Biology subjects

Deming, Y.

Publications and source records attributed to Deming, Y..

3 recordsLinked to original sources

bioRxiv2018

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15x10-15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

genomics↗

bioRxiv2018

Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

Gene-based tests to study the combined effect of rare variants towards a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially for complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We have examined the performance of several collapsing, variance-component and transmission disequilibrium tests across eight different software and twenty-two models utilizing a cohort of 285 families (N=1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the studied phenotype with high confidence and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, MAS1L) as candidates genes for familial LOAD.

genetics↗

bioRxiv2017

A common haplotype lowers SPI1 (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease

In this study we used age at onset of Alzheimers disease (AD), cerebrospinal fluid (CSF) biomarkers, and cis-expression quantitative trait loci (cis-eQTL) datasets to identify candidate causal genes and mechanisms underlying AD GWAS loci. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (P < 5x10-8) or suggestively (P < 1x10-5) associated with age at onset-defined survival (AAOS) and a further fourteen novel loci reached suggestive significance. Using stratified LD score regression we demonstrated a significant enrichment of AD heritability in hematopoietic cells of the myeloid and B-lymphoid lineage. We then investigated the impact of these 22 AAOS-associated variants on CSF biomarkers and gene expression in cells of the myeloid lineage. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (P=8.40x10-6), higher CSF levels of A{beta}42 (P=1.2x10-4), and lower expression of SPI1 in monocytes (P=1.50x10-105) and macrophages (P=6.41x10-87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD-associated genes, APOE, CLU/APOJ, CD33, MS4A4A/MS4A6A, and TYROBP. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.

neuroscience↗