1. Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer's Disease Risk Reveal a Potential Role for SIGLEC14
- Author
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Yuriko Katsumata, David W. Fardo, Steven Estus, James F. Simpson, and Benjamin C. Shaw
- Subjects
0301 basic medicine ,Male ,DNA Copy Number Variations ,Quantitative Trait Loci ,SIGLEC5 ,CNV ,Genome-wide association study ,Receptors, Cell Surface ,QH426-470 ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,ITAM ,SIGLEC14 ,Lectins ,Gene expression ,Genetics ,SNP ,Humans ,GWAS ,Copy-number variation ,Gene ,Genetics (clinical) ,Genetic association ,Aged, 80 and over ,Inflammation ,TREM2 ,copy number variation ,ITIM ,030104 developmental biology ,Case-Control Studies ,Female ,030217 neurology & neurosurgery ,Biomarkers ,Gene Deletion ,Genome-Wide Association Study - Abstract
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.
- Published
- 2021