Browsing by Author "Liu, Yiyuan"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes
    (Springer Nature, 2021-03-12) Novikova, Gloriia; Kapoor, Manav; TCW, Julia; Abud, Edsel M.; Efthymiou, Anastasia G.; Chen, Steven X.; Cheng, Haoxiang; Fullard, John F.; Bendl, Jaroslav; Liu, Yiyuan; Roussos, Panos; Björkegren, Johan LM; Liu, Yunlong; Poon, Wayne W.; Hao, Ke; Marcora, Edoardo; Goate, Alison M.; Medical and Molecular Genetics, School of Medicine
    Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
  • Thumbnail Image
    Item
    Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons
    (Society for Neuroscience, 2024-04-17) Prytkova, Iya; Liu, Yiyuan; Fernando, Michael; Gameiro-Ros, Isabel; Popova, Dina; Kamarajan, Chella; Xuei, Xiaoling; Chorlian, David B.; Edenberg, Howard J.; Tischfield, Jay A.; Porjesz, Bernice; Pang, Zhiping P.; Hart, Ronald P.; Goate, Alison; Slesinger, Paul A.; Medical and Molecular Genetics, School of Medicine
    Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the KCNJ6 gene. KCNJ6 encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating KCNJ6 using an isogenic approach with human glutamatergic neurons derived from induced pluripotent stem cells (male and female donors). Using multielectrode arrays, population calcium imaging, single-cell patch-clamp electrophysiology, and mitochondrial stress tests, we find that elevated GIRK2 acts in concert with 7–21 d of ethanol exposure to inhibit neuronal activity, to counteract ethanol-induced increases in glutamate response, and to promote an increase intrinsic excitability. Furthermore, elevated GIRK2 prevented ethanol-induced changes in basal and activity-dependent mitochondrial respiration. These data support a role for GIRK2 in mitigating the effects of ethanol and a previously unknown connection to mitochondrial function in human glutamatergic neurons.