Browsing by Author "Raj, Towfique"
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Item Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism(Springer Nature, 2019-02-14) Kapoor, Manav; Wang, Jen-Chyong; Farris, Sean P.; Liu, Yunlong; McClintick, Jeanette; Gupta, Ishaan; Meyers, Jacquelyn L.; Bertelsen, Sarah; Chao, Michael; Nurnberger, John; Tischfield, Jay; Harari, Oscar; Zeran, Li; Hesselbrock, Victor; Bauer, Lance; Raj, Towfique; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Edenberg, Howard J.; Mayfield, R. Dayne; Goate, Alison; Medical and Molecular Genetics, School of MedicineAlcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank's alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.Item Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals(American Medical Association, 2015-11) Ghani, Mahdi; Reitz, Christiane; Cheng, Rong; Vardarajan, Badri Narayan; Jun, Gyungah; Sato, Christine; Naj, Adam; Rajbhandary, Ruchita; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick A.; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Lee, Joseph H.; Schellenberg, Gerard D.; St. George-Hyslop, Peter; Mayeux, Richard; Rogaeva, Ekaterina; Department of Psychiatry, IU School of MedicineIMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.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 MedicineBipolar 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).Item Genetic architecture of age-related cognitive decline in African Americans(American Academy of Neurology, 2016-12-21) Raj, Towfique; Chibnik, Lori B.; McCabe, Cristin; Wong, Andus; Replogle, Joseph M.; Yu, Lei; Gao, Sujuan; Unverzagt, Frederick W.; Stranger, Barbara; Murrell, Jill; Barnes, Lisa; Hendrie, Hugh C.; Foroud, Tatiana; Krichevsky, Anna; Bennett, David A.; Hall, Kathleen S.; Evans, Denis A.; De Jager, Philip L.; Department of Biostatistics, Richard M. Fairbanks School of Public HealthOBJECTIVE: To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs). METHODS: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS. RESULTS: We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility. CONCLUSIONS: The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD.Item Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria(Wiley, 2019-06-04) Lai, Dongbing; Wetherill, Leah; Bertelsen, Sarah; Carey, Caitlin E.; Kamarajan, Chella; Kapoor, Manav; Meyers, Jacquelyn L.; Anokhin, Andrey P.; Bennett, David A.; Bucholz, Kathleen K.; Chang, Katharine K.; Jager, Philip L. De; Dick, Danielle M.; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John I.; Raj, Towfique; Schuckit, Marc; Scott, Denise M.; Taylor, Robert E.; Tischfield, Jay; Hariri, Ahmad R.; Edenberg, Howard J.; Agrawal, Arpana; Bogdan, Ryan; Porjesz, Bernice; Goate, Alison M.; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineGenome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (e.g., ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWASs of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7,418 (1,121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3,175 (585 families) African American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (p=4.16E-11) and Desire to cut drinking (p=1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, p=6.72E-09); rs1912461 (chromosome 15, Time spent drinking, p=1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, p=8.42E-11); rs7597960 (chromosome 2, Time spent drinking, p=1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (p<0.01; 0.61-1.82% of variance). Identified novel variants (i.e., rs1912461, rs61826952) were associated with differential central evoked theta power (loss minus gain; p=0.0037) and reward-related ventral striatum reactivity (p=0.008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.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 MedicineBipolar 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.Item New insights into the genetic etiology of Alzheimer's disease and related dementias(Springer Nature, 2022) Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E.; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf; Naj, Adam C.; Campos-Martin, Rafael; Grenier-Boley, Benjamin; Andrade, Victor; Holmans, Peter A.; Boland, Anne; Damotte, Vincent; van der Lee, Sven J.; Costa, Marcos R.; Kuulasmaa, Teemu; Yang, Qiong; de Rojas, Itziar; Bis, Joshua C.; Yaqub, Amber; Prokic, Ivana; Chapuis, Julien; Ahmad, Shahzad; Giedraitis, Vilmantas; Aarsland, Dag; Garcia-Gonzalez, Pablo; Abdelnour, Carla; Alarcón-Martín, Emilio; Alcolea, Daniel; Alegret, Montserrat; Alvarez, Ignacio; Álvarez, Victoria; Armstrong, Nicola J.; Tsolaki, Anthoula; Antúnez, Carmen; Appollonio, Ildebrando; Arcaro, Marina; Archetti, Silvana; Arias Pastor, Alfonso; Arosio, Beatrice; Athanasiu, Lavinia; Bailly, Henri; Banaj, Nerisa; Baquero, Miquel; Barral, Sandra; Beiser, Alexa; Belén Pastor, Ana; Below, Jennifer E.; Benchek, Penelope; Benussi, Luisa; Berr, Claudine; Besse, Céline; Bessi, Valentina; Binetti, Giuliano; Bizarro, Alessandra; Blesa, Rafael; Boada, Mercè; Boerwinkle, Eric; Borroni, Barbara; Boschi, Silvia; Bossù, Paola; Bråthen, Geir; Bressler, Jan; Bresner, Catherine; Brodaty, Henry; Brookes, Keeley J.; Brusco, Luis Ignacio; Buiza-Rueda, Dolores; Bûrger, Katharina; Burholt, Vanessa; Bush, William S.; Calero, Miguel; Cantwell, Laura B.; Chene, Geneviève; Chung, Jaeyoon; Cuccaro, Michael L.; Carracedo, Ángel; Cecchetti, Roberta; Cervera-Carles, Laura; Charbonnier, Camille; Chen, Hung-Hsin; Chillotti, Caterina; Ciccone, Simona; Claassen, Jurgen A. H. R.; Clark, Christopher; Conti, Elisa; Corma-Gómez, Anaïs; Costantini, Emanuele; Custodero, Carlo; Daian, Delphine; Dalmasso, Maria Carolina; Daniele, Antonio; Dardiotis, Efthimios; Dartigues, Jean-François; de Deyn, Peter Paul; de Paiva Lopes, Katia; de Witte, Lot D.; Debette, Stéphanie; Deckert, Jürgen; Del Ser, Teodoro; Denning, Nicola; DeStefano, Anita; Dichgans, Martin; Diehl-Schmid, Janine; Diez-Fairen, Mónica; Dionigi Rossi, Paolo; Djurovic, Srdjan; Duron, Emmanuelle; Düzel, Emrah; Dufouil, Carole; Eiriksdottir, Gudny; Engelborghs, Sebastiaan; Escott-Price, Valentina; Espinosa, Ana; Ewers, Michael; Faber, Kelley M.; Fabrizio, Tagliavini; Fallgaard Nielsen, Sune; Fardo, David W.; Farotti, Lucia; Fenoglio, Chiara; Fernández-Fuertes, Marta; Ferrari, Raffaele; Ferreira, Catarina B.; Ferri, Evelyn; Fin, Bertrand; Fischer, Peter; Fladby, Tormod; Fließbach, Klaus; Fongang, Bernard; Fornage, Myriam; Fortea, Juan; Foroud, Tatiana M.; Fostinelli, Silvia; Fox, Nick C.; Franco-Macías, Emlio; Bullido, María J.; Frank-García, Ana; Froelich, Lutz; Fulton-Howard, Brian; Galimberti, Daniela; García-Alberca, Jose Maria; García-González, Pablo; Garcia-Madrona, Sebastian; Garcia-Ribas, Guillermo; Ghidoni, Roberta; Giegling, Ina; Giorgio, Giaccone; Goate, Alison M.; Goldhardt, Oliver; Gomez-Fonseca, Duber; González-Pérez, Antonio; Graff, Caroline; Grande, Giulia; Green, Emma; Grimmer, Timo; Grünblatt, Edna; Grunin, Michelle; Gudnason, Vilmundur; Guetta-Baranes, Tamar; Haapasalo, Annakaisa; Hadjigeorgiou, Georgios; Haines, Jonathan L.; Hamilton-Nelson, Kara L.; Hampel, Harald; Hanon, Olivier; Hardy, John; Hartmann, Annette M.; Hausner, Lucrezia; Harwood, Janet; Heilmann-Heimbach, Stefanie; Helisalmi, Seppo; Heneka, Michael T.; Hernández, Isabel; Herrmann, Martin J.; Hoffmann, Per; Holmes, Clive; Holstege, Henne; Huerto Vilas, Raquel; Hulsman, Marc; Humphrey, Jack; Jan Biessels, Geert; Jian, Xueqiu; Johansson, Charlotte; Jun, Gyungah R.; Kastumata, Yuriko; Kauwe, John; Kehoe, Patrick G.; Kilander, Lena; Kinhult Ståhlbom, Anne; Kivipelto, Miia; Koivisto, Anne; Kornhuber, Johannes; Kosmidis, Mary H.; Kukull, Walter A.; Kuksa, Pavel P.; Kunkle, Brian W.; Kuzma, Amanda B.; Lage, Carmen; Laukka, Erika J.; Launer, Lenore; Lauria, Alessandra; Lee, Chien-Yueh; Lehtisalo, Jenni; Lerch, Ondrej; Lleó, Alberto; Longstreth, William, Jr.; Lopez, Oscar; Lopez de Munain, Adolfo; Love, Seth; Löwemark, Malin; Luckcuck, Lauren; Lunetta, Kathryn L.; Ma, Yiyi; Macías, Juan; MacLeod, Catherine A.; Maier, Wolfgang; Mangialasche, Francesca; Spallazzi, Marco; Marquié, Marta; Marshall, Rachel; Martin, Eden R.; Martín Montes, Angel; Martínez Rodríguez, Carmen; Masullo, Carlo; Mayeux, Richard; Mead, Simon; Mecocci, Patrizia; Medina, Miguel; Meggy, Alun; Mehrabian, Shima; Mendoza, Silvia; Menéndez-González, Manuel; Mir, Pablo; Moebus, Susanne; Mol, Merel; Molina-Porcel, Laura; Montrreal, Laura; Morelli, Laura; Moreno, Fermin; Morgan, Kevin; Mosley, Thomas; Nöthen, Markus M.; Muchnik, Carolina; Mukherjee, Shubhabrata; Nacmias, Benedetta; Ngandu, Tiia; Nicolas, Gael; Nordestgaard, Børge G.; Olaso, Robert; Orellana, Adelina; Orsini, Michela; Ortega, Gemma; Padovani, Alessandro; Paolo, Caffarra; Papenberg, Goran; Parnetti, Lucilla; Pasquier, Florence; Pastor, Pau; Peloso, Gina; Pérez-Cordón, Alba; Pérez-Tur, Jordi; Pericard, Pierre; Peters, Oliver; Pijnenburg, Yolande A. L.; Pineda, Juan A.; Piñol-Ripoll, Gerard; Pisanu, Claudia; Polak, Thomas; Popp, Julius; Posthuma, Danielle; Priller, Josef; Puerta, Raquel; Quenez, Olivier; Quintela, Inés; Qvist Thomassen, Jesper; Rábano, Alberto; Rainero, Innocenzo; Rajabli, Farid; Ramakers, Inez; Real, Luis M.; Reinders, Marcel J. T.; Reitz, Christiane; Reyes-Dumeyer, Dolly; Ridge, Perry; Riedel-Heller, Steffi; Riederer, Peter; Roberto, Natalia; Rodriguez-Rodriguez, Eloy; Rongve, Arvid; Rosas Allende, Irene; Rosende-Roca, Maitée; Royo, Jose Luis; Rubino, Elisa; Rujescu, Dan; Sáez, María Eugenia; Sakka, Paraskevi; Saltvedt, Ingvild; Sanabria, Ángela; Sánchez-Arjona, María Bernal; Sanchez-Garcia, Florentino; Sánchez Juan, Pascual; Sánchez-Valle, Raquel; Sando, Sigrid B.; Sarnowski, Chloé; Satizabal, Claudia L.; Scamosci, Michela; Scarmeas, Nikolaos; Scarpini, Elio; Scheltens, Philip; Scherbaum, Norbert; Scherer, Martin; Schmid, Matthias; Schneider, Anja; Schott, Jonathan M.; Selbæk, Geir; Seripa, Davide; Serrano, Manuel; Sha, Jin; Shadrin, Alexey A.; Skrobot, Olivia; Slifer, Susan; Snijders, Gijsje J. L.; Soininen, Hilkka; Solfrizzi, Vincenzo; Solomon, Alina; Song, Yeunjoo; Sorbi, Sandro; Sotolongo-Grau, Oscar; Spalletta, Gianfranco; Spottke, Annika; Squassina, Alessio; Stordal, Eystein; Tartan, Juan Pablo; Tárraga, Lluís; Tesí, Niccolo; Thalamuthu, Anbupalam; Thomas, Tegos; Tosto, Giuseppe; Traykov, Latchezar; Tremolizzo, Lucio; Tybjærg-Hansen, Anne; Uitterlinden, Andre; Ullgren, Abbe; Ulstein, Ingun; Valero, Sergi; Valladares, Otto; Van Broeckhoven, Christine; Vance, Jeffery; Vardarajan, Badri N.; van der Lugt, Aad; Van Dongen, Jasper; van Rooij, Jeroen; van Swieten, John; Vandenberghe, Rik; Verhey, Frans; Vidal, Jean-Sébastien; Vogelgsang, Jonathan; Vyhnalek, Martin; Wagner, Michael; Wallon, David; Wang, Li-San; Wang, Ruiqi; Weinhold, Leonie; Wiltfang, Jens; Windle, Gill; Woods, Bob; Yannakoulia, Mary; Zare, Habil; Zhao, Yi; Zhang, Xiaoling; Zhu, Congcong; Zulaica, Miren; EADB; GR@ACE; DEGESCO; EADI; GERAD; Demgene; FinnGen; ADGC; CHARGE; Farrer, Lindsay A.; Psaty, Bruce M.; Ghanbari, Mohsen; Raj, Towfique; Sachdev, Perminder; Mather, Karen; Jessen, Frank; Ikram, M. Arfan; de Mendonça, Alexandre; Hort, Jakub; Tsolaki, Magda; Pericak-Vance, Margaret A.; Amouyel, Philippe; Williams, Julie; Frikke-Schmidt, Ruth; Clarimon, Jordi; Deleuze, Jean-François; Rossi, Giacomina; Seshadri, Sudha; Andreassen, Ole A.; Ingelsson, Martin; Hiltunen, Mikko; Sleegers, Kristel; Schellenberg, Gerard D.; van Duijn, Cornelia M.; Sims, Rebecca; van der Flier, Wiesje M.; Ruiz, Agustín; Ramirez, Alfredo; Lambert, Jean-Charles; Medical and Molecular Genetics, School of MedicineCharacterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.Item Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans(American Medical Association, 2013) Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Mayeux, Richard; Alzheimer Disease Genetics Consortium; Psychiatry, School of MedicineImportance: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. Objective: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. Design, setting, and participants: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. Main outcomes and measures: Presence of Alzheimer disease according to standardized criteria. Results: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE ϵ4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 × 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). Conclusions and relevance: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.