Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer's Disease Risk Reveal a Potential Role for SIGLEC14

• Published in: Genes Vol. 12; no. 7; p. 1008
• Main Authors: Shaw, Benjamin C, Katsumata, Yuriko, Simpson, James F, Fardo, David W, Estus, Steven
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.06.2021; MDPI
• Subjects: Aged, 80 and over; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Biomarkers - analysis; Brain; Case-Control Studies; Consortia; Copy number; Datasets; DNA Copy Number Variations; Female; Gene Deletion; Gene expression; Genetic analysis; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health risk assessment; Humans; Hypotheses; Immunomodulation; Inflammation; Inflammation - genetics; Kinases; Lectins - genetics; Male; Neurodegenerative diseases; Phagocytosis; Polymorphism; Polymorphism, Single Nucleotide; Proteins; Proteomics; Quantitative Trait Loci; Receptors, Cell Surface - genetics; Risk factors; Single-nucleotide polymorphism; Tyrosine; Variance analysis; United States > US; GWAS; SIGLEC14; copy number variation; ITAM; CNV; ITIM; SIGLEC5
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes12071008

Genome-wide association studies (GWAS) have identified immune-related genes as risk factors for Alzheimer's disease (AD), including and , 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, 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 deletion increases the expression of , 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.