Browsing by Author "Marcora, Edoardo"

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    Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference
    (Wiley, 2024) Kloske, Courtney M.; Belloy, Michael E.; Blue, Elizabeth E.; Bowman, Gregory R.; Carrillo, Maria C.; Chen, Xiaoying; Chiba-Falek, Ornit; Davis, Albert A.; Di Paolo, Gilbert; Garretti, Francesca; Gate, David; Golden, Lesley R.; Heinecke, Jay W.; Herz, Joachim; Huang, Yadong; Iadecola, Costantino; Johnson, Lance A.; Kanekiyo, Takahisa; Karch, Celeste M.; Khvorova, Anastasia; Koppes-den Hertog, Sascha J.; Lamb, Bruce T.; Lawler, Paige E.; Le Guen, Yann; Litvinchuk, Alexandra; Liu, Chia-Chen; Mahinrad, Simin; Marcora, Edoardo; Marino, Claudia; Michaelson, Danny M.; Miller, Justin J.; Morganti, Josh M.; Narayan, Priyanka S.; Naslavsky, Michel S.; Oosthoek, Marlies; Ramachandran, Kapil V.; Ramakrishnan, Abhirami; Raulin, Ana-Caroline; Robert, Aiko; Saleh, Rasha N. M.; Sexton, Claire; Shah, Nilomi; Shue, Francis; Sible, Isabel J.; Soranno, Andrea; Strickland, Michael R.; Tcw, Julia; Thierry, Manon; Tsai, Li-Huei; Tuckey, Ryan A.; Ulrich, Jason D.; van der Kant, Rik; Wang, Na; Wellington, Cheryl L.; Weninger, Stacie C.; Yassine, Hussein N.; Zhao, Na; Bu, Guojun; Goate, Alison M.; Holtzman, David M.; Neurology, School of Medicine
    Introduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. Methods: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. Results: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. Discussion: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. Highlights: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.
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    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.
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    Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases
    (Springer Nature, 2021-08-20) Kapoor, Manav; Chao, Michael J.; Johnson, Emma C.; Novikova, Gloriia; Lai, Dongbing; Meyers, Jacquelyn L.; Schulman, Jessica; Nurnberger, John I., Jr.; Porjesz, Bernice; Liu, Yunlong; Foroud, Tatiana; Edenberg, Howard J.; Marcora, Edoardo; Agrawal, Arpana; Goate, Alison; Medical and Molecular Genetics, School of Medicine
    Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.
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    Novel rare variant associations with late‐life cognitive performance
    (Wiley, 2025-01-09) Regelson, Alexandra N.; Archer, Derek B.; Durant, Alaina; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo-Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse; Bush, William S.; Kuzma, Amanda B.; Cuccaro, Michael L.; Cruchaga, Carlos; Farrer, Lindsay A.; Wang, Li-San; Schellenberg, Gerard D.; Mayeux, Richard; Kukull, Walter A.; Keene, C. Dirk; Saykin, Andrew J.; Johnson, Sterling C.; Engelman, Corinne D.; Bennett, David A.; Barnes, Lisa L.; Larson, Eric B.; Nho, Kwangsik; Goate, Alison M.; Renton, Alan E.; Marcora, Edoardo; Fulton-Howard, Brian; Patel, Tulsi; Risacher, Shannon L.; DeStefano, Anita L.; Schneider, Julie A.; Habes, Mohamad; Seshadri, Sudha; Satizabal, Claudia L.; Maillard, Pauline; Toga, Arthur W.; Crawford, Karen; Tosun, Duygu; Vance, Jeffery M.; Mormino, Elizabeth; DeCarli, Charles S.; Montine, Thomas J.; Beecham, Gary; Biber, Sarah A.; De Jager, Philip L.; Vardarajan, Badri N.; Lee, Annie J.; Brickman, Adam M.; Reitz, Christiane; Manly, Jennifer J.; Lu, Qiongshi; Rentería, Miguel Arce; Deming, Yuetiva; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Crane, Paul K.; Hohman, Timothy J.; Dumitrescu, Logan C.; Medical and Molecular Genetics, School of Medicine
    Background: Despite evidence that Alzheimer’s disease (AD) is highly heritable, there remains substantial “missing” heritability, likely due in part to the effect of rare variants and to the past reliance on case‐control analysis. Here, we leverage powerful endophenotypes of AD (cognitive performance across multiple cognitive domains) in a rare variant analysis to identify novel genetic drivers of cognition in aging and disease. Method: We leveraged 8 cohorts of cognitive aging with whole genome sequencing data from the AD Sequencing Project to conduct rare variant analyses of multiple domains of cognition (N = 9,317; mean age = 73; 56% female; 52% cognitively unimpaired). Harmonized scores for memory, executive function, and language were derived using confirmatory factor analysis models. Participants genetically similar to the 1000Genomes EUR reference panel were included in analysis. Variants included in the analysis had a minor allele frequency < 0.01, a minor allele count of ≥ 10, and were annotated as a high or moderate impact SNP using VEP. Associations of baseline scores in each cognitive domain were performed using SKAT‐O, including 92,905 rare variants among 16,243 genes. All tests were adjusted for sex, baseline age, sequencing center and platform, and genetic principal components. Correction for multiple comparisons was completed using the Benjamini‐Hochberg false discovery rate (FDR) procedure. Result: APOE was associated with baseline memory, language, and executive function, though only memory survived multiple‐test correction (p.FDR = 0.001). Outside of APOE, ITPKB was associated with baseline executive function (p.FDR = 0.048). AKTIP, SHCBP1L, and CCNF showed nominal associations with multiple domains of cognition that did not survive correction for multiple comparisons (p.FDRs<0.07). Conclusion: These results highlight novel rare variants associated with cognition. IPTKB is an AGORA nominated gene target for potential AD treatment. It is important in the regulation of immune cells and displays higher expression in the cortex of AD patients compared to controls. CCNF and AKTIP are brain eQTLs and have differential RNA expression in AD brains. Previously, variants in AKTIP have been associated with educational attainment, intelligence, and memory, while variants in CCNF have been associated with neuritic plaques and neurofibrillary tangles. Future analyses will incorporate longitudinal cognition and expand into additional populations.