56AG057191 (D.W.F. & Y.K.), R01AG057187 (D.W.F. & Y.K.), R21AG061551 (D.W.F. & Y.K.), R01AG054060 (D.W.F. & Y.K.), and the UK-ADC P30AG028383 from the National Institute on Aging.
The Sun et al. proteomics dataset is available through the supplementary materials provided in the original publication, accessed on 30 January 2020 .
The Jansen et al. AD summary statistics are available through: https://ctg.cncr.nl/software/summary_statistics, accessed on 10 January 2019.
The following are available online at https://www.mdpi.com/article/10.3390/genes12071008/s1, Figure S1: Whole genome sequencing (WGS) read depth data from the Alzheimer’s Disease Sequencing Project (ASDP) in Caucasian population, Figure S2: WGS read depth data from the ASDP in African American population, Figure S3: WGS read depth data from the ASDP in all other populations, Table S1: List of ITIM/ITAM genes and their aliases.
The above materials are also available for download as the additional file listed at the end of this record.
Shaw, Benjamin C.; Katsumata, Yuriko; Simpson, James F.; Fardo, David W.; and Estus, Steven, "Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer’s Disease Risk Reveal a Potential Role for SIGLEC14" (2021). Biostatistics Faculty Publications. 53.
Published in Genes, v. 12, issue 7, 1008.
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