Browsing by Author "Won, Hong-Hee"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Fine-mapping genomic loci refines bipolar disorder risk genes
    (medRxiv, 2024-02-13) Koromina, Maria; Ravi, Ashvin; Panagiotaropoulou, Georgia; Schilder, Brian M.; Humphrey, Jack; Braun, Alice; Bidgeli, Tim; Chatzinakos, Chris; Coombes, Brandon; Kim, Jaeyoung; Liu, Xiaoxi; Terao, Chikashi; O'Connell, Kevin S.; Adams, Mark; Adolfsson, Rolf; Alda, Martin; Alfredsson, Lars; Andlauer, Till F. M.; Andreassen, Ole A.; Antoniou, Anastasia; Baune, Bernhard T.; Bengesser, Susanne; Biernacka, Joanna; Boehnke, Michael; Bosch, Rosa; Cairns, Murray; Carr, Vaughan J.; Casas, Miquel; Catts, Stanley; Cichon, Sven; Corvin, Aiden; Craddock, Nicholas; Dafnas, Konstantinos; Dalkner, Nina; Dannlowski, Udo; Degenhardt, Franziska; Di Florio, Arianna; Dikeos, Dimitris; Fellendorf, Frederike Tabea; Ferentinos, Panagiotis; Forstner, Andreas J.; Forty, Liz; Frye, Mark; Fullerton, Janice M.; Gawlik, Micha; Gizer, Ian R.; Gordon-Smith, Katherine; Green, Melissa J.; Grigoroiu-Serbanescu, Maria; Guzman-Parra, José; Hahn, Tim; Henskens, Frans; Hillert, Jan; Jablensky, Assen V.; Jones, Lisa; Jones, Ian; Jonsson, Lina; Kelsoe, John R.; Kircher, Tilo; Kirov, George; Kittel-Schneider, Sarah; Kogevinas, Manolis; Landén, Mikael; Leboyer, Marion; Lenger, Melanie; Lissowska, Jolanta; Lochner, Christine; Loughland, Carmel; MacIntyre, Donald; Martin, Nicholas G.; Maratou, Eirini; Mathews, Carol A.; Mayoral, Fermin; McElroy, Susan L.; McGregor, Nathaniel W.; McIntosh, Andrew; McQuillin, Andrew; Michie, Patricia; Milanova, Vihra; Mitchell, Philip B.; Moutsatsou, Paraskevi; Mowry, Bryan; Müller-Myhsok, Bertram; Myers, Richard; Nenadić, Igor; Nöthen, Markus M.; O'Donovan, Claire; O'Donovan, Michael; Ophoff, Roel A.; Owen, Michael J.; Pantelis, Chris; Pato, Carlos; Pato, Michele T.; Patrinos, George P.; Pawlak, Joanna M.; Perlis, Roy H.; Porichi, Evgenia; Posthuma, Danielle; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Reininghaus, Eva Z.; Ribasés, Marta; Rietschel, Marcella; Schall, Ulrich; Schulze, Thomas G.; Scott, Laura; Scott, Rodney J.; Serretti, Alessandro; Shannon Weickert, Cynthia; Smoller, Jordan W.; Soler Artigas, Maria; Stein, Dan J.; Streit, Fabian; Toma, Claudio; Tooney, Paul; Vieta, Eduard; Vincent, John B.; Waldman, Irwin D.; Weickert, Thomas; Witt, Stephanie H.; Hong, Kyung Sue; Ikeda, Masashi; Iwata, Nakao; Świątkowska, Beata; Won, Hong-Hee; Edenberg, Howard J.; Ripke, Stephan; Raj, Towfique; Coleman, Jonathan R. I.; Mullins, Niamh; Biochemistry and Molecular Biology, School of Medicine
    Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
  • Thumbnail Image
    Item
    Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
    (Springer Nature, 2021-06) Mullins, Niamh; Forstner, Andreas J.; O'Connell, Kevin S.; Coombes, Brandon; Coleman, Jonathan R.I.; Qiao, Zhen; Als, Thomas D.; Bigdeli, Tim B.; Børte, Sigrid; Bryois, Julien; Charney, Alexander W.; Drange, Ole Kristian; Gandal, Michael J.; Hagenaars, Saskia P.; Ikeda, Masashi; Kamitaki, Nolan; Kim, Minsoo; Krebs, Kristi; Panagiotaropoulou, Georgia; Schilder, Brian M.; Sloofman, Laura G.; Steinberg, Stacy; Trubetskoy, Vassily; Winsvold, Bendik S.; Won, Hong-Hee; Abramova, Liliya; Adorjan, Kristina; Agerbo, Esben; Al Eissa, Mariam; Albani, Diego; Alliey-Rodriguez, Ney; Anjorin, Adebayo; Antilla, Verneri; Antoniou, Anastasia; Awasthi, Swapnil; Baek, Ji Hyun; Bækvad-Hansen, Marie; Bass, Nicholas; Bauer, Michael; Beins, Eva C.; Bergen, Sarah E.; Birner, Armin; Pedersen, Carsten Bøcker; Bøen, Erlend; Boks, Marco P.; Bosch, Rosa; Brum, Murielle; Brumpton, Ben M.; Brunkhorst-Kanaan, Nathalie; Budde, Monika; Bybjerg-Grauholm, Jonas; Byerley, William; Cairns, Murray; Casas, Miquel; Cervantes, Pablo; Clarke, Toni-Kim; Cruceanu, Cristiana; Cuellar-Barboza, Alfredo; Cunningham, Julie; Curtis, David; Czerski, Piotr M.; Dale, Anders M.; Dalkner, Nina; David, Friederike S.; Degenhardt, Franziska; Djurovic, Srdjan; Dobbyn, Amanda L.; Douzenis, Athanassios; Elvsåshagen, Torbjørn; Escott-Price, Valentina; Ferrier, I. Nicol; Fiorentino, Alessia; Foroud, Tatiana M.; Forty, Liz; Frank, Josef; Frei, Oleksandr; Freimer, Nelson B.; Frisén, Louise; Gade, Katrin; Garnham, Julie; Gelernter, Joel; Pedersen, Marianne Giørtz; Gizer, Ian R.; Gordon, Scott D.; Gordon-Smith, Katherine; Greenwood, Tiffany A.; Grove, Jakob; Guzman-Parra, José; Ha, Kyooseob; Haraldsson, Magnus; Hautzinger, Martin; Heilbronner, Urs; Hellgren, Dennis; Herms, Stefan; Hoffmann, Per; Holmans, Peter A.; Huckins, Laura; Jamain, Stéphane; Johnson, Jessica S.; Kalman, Janos L.; Kamatani, Yoichiro; Kennedy, James L.; Kittel-Schneider, Sarah; Knowles, James A.; Kogevinas, Manolis; Koromina, Maria; Kranz, Thorsten M.; Kranzler, Henry R.; Kubo, Michiaki; Kupka, Ralph; Kushner, Steven A.; Lavebratt, Catharina; Lawrence, Jacob; Leber, Markus; Lee, Heon-Jeong; Lee, Phil H.; Levy, Shawn E.; Lewis, Catrin; Liao, Calwing; Lucae, Susanne; Lundberg, Martin; MacIntyre, Donald J.; Magnusson, Sigurdur H.; Maier, Wolfgang; Maihofer, Adam; Malaspina, Dolores; Maratou, Eirini; Martinsson, Lina; Mattheisen, Manuel; McCarroll, Steven A.; McGregor, Nathaniel W.; McGuffin, Peter; McKay, James D.; Medeiros, Helena; Medland, Sarah E.; Millischer, Vincent; Montgomery, Grant W.; Moran, Jennifer L.; Morris, Derek W.; Mühleisen, Thomas W.; O'Brien, Niamh; O'Donovan, Claire; Loohuis, Loes M. Olde; Oruc, Lilijana; Papiol, Sergi; Pardiñas, Antonio F.; Perry, Amy; Pfennig, Andrea; Porichi, Evgenia; Potash, James B.; Quested, Digby; Raj, Towfique; Rapaport, Mark H.; DePaulo, J. Raymond; Regeer, Eline J.; Rice, John P.; Rivas, Fabio; Rivera, Margarita; Roth, Julian; Roussos, Panos; Ruderfer, Douglas M.; Sánchez-Mora, Cristina; Schulte, Eva C.; Senner, Fanny; Sharp, Sally; Shilling, Paul D.; Sigurdsson, Engilbert; Sirignano, Lea; Slaney, Claire; Smeland, Olav B.; Smith, Daniel J.; Sobell, Janet L.; Søholm Hansen, Christine; Artigas, Maria Soler; Spijker, Anne T.; Stein, Dan J.; Strauss, John S.; Świątkowska, Beata; Terao, Chikashi; Thorgeirsson, Thorgeir E.; Toma, Claudio; Tooney, Paul; Tsermpini, Evangelia-Eirini; Vawter, Marquis P.; Vedder, Helmut; Walters, James T.R.; Witt, Stephanie H.; Xi, Simon; Xu, Wei; Yang, Jessica Mei Kay; Young, Allan H.; Young, Hannah; Zandi, Peter P.; Zhou, Hang; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Alda, Martin; Alfredsson, Lars; Babadjanova, Gulja; Backlund, Lena; Baune, Bernhard T.; Bellivier, Frank; Bengesser, Susanne; Berrettini, Wade H.; Blackwood, Douglas H.R.; Boehnke, Michael; Børglum, Anders D.; Breen, Gerome; Carr, Vaughan J.; Catts, Stanley; Corvin, Aiden; Craddock, Nicholas; Dannlowski, Udo; Dikeos, Dimitris; Esko, Tõnu; Etain, Bruno; Ferentinos, Panagiotis; Frye, Mark; Fullerton, Janice M.; Gawlik, Micha; Gershon, Elliot S.; Goes, Fernando S.; Green, Melissa J.; Grigoroiu-Serbanescu, Maria; Hauser, Joanna; Henskens, Frans; Hillert, Jan; Hong, Kyung Sue; Hougaard, David M.; Hultman, Christina M.; Hveem, Kristian; Iwata, Nakao; Jablensky, Assen V.; Jones, Ian; Jones, Lisa A.; Kahn, René S.; Kelsoe, John R.; Kirov, George; Landén, Mikael; Leboyer, Marion; Lewis, Cathryn M.; Li, Qingqin S.; Lissowska, Jolanta; Lochner, Christine; Loughland, Carmel; Martin, Nicholas G.; Mathews, Carol A.; Mayoral, Fermin; McElroy, Susan L.; McIntosh, Andrew M.; McMahon, Francis J.; Melle, Ingrid; Michie, Patricia; Milani, Lili; Mitchell, Philip B.; Morken, Gunnar; Mors, Ole; Mortensen, Preben Bo; Mowry, Bryan; Müller-Myhsok, Bertram; Myers, Richard M.; Neale, Benjamin M.; Nievergelt, Caroline M.; Nordentoft, Merete; Nöthen, Markus M.; O'Donovan, Michael C.; Oedegaard, Ketil J.; Olsson, Tomas; Owen, Michael J.; Paciga, Sara A.; Pantelis, Chris; Pato, Carlos; Pato, Michele T.; Patrinos, George P.; Perlis, Roy H.; Posthuma, Danielle; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Reininghaus, Eva Z.; Ribasés, Marta; Rietschel, Marcella; Ripke, Stephan; Rouleau, Guy A.; Saito, Takeo; Schall, Ulrich; Schalling, Martin; Schofield, Peter R.; Schulze, Thomas G.; Scott, Laura J.; Scott, Rodney J.; Serretti, Alessandro; Weickert, Cynthia Shannon; Smoller, Jordan W.; Stefansson, Hreinn; Stefansson, Kari; Stordal, Eystein; Streit, Fabian; Sullivan, Patrick F.; Turecki, Gustavo; Vaaler, Arne E.; Vieta, Eduard; Vincent, John B.; Waldman, Irwin D.; Weickert, Thomas W.; Werge, Thomas; Wray, Naomi R.; Zwart, John-Anker; Biernacka, Joanna M.; Nurnberger, John I.; Cichon, Sven; Edenberg, Howard J.; Stahl, Eli A.; McQuillin, Andrew; Florio, Arianna Di; Ophoff, Roel A.; Andreassen, Ole A.; Medical and Molecular Genetics, School of Medicine
    Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
  • Thumbnail Image
    Item
    Identifying genetic variants for amyloid β in subcortical vascular cognitive impairment
    (Frontiers Media, 2023-04-18) Kim, Hang-Rai; Jung, Sang-Hyuk; Kim, Beomsu; Kim, Jaeho; Jang, Hyemin; Kim, Jun Pyo; Kim, So Yeon; Na, Duk L.; Kim, Hee Jin; Nho, Kwangsik; Won, Hong-Hee; Seo, Sang Won; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Background: The genetic basis of amyloid β (Aβ) deposition in subcortical vascular cognitive impairment (SVCI) is still unknown. Here, we investigated genetic variants involved in Aβ deposition in patients with SVCI. Methods: We recruited a total of 110 patients with SVCI and 424 patients with Alzheimer's disease-related cognitive impairment (ADCI), who underwent Aβ positron emission tomography and genetic testing. Using candidate AD-associated single nucleotide polymorphisms (SNPs) that were previously identified, we investigated Aβ-associated SNPs that were shared or distinct between patients with SVCI and those with ADCI. Replication analyses were performed using the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Rush Memory and Aging Project cohorts (ROS/MAP). Results: We identified a novel SNP, rs4732728, which showed distinct associations with Aβ positivity in patients with SVCI (P interaction = 1.49 × 10-5); rs4732728 was associated with increased Aβ positivity in SVCI but decreased Aβ positivity in ADCI. This pattern was also observed in ADNI and ROS/MAP cohorts. Prediction performance for Aβ positivity in patients with SVCI increased (area under the receiver operating characteristic curve = 0.780; 95% confidence interval = 0.757-0.803) when rs4732728 was included. Cis-expression quantitative trait loci analysis demonstrated that rs4732728 was associated with EPHX2 expression in the brain (normalized effect size = -0.182, P = 0.005). Conclusion: The novel genetic variants associated with EPHX2 showed a distinct effect on Aβ deposition between SVCI and ADCI. This finding may provide a potential pre-screening marker for Aβ positivity and a candidate therapeutic target for SVCI.
  • Thumbnail Image
    Item
    Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population
    (BMC, 2021-06-21) Kim, Hang-Rai; Jung, Sang-Hyuk; Kim, Jaeho; Jang, Hyemin; Kang, Sung Hoon; Hwangbo, Song; Kim, Jun Pyo; Kim, So Yeon; Kim, Beomsu; Kim, Soyeon; Jeong, Jee Hyang; Yoon, Soo Jin; Park, Kyung Won; Kim, Eun-Joo; Yoon, Bora; Jang, Jae-Won; Hong, Jin Yong; Choi, Seong Hye; Noh, Young; Kim, Ko Woon; Kim, Si Eun; Lee, Jin San; Jung, Na-Yeon; Lee, Juyoun; Kim, Byeong C.; Son, Sang Joon; Hong, Chang Hyung; Na, Duk L.; Seo, Sang Won; Won, Hong-Hee; Kim, Hee Jin; Radiology and Imaging Sciences, School of Medicine
    Background: Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer's disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods: One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results: In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10-8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74-0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion: The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.
  • Thumbnail Image
    Item
    Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study
    (IOS, 2021) Kim, Soyeon; Kim, Kiwon; Nho, Kwangsik; Myung, Woojae; Won, Hong-Hee; Radiology and Imaging Sciences, School of Medicine
    Background: Whether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer’s disease (AD) is causal remains unclear. Recent failures to demonstrate the efficacy of several Aβ-modifying drugs may indicate a possibility that the observed association is not causal, which led to efforts to develop tau-directed treatments whose efficacy remains tentative. Methods: Herein, we conducted a two-sample Mendelian randomisation analysis to investigate shared genetic background between cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and risk for AD, and to find genetic evidence for causal association between these CSF biomarkers and risk for AD. We used summary statistics of genome-wide association study (GWAS) for CSF biomarkers (Aβ 1-42 , phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively-normal controls. We tested association between changes in the genetically-predicted CSF biomarkers and LOAD risk. Results: We found a decrease in the LOAD risk per one-standard deviation (SD) increase in the genetically-predicted CSF Aβ (odds ratio [OR], 2.87×10 -3 for AD; 95% confidence interval [CI], 1.54×10 -4 –0.05; p = 8.91×10 -5 ). Conversely, we observed an increase in the LOAD risk per one-SD increase in the genetically-predicted CSF p-tau (OR, 19.46; 95% CI, 1.50–2.52×10 2 ; p = 0.02) and t-tau (OR, 33.80; 95% CI, 1.57–7.29×10 2 ; p = 0.02). Conclusions: Our findings suggest a shared genetic background between the CSF biomarkers and LOAD risk. Although it requires validation by future studies including more genetic variants identified in large-scale GWASs for CSF biomarkers, our results suggest a causal association between CSF biomarkers and risk for LOAD.