Browsing by Subject "Genome-wide association study"

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  • Yu, Yoshihiko; Creighton, Erica K.; Buckley, Reuben M.; Lyons, Leslie A.; Buckley, Reuben M.; Aberdein, Danielle; Alves, Paulo C.; Barsh, Gregory S.; Bellone, Rebecca R.; Bergström, Tomas F.; Boyko, Adam R.; Brockman, Jeffrey A.; Casal, Margret L.; Castelhano, Marta G.; Distl, Ottmar; Dodman, Nicholas H.; Ellinwood, N. Matthew; Fogle, Jonathan E.; Forman, Oliver P.; Garrick, Dorian J.; Ginns, Edward I.; Häggström, Jens; Harvey, Robert J.; Hasegawa, Daisuke; Haase, Bianca; Helps, Christopher R.; Hernandez, Isabel; Hytönen, Marjo K.; Kaukonen, Maria; Kaelin, Christopher B.; Kosho, Tomoki; Leclerc, Emilie; Lear, Teri L.; Leeb, Tosso; Li, Ronald H.L.; Lohi, Hannes; Longeri, Maria; Magnuson, Mark A.; Malik, Richard; Mane, Shrinivasrao P.; Munday, John S.; Murphy, William J.; Pedersen, Niels C.; Peterson-Jones, Simon M.; Rothschild, Max F.; Rusbridge, Clare; Shapiro, Beth; Stern, Joshua A.; Swanson, William F.; Terio, Karen A.; Todhunter, Rory J.; Warren, Wesley C.; Wilcox, Elizabeth A.; Wildschutte, Julia H.; Yu, Yoshihiko; Lyons, Leslie A. (2020)
    An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation, concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test and a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats, by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasized the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.
  • Ahluwalia, Tarunveer S.; Schulz, Christina-Alexandra; Waage, Johannes; Skaaby, Tea; Sandholm, Niina; van Zuydam, Natalie; Charmet, Romain; Bork-Jensen, Jette; Almgren, Peter; Thuesen, Betina H.; Bedin, Mathilda; Brandslund, Ivan; Christensen, Cramer K.; Linneberg, Allan; Ahlqvist, Emma; Groop, Per-Henrik; Hadjadj, Samy; Tregouet, David-Alexandre; Jorgensen, Marit E.; Grarup, Niels; Pedersen, Oluf; Simons, Matias; Groop, Leif; Orho-Melander, Marju; McCarthy, Mark I.; Melander, Olle; Rossing, Peter; Kilpeläinen, Tuomas O.; Hansen, Torben (2019)
    Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, =0.27, p=1.3x10(-11)) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p(interaction)=7.0x10(-4), with diabetes=0.69, without diabetes=0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p(Bonferroni)
  • Direk, Nese; Williams, Stephanie; Smith, Jennifer A.; Ripke, Stephan; Air, Tracy; Amare, Azmeraw T.; Amin, Najaf; Baune, Bernhard T.; Bennett, David A.; Blackwood, Douglas H. R.; Boomsma, Dorret; Breen, Gerome; Buttenschon, Henriette N.; Byrne, Enda M.; Borglum, Anders D.; Castelao, Enrique; Cichon, Sven; Clarke, Toni-Kim; Cornelis, Marilyn C.; Dannlowski, Udo; De Jager, Philip L.; Demirkan, Ayse; Domenici, Enrico; van Duijn, Cornelia M.; Dunn, Erin C.; Eriksson, Johan G.; Esko, Tonu; Faul, Jessica D.; Ferrucci, Luigi; Fornage, Myriam; de Geus, Eco; Gill, Michael; Gordon, Scott D.; Grabe, Hans Joergen; van Grootheest, Gerard; Hamilton, Steven P.; Hartman, Catharina A.; Heath, Andrew C.; Hek, Karin; Hofman, Albert; Homuth, Georg; Horn, Carsten; Hottenga, Jouke Jan; Kardia, Sharon L. R.; Kloiber, Stefan; Koenen, Karestan; Kutalik, Zoltan; Ladwig, Karl-Heinz; Lahti, Jari; Levinson, Douglas F.; Lewis, Cathryn M.; Lewis, Glyn; Li, Qingqin S.; Llewellyn, David J.; Lucae, Susanne; Lunetta, Kathryn L.; MacIntyre, Donald J.; Madden, Pamela; Martin, Nicholas G.; McIntosh, Andrew M.; Metspalu, Andres; Milaneschi, Yuri; Montgomery, Grant W.; Mors, Ole; Mosley, Thomas H.; Murabito, Joanne M.; Mueller-Myhsok, Bertram; Nothen, Markus M.; Nyholt, Dale R.; O'Donovan, Michael C.; Penninx, Brenda W.; Pergadia, Michele L.; Perlis, Roy; Potash, James B.; Preisig, Martin; Purcell, Shaun M.; Quiroz, Jorge A.; Raikkonen, Katri; Rice, John P.; Rietschel, Marcella; Rivera, Margarita; Schulze, Thomas G.; Shi, Jianxin; Shyn, Stanley; Sinnamon, Grant C.; Smit, Johannes H.; Smoller, Jordan W.; Snieder, Harold; Tanaka, Toshiko; Tansey, Katherine E.; Teumer, Alexander; Uher, Rudolf; Umbricht, Daniel; Van der Auwera, Sandra; Ware, Erin B.; Weir, David R.; Weissman, Myrna M.; Willemsen, Gonneke; Yang, Jingyun; Zhao, Wei; Tiemeier, Henning; Sullivan, Patrick F. (2017)
    BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 x 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 x 10(-9)). CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.
  • Ottensmann, Linda (Helsingin yliopisto, 2020)
    It is challenging to identify causal genes and pathways explaining the associations with diseases and traits found by genome-wide association studies (GWASs). To solve this problem, a variety of methods that prioritize genes based on the variants identified by GWASs have been developed. In this thesis, the methods Data-driven Expression Prioritized Integration for Complex Traits (DEPICT) and Multi-marker Analysis of GenoMic Annotation (MAGMA) are used to prioritize causal genes based on the most recently published publicly available schizophrenia GWAS summary statistics. The two methods are compared using the Benchmarker framework, which allows an unbiased comparison of gene prioritization methods. The study has four aims. Firstly, to explain what are the differences between the gene prioritization methods DEPICT and MAGMA and how the two methods work. Secondly, to explain how the Benchmarker framework can be used to compare gene prioritization methods in an unbiased way. Thirdly, to compare the performance of DEPICT and MAGMA in prioritizing genes based on the latest schizophrenia summary statistics from 2018 using the Benchmarker framework. Lastly, to compare the performance of DEPICT and MAGMA on a schizophrenia GWAS with a smaller sample size by using Benchmarker. Firstly, the published results of the Benchmarker analyses using schizophrenia GWAS from 2014 were replicated to make sure that the framework is run correctly. The results were very similar and both the original and the replicated results show that DEPICT and MAGMA do not perform significantly differently. Furthermore, they show that the intersection of genes prioritized by DEPICT and MAGMA outperforms the outersection, which is defined as genes prioritized by only one of these methods. Secondly, Benchmarker was used to compare the performance of DEPICT and MAGMA on prioritizing genes using the schizophrenia GWAS from 2018. The results of the Benchmarker analyses suggest that DEPICT and MAGMA perform similarly with the GWAS from 2018 compared to the GWAS from 2014. Furthermore, an earlier schizophrenia GWAS from 2011 was used to check if the performance of DEPICT and MAGMA differs when a GWAS with lower statistical power is used. The results of the Benchmarker analyses make clear that MAGMA performs better than DEPICT in prioritizing genes using this smaller data set. Furthermore, for the schizophrenia GWAS from 2011 the outersection of genes prioritized by DEPICT and MAGMA outperforms the intersection. To conclude, the Benchmarker framework is a useful tool for comparing gene prioritization methods in an unbiased way. For the most recently published schizophrenia GWAS from 2018 there is no significant difference between the performance of DEPICT and MAGMA in prioritizing genes according to Benchmarker. For the smaller schizophrenia GWAS from 2011, however, MAGMA outperformed DEPICT.
  • Mullins, Niamh; Kang, JooEun; Campos, Adrian I.; Coleman, Jonathan R.I.; Edwards, Alexis C.; Galfalvy, Hanga; Levey, Daniel F.; Lori, Adriana; Shabalin, Andrey; Starnawska, Anna; Su, Mei-Hsin; Watson, Hunna J.; Adams, Mark; Awasthi, Swapnil; Gandal, Michael; Hafferty, Jonathan D.; Hishimoto, Akitoyo; Kim, Minsoo; Okazaki, Satoshi; Otsuka, Ikuo; Ripke, Stephan; Ware, Erin B.; Bergen, Andrew W.; Berrettini, Wade H.; Bohus, Martin; Brandt, Harry; Chang, Xiao; Chen, Wei J.; Chen, Hsi-Chung; Crawford, Steven; Crow, Scott; DiBlasi, Emily; Duriez, Philibert; Fernández-Aranda, Fernando; Fichter, Manfred M.; Gallinger, Steven; Glatt, Stephen J.; Gorwood, Philip; Guo, Yiran; Hakonarson, Hakon; Halmi, Katherine A.; Hwu, Hai-Gwo; Jain, Sonia; Jamain, Stéphane; Jiménez-Murcia, Susana; Johnson, Craig; Kaplan, Allan S.; Kaye, Walter H.; Keel, Pamela K.; Kennedy, James L.; Klump, Kelly L.; Li, Dong; Liao, Shih-Cheng; Lieb, Klaus; Lilenfeld, Lisa; Liu, Chih-Min; Magistretti, Pierre J.; Marshall, Christian R.; Mitchell, James E.; Monson, Eric T.; Myers, Richard M.; Pinto, Dalila; Powers, Abigail; Ramoz, Nicolas; Roepke, Stefan; Rozanov, Vsevolod; Scherer, Stephen W.; Schmahl, Christian; Sokolowski, Marcus; Strober, Michael; Thornton, Laura M.; Treasure, Janet; Tsuang, Ming T.; Witt, Stephanie H.; Woodside, D. Blake; Yilmaz, Zeynep; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Air, Tracy M.; Alda, Martin; Alfredsson, Lars; Andreassen, Ole A.; Anjorin, Adebayo; Appadurai, Vivek; Soler Artigas, María; der Auwera, Sandra Van; Azevedo, M. Helena; Bass, Nicholas; Bau, Claiton H.D.; Baune, Bernhard T.; Bellivier, Frank; Berger, Klaus; Biernacka, Joanna M.; Bigdeli, Tim B.; Binder, Elisabeth B.; Boehnke, Michael; Boks, Marco P.; Bosch, Rosa; Braff, David L.; Bryant, Richard; Budde, Monika; Byrne, Enda M.; Cahn, Wiepke; Casas, Miguel; Castelao, Enrique; Cervilla, Jorge A.; Chaumette, Boris; Cichon, Sven; Corvin, Aiden; Craddock, Nicholas; Craig, David; Degenhardt, Franziska; Djurovic, Srdjan; Edenberg, Howard J.; Fanous, Ayman H.; Foo, Jerome C.; Forstner, Andreas J.; Frye, Mark; Fullerton, Janice M.; Gatt, Justine M.; Gejman, Pablo V.; Giegling, Ina; Grabe, Hans J.; Green, Melissa J.; Grevet, Eugenio H.; Grigoroiu-Serbanescu, Maria; Gutierrez, Blanca; Guzman-Parra, Jose; Hamilton, Steven P.; Hamshere, Marian L.; Hartmann, Annette; Hauser, Joanna; Heilmann-Heimbach, Stefanie; Hoffmann, Per; Ising, Marcus; Jones, Ian; Jones, Lisa A.; Jonsson, Lina; Kahn, René S.; Kelsoe, John R.; Kendler, Kenneth S.; Kloiber, Stefan; Koenen, Karestan C.; Kogevinas, Manolis; Konte, Bettina; Krebs, Marie-Odile; Landén, Mikael; Lawrence, Jacob; Leboyer, Marion; Lee, Phil H.; Levinson, Douglas F.; Liao, Calwing; Lissowska, Jolanta; Lucae, Susanne; Mayoral, Fermin; McElroy, Susan L.; McGrath, Patrick; McGuffin, Peter; McQuillin, Andrew; Medland, Sarah E.; Mehta, Divya; Melle, Ingrid; Milaneschi, Yuri; Mitchell, Philip B.; Molina, Esther; Morken, Gunnar; Mortensen, Preben Bo; Müller-Myhsok, Bertram; Nievergelt, Caroline M.; Nimgaonkar, Vishwajit; Nöthen, Markus M.; O’Donovan, Michael C.; Ophoff, Roel A.; Owen, Michael J.; Pato, Carlos; Pato, Michele T.; Penninx, Brenda W.J.H.; Pimm, Jonathan; Pistis, Giorgio; Potash, James B.; Power, Robert A.; Preisig, Martin; Quested, Digby; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Ribasés, Marta; Richarte, Vanesa; Rietschel, Marcella; Rivera, Margarita; Roberts, Andrea; Roberts, Gloria; Rouleau, Guy A.; Rovaris, Diego L.; Rujescu, Dan; Sánchez-Mora, Cristina; Sanders, Alan R.; Schofield, Peter R.; Schulze, Thomas G.; Scott, Laura J.; Serretti, Alessandro; Shi, Jianxin; Shyn, Stanley I.; Sirignano, Lea; Sklar, Pamela; Smeland, Olav B.; Smoller, Jordan W.; Sonuga-Barke, Edmund J.S.; Spalletta, Gianfranco; Strauss, John S.; Świątkowska, Beata; Trzaskowski, Maciej; Turecki, Gustavo; Vilar-Ribó, Laura; Vincent, John B.; Völzke, Henry; Walters, James T.R.; Shannon Weickert, Cynthia; Weickert, Thomas W.; Weissman, Myrna M.; Williams, Leanne M.; Wray, Naomi R.; Zai, Clement C.; Ashley-Koch, Allison E.; Beckham, Jean C.; Hauser, Elizabeth R.; Hauser, Michael A.; Kimbrel, Nathan A.; Lindquist, Jennifer H.; McMahon, Benjamin; Oslin, David W.; Qin, Xuejun; Mattheisen, Manuel; Abdellaoui, Abdel; Adams, Mark J.; Agerbo, Esben; Andlauer, Till F.M.; Bacanu, Silviu-Alin; Bækvad-Hansen, Marie; Beekman, Aartjan T.F.; Bryois, Julien; Buttenschøn, Henriette N.; Bybjerg-Grauholm, Jonas; Cai, Na; Christensen, Jane Hvarregaard; Clarke, Toni-Kim; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E.; Davies, Gail; Derks, Eske M.; Direk, Nese; Dolan, Conor V.; Dunn, Erin C.; Eley, Thalia C.; Escott-Price, Valentina; Hassan Kiadeh, Farnush Farhadi; Finucane, Hilary K.; Frank, Josef; Gaspar, Héléna A.; Gill, Michael; Goes, Fernando S.; Gordon, Scott D.; Weinsheimer, Shantel Marie; Wellmann, Jürgen; Willemsen, Gonneke; Wu, Yang; Xi, Simon; Yang, Jian; Zhang, Futao; Arolt, Volker; Boomsma, Dorret I.; Dannlowski, Udo; de Geus, E.J.C.; Depaulo, J. Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grove, Jakob; Hall, Lynsey S.; Hansen, Christine Søholm; Hansen, Thomas F.; Herms, Stefan; Hickie, Ian B.; Homuth, Georg; Horn, Carsten; Hottenga, Jouke-Jan; Hougaard, David M.; Howard, David M.; Jansen, Rick; Jorgenson, Eric; Knowles, James A.; Kohane, Isaac S.; Kraft, Julia; Kretzschmar, Warren W.; Kutalik, Zoltán; Li, Yihan; Lind, Penelope A.; MacIntyre, Donald J.; MacKinnon, Dean F.; Maier, Robert M.; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; Middeldorp, Christel M.; Mihailov, Evelin; Milani, Lili; Mondimore, Francis M.; Montgomery, Grant W.; Mostafavi, Sara; Nauck, Matthias; Ng, Bernard; Nivard, Michel G.; Nyholt, Dale R.; O’Reilly, Paul F.; Oskarsson, Hogni; Hayward, Caroline; Heath, Andrew C.; Lewis, Glyn; Li, Qingqin S.; Madden, Pamela A.F.; Magnusson, Patrik K.; Martin, Nicholas G.; McIntosh, Andrew M.; Metspalu, Andres; Mors, Ole; Nordentoft, Merete; Paciga, Sara A.; Pedersen, Nancy L.; Painter, Jodie N.; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Peterson, Roseann E.; Peyrot, Wouter J.; Posthuma, Danielle; Quiroz, Jorge A.; Qvist, Per; Rice, John P.; Riley, Brien P.; Mirza, Saira Saeed; Schoevers, Robert; Schulte, Eva C.; Shen, Ling; Sigurdsson, Engilbert; Sinnamon, Grant C.B.; Smit, Johannes H.; Smith, Daniel J.; Stefansson, Hreinn; Steinberg, Stacy; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E.; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A.; Thorgeirsson, Thorgeir E.; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G.; Umbricht, Daniel; der Auwera, Sandra Van; van Hemert, Albert M.; Viktorin, Alexander; Visscher, Peter M.; Wang, Yunpeng; Webb, Bradley T.; Perlis, Roy H.; Porteous, David J.; Schaefer, Catherine; Stefansson, Kari; Tiemeier, Henning; Uher, Rudolf; Werge, Thomas; Lewis, Cathryn M.; Breen, Gerome; Børglum, Anders D.; Sullivan, Patrick F.; O’Connell, Kevin S.; Coombes, Brandon; Qiao, Zhen; Als, Thomas D.; Børte, Sigrid; Charney, Alexander W.; Drange, Ole Kristian; Gandal, Michael J.; Hagenaars, Saskia P.; Ikeda, Masashi; Kamitaki, Nolan; Krebs, Kristi; Panagiotaropoulou, Georgia; Schilder, Brian M.; Sloofman, Laura G.; Winsvold, Bendik S.; Won, Hong-Hee; Abramova, Liliya; Adorjan, Kristina; Al Eissa, Mariam; Albani, Diego; Alliey-Rodriguez, Ney; Antilla, Verneri; Antoniou, Anastasia; Baek, Ji Hyun; Bauer, Michael; Beins, Eva C.; Bergen, Sarah E.; Birner, Armin; Bøen, Erlend; Brum, Murielle; Brumpton, Ben M.; Brunkhorst-Kanaan, Nathalie; Byerley, William; Cairns, Murray; Casas, Miquel; Cervantes, Pablo; Cruceanu, Cristiana; Cuellar-Barboza, Alfredo; Cunningham, Julie; Curtis, David; Czerski, Piotr M.; Dale, Anders M.; Dalkner, Nina; David, Friederike S.; Dobbyn, Amanda L.; Douzenis, Athanassios; Elvsåshagen, Torbjørn; Ferrier, I. Nicol; Fiorentino, Alessia; Foroud, Tatiana M.; Forty, Liz; Frei, Oleksandr; Freimer, Nelson B.; Frisén, Louise; Gade, Katrin; Garnham, Julie; Gelernter, Joel; Gizer, Ian R.; Gordon-Smith, Katherine; Greenwood, Tiffany A.; Guzman-Parra, José; Ha, Kyooseob; Haraldsson, Magnus; Hautzinger, Martin; Heilbronner, Urs; Hellgren, Dennis; Holmans, Peter A.; Huckins, Laura; Johnson, Jessica S.; Kalman, Janos L.; Kamatani, Yoichiro; Kittel-Schneider, Sarah; Koromina, Maria; Kranz, Thorsten M.; Kranzler, Henry R.; Kubo, Michiaki; Kupka, Ralph; Kushner, Steven A.; Lavebratt, Catharina; Leber, Markus; Lee, Heon-Jeong; Levy, Shawn E.; Lewis, Catrin; Lundberg, Martin; Magnusson, Sigurdur H.; Maihofer, Adam; Malaspina, Dolores; Maratou, Eirini; Martinsson, Lina; McGregor, Nathaniel W.; McKay, James D.; Medeiros, Helena; Millischer, Vincent; Moran, Jennifer L.; Morris, Derek W.; Mühleisen, Thomas W.; O’Brien, Niamh; O’Donovan, Claire; Olde Loohuis, Loes M.; Oruc, Lilijana; Papiol, Sergi; Pardiñas, Antonio F.; Perry, Amy; Pfennig, Andrea; Porichi, Evgenia; Raj, Towfique; Rapaport, Mark H.; DePaulo, J. Raymond; Regeer, Eline J.; Rivas, Fabio; Roth, Julian; Roussos, Panos; Ruderfer, Douglas M.; Senner, Fanny; Sharp, Sally; Shilling, Paul D.; Slaney, Claire; Sobell, Janet L.; Artigas, Maria Soler; Spijker, Anne T.; Stein, Dan J.; Terao, Chikashi; Toma, Claudio; Tooney, Paul; Tsermpini, Evangelia-Eirini; Vawter, Marquis P.; Vedder, Helmut; Xi, Simon; Xu, Wei; Kay Yang, Jessica Mei; Young, Allan H.; Young, Hannah; Zandi, Peter P.; Zhou, Hang; Psychiatry, HUNT All-In; Babadjanova, Gulja; Backlund, Lena; Bengesser, Susanne; Blackwood, Douglas H.R.; Carr, Vaughan J.; Catts, Stanley; Dikeos, Dimitris; Etain, Bruno; Ferentinos, Panagiotis; Gawlik, Micha; Gershon, Elliot S.; Henskens, Frans; Hillert, Jan; Hong, Kyung Sue; Hultman, Christina M.; Hveem, Kristian; Iwata, Nakao; Jablensky, Assen V.; Kirov, George; Lochner, Christine; Loughland, Carmel; Mathews, Carol A.; McMahon, Francis J.; Michie, Patricia; Mowry, Bryan; Neale, Benjamin M.; Nievergelt, Caroline M.; Oedegaard, Ketil J.; Olsson, Tomas; Pantelis, Chris; Patrinos, George P.; Reininghaus, Eva Z.; Saito, Takeo; Schall, Ulrich; Schalling, Martin; Scott, Rodney J.; Weickert, Cynthia Shannon; Stordal, Eystein; Vaaler, Arne E.; Vieta, Eduard; Waldman, Irwin D.; Zwart, John-Anker; Nurnberger, John I.; Stahl, Eli A.; Di Florio, Arianna; Adan, Roger A.H.; Ando, Tetsuya; Aschauer, Harald; Baker, Jessica H.; Bencko, Vladimir; Birgegård, Andreas; Boden, Joseph M.; Boehm, Ilka; Boni, Claudette; Perica, Vesna Boraska; Buehren, Katharina; Bulik, Cynthia M.; Burghardt, Roland; Carlberg, Laura; Cassina, Matteo; Clementi, Maurizio; Cone, Roger D.; Courtet, Philippe; Crowley, James J.; Danner, Unna N.; Davis, Oliver S.P.; de Zwaan, Martina; Dedoussis, George; Degortes, Daniela; DeSocio, Janiece E.; Dick, Danielle M.; Dina, Christian; Dmitrzak-Weglarz, Monika; Martinez, Elisa Docampo; Duncan, Laramie E.; Egberts, Karin; Mattingsdal, Morten; McDevitt, Sara; Meulenbelt, Ingrid; Micali, Nadia; Mitchell, James; Mitchell, Karen; Monteleone, Palmiero; Monteleone, Alessio Maria; Munn-Chernoff, Melissa A.; Nacmias, Benedetta; Navratilova, Marie; Ntalla, Ioanna; Olsen, Catherine M.; O’Toole, Julie K.; Padyukov, Leonid; Palotie, Aarno; Pantel, Jacques; Papezova, Hana; Parker, Richard; Pearson, John F.; Ehrlich, Stefan; Escaramís, Geòrgia; Espeseth, Thomas; Estivill, Xavier; Farmer, Anne; Favaro, Angela; Fischer, Krista; Floyd, James A.B.; Föcker, Manuel; Foretova, Lenka; Forzan, Monica; Franklin, Christopher S.; Gambaro, Giovanni; Giuranna, Johanna; Giusti-Rodríquez, Paola; Gonidakis, Fragiskos; Gordon, Scott; Mayora, Monica Gratacos; Guillaume, Sébastien; Hanscombe, Ken B.; Hatzikotoulas, Konstantinos; Hebebrand, Johannes; Helder, Sietske G.; Henders, Anjali K.; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Hinney, Anke; Horwood, L. John; Hübel, Christopher; Petersen, Liselotte V.; Purves, Kirstin L.; Raevuori, Anu; Reichborn-Kjennerud, Ted; Ricca, Valdo; Ripatti, Samuli; Ritschel, Franziska; Roberts, Marion; Rybakowski, Filip; Santonastaso, Paolo; Scherag, André; Schmidt, Ulrike; Schork, Nicholas J.; Schosser, Alexandra; Seitz, Jochen; Slachtova, Lenka; Slagboom, P. Eline; Slof-Op ‘t Landt, Margarita C.T.; Slopien, Agnieszka; Soranzo, Nicole; Sorbi, Sandro; Southam, Lorraine; Steen, Vidar W.; Huckins, Laura M.; Hudson, James I.; Imgart, Hartmut; Inoko, Hidetoshi; Janout, Vladimir; Jordan, Jennifer; Julià, Antonio; Kalsi, Gursharan; Kaminská, Deborah; Kaprio, Jaakko; Karhunen, Leila; Karwautz, Andreas; Kas, Martien J.H.; Kennedy, Martin A.; Keski-Rahkonen, Anna; Kiezebrink, Kirsty; Kim, Youl-Ri; Kirk, Katherine M.; Klareskog, Lars; Knudsen, Gun Peggy S.; Larsen, Janne T.; Le Hellard, Stephanie; Leppä, Virpi M.; Lichtenstein, Paul; Lin, Bochao Danae; Lundervold, Astri; Luykx, Jurjen; Maj, Mario; Mannik, Katrin; Marsal, Sara; Stuber, Garret D.; Szatkiewicz, Jin P.; Tachmazidou, Ioanna; Tenconi, Elena; Tortorella, Alfonso; Tozzi, Federica; Tsitsika, Artemis; Tyszkiewicz-Nwafor, Marta; Tziouvas, Konstantinos; van Elburg, Annemarie A.; van Furth, Eric F.; Wade, Tracey D.; Wagner, Gudrun; Walton, Esther; Whiteman, David C.; Wichmann, H. Erich; Widen, Elisabeth; Yao, Shuyang; Zeggini, Eleftheria; Zerwas, Stephanie; Zipfel, Stephan; Jungkunz, Martin; Dietl, Lydie; Schwarze, Cornelia E.; Dahmen, Norbert; Schott, Björn H.; Mobascher, Arian; Crivelli, Silvia; Dennis, Michelle F.; Harvey, Phillip D.; Carter, Bruce W.; Huffman, Jennifer E.; Jacobson, Daniel; Madduri, Ravi; Olsen, Maren K.; Pestian, John; Gaziano, J. Michael; Muralidhar, Sumitra; Ramoni, Rachel; Beckham, Jean; Chang, Kyong-Mi; O’Donnell, Christopher J.; Tsao, Philip; Breeling, James; Huang, Grant; Romero, J.P. Casas; Moser, Jennifer; Whitbourne, Stacey B.; Brewer, Jessica V.; Aslan, Mihaela; Connor, Todd; Argyres, Dean P.; Stephens, Brady; Brophy, Mary T.; Humphries, Donald E.; Selva, Luis E.; Do, Nhan; Shayan, Shahpoor; Cho, Kelly; Pyarajan, Saiju; Hauser, Elizabeth; Sun, Yan; Zhao, Hongyu; Wilson, Peter; McArdle, Rachel; Dellitalia, Louis; Mattocks, Kristin; Harley, John; Zablocki, Clement J.; Whittle, Jeffrey; Jacono, Frank; Gutierrez, Salvador; Gibson, Gretchen; Hammer, Kimberly; Kaminsky, Laurence; Villareal, Gerardo; Kinlay, Scott; Xu, Junzhe; Hamner, Mark; Mathew, Roy; Bhushan, Sujata; Iruvanti, Pran; Godschalk, Michael; Ballas, Zuhair; Ivins, Douglas; Mastorides, Stephen; Moorman, Jonathan; Gappy, Saib; Klein, Jon; Ratcliffe, Nora; Florez, Hermes; Okusaga, Olaoluwa; Murdoch, Maureen; Sriram, Peruvemba; Yeh, Shing Shing; Tandon, Neeraj; Jhala, Darshana; Aguayo, Samuel; Cohen, David; Sharma, Satish; Liangpunsakul, Suthat; Oursler, Kris Ann; Whooley, Mary; Ahuja, Sunil; Constans, Joseph; Meyer, Paul; Greco, Jennifer; Rauchman, Michael; Servatius, Richard; Gaddy, Melinda; Wallbom, Agnes; Morgan, Timothy; Stapley, Todd; Sherman, Scott; Ross, George; Tsao, Philip; Strollo, Patrick; Boyko, Edward; Meyer, Laurence; Gupta, Samir; Huq, Mostaqul; Fayad, Joseph; Hung, Adriana; Lichy, Jack; Hurley, Robin; Robey, Brooks; Striker, Robert; Erlangsen, Annette; Kessler, Ronald C.; Porteous, David; Ursano, Robert J.; Wasserman, Danuta; Coon, Hilary; Demontis, Ditte; Docherty, Anna R.; Kuo, Po-Hsiu; Mann, J. John; Rentería, Miguel E.; Stein, Murray B.; Willour, Virginia (2022)
    Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
  • Mikkola, Lea; Holopainen, Saila; Pessa-Morikawa, Tiina; Lappalainen, Anu K.; Hytönen, Marjo K.; Lohi, Hannes; Iivanainen, Antti (BioMed Central, 2019)
    Abstract Background Hip dysplasia and osteoarthritis continue to be prevalent problems in veterinary and human medicine. Canine hip dysplasia is particularly problematic as it massively affects several large-sized breeds and can cause a severe impairment of the quality of life. In Finland, the complex condition is categorized to five classes from normal to severe dysplasia, but the categorization includes several sub-traits: congruity of the joint, Norberg angle, subluxation degree of the joint, shape and depth of the acetabulum, and osteoarthritis. Hip dysplasia and osteoarthritis have been proposed to have separate genetic etiologies. Results Using Fédération Cynologique Internationale -standardized ventrodorsal radiographs, German shepherds were rigorously phenotyped for osteoarthritis, and for joint incongruity by Norberg angle and femoral head center position in relation to dorsal acetabular edge. The affected dogs were categorized into mild, moderate and severe dysplastic phenotypes using official hip scores. Three different genome-wide significant loci were uncovered. The strongest candidate genes for hip joint incongruity were noggin (NOG), a bone and joint developmental gene on chromosome 9, and nanos C2HC-type zinc finger 1 (NANOS1), a regulator of matrix metalloproteinase 14 (MMP14) on chromosome 28. Osteoarthritis mapped to a long intergenic region on chromosome 1, between genes encoding for NADPH oxidase 3 (NOX3), an intriguing candidate for articular cartilage degradation, and AT-rich interactive domain 1B (ARID1B) that has been previously linked to joint laxity. Conclusions Our findings highlight the complexity of canine hip dysplasia phenotypes. In particular, the results of this study point to the potential involvement of specific and partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderate-to-severe dysplasia and osteoarthritis of canine hip joints. Further studies should unravel the unique and common mechanisms for the various sub-traits.
  • Mikkola, Lea; Holopainen, Saila; Pessa-Morikawa, Tiina; Lappalainen, Anu K.; Hytönen, Marjo K.; Lohi, Hannes; Iivanainen, Antti (2019)
    Background Hip dysplasia and osteoarthritis continue to be prevalent problems in veterinary and human medicine. Canine hip dysplasia is particularly problematic as it massively affects several large-sized breeds and can cause a severe impairment of the quality of life. In Finland, the complex condition is categorized to five classes from normal to severe dysplasia, but the categorization includes several sub-traits: congruity of the joint, Norberg angle, subluxation degree of the joint, shape and depth of the acetabulum, and osteoarthritis. Hip dysplasia and osteoarthritis have been proposed to have separate genetic etiologies. Results Using Federation Cynologique Internationale -standardized ventrodorsal radiographs, German shepherds were rigorously phenotyped for osteoarthritis, and for joint incongruity by Norberg angle and femoral head center position in relation to dorsal acetabular edge. The affected dogs were categorized into mild, moderate and severe dysplastic phenotypes using official hip scores. Three different genome-wide significant loci were uncovered. The strongest candidate genes for hip joint incongruity were noggin (NOG), a bone and joint developmental gene on chromosome 9, and nanos C2HC-type zinc finger 1 (NANOS1), a regulator of matrix metalloproteinase 14 (MMP14) on chromosome 28. Osteoarthritis mapped to a long intergenic region on chromosome 1, between genes encoding for NADPH oxidase 3 (NOX3), an intriguing candidate for articular cartilage degradation, and AT-rich interactive domain 1B (ARID1B) that has been previously linked to joint laxity. Conclusions Our findings highlight the complexity of canine hip dysplasia phenotypes. In particular, the results of this study point to the potential involvement of specific and partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderate-to-severe dysplasia and osteoarthritis of canine hip joints. Further studies should unravel the unique and common mechanisms for the various sub-traits.
  • Safdar, Luqman Bin; Almas, Fakhrah; Rehman, Attiq Ur; Umer, Muhammad Jawad; Shah, Syed Mashab Ali; Uddin, Siraj; Ashfaq, Shomaila; Rahman, Hamid Ur; Quraishi, Umar Masood (2020)
    Excess Ni intake has harmful implications on human health, which include chronic bronchitis, reduced lung function, and cancer of lung and nasal sinuses. Like other toxic metals, higher Ni accumulation in grains leads to excess intake by humans when the contaminated grains are consumed as food. There is little information about the genetic factors that regulate Ni uptake in plants. To investigate genetic architecture of Ni uptake in leaf and translocation to grain, we performed a genome-wide association study with genotyping from 90 K array in a historical bread wheat diversity panel from Pakistan. We observed that Ni toxicity caused more than 50 % reductions in biological yield and grain yield, other agronomic traits were also partly or severely affected. Genetic association study helped identify 23 SNP-trait associations involved in Ni uptake in leaf and translocation to grains. These 23 SNPs covered 15 genomic loci at chromosomes 1A, 2D, 3B, 4A and 4B of wheat. The favorable alleles of these SNPs were randomly distributed in subpopulations indicating no selection pressure for this trait during breeding improvement. These regions had 283 low-confidence and 248 high-confidence protein coding genes. Among these, 156 were annotated using databases of wheat and closely related grass species. Since there is no previous report on genetic information of Ni uptake and translocation, these results provide sufficient grounds for further research of candidate genes and varietal development.
  • Eising, Else; Mirza-Schreiber, Nazanin; de Zeeuw, Eveline L.; Wang, Carol A.; Truong, Dongnhu T.; Allegrini, Andrea G.; Shapland, Chin Yang; Zhu, Gu; Wigg, Karen G.; Gerritse, Margot L.; Molz, Barbara; Alagoz, Gokberk; Gialluisi, Alessandro; Abbondanza, Filippo; Rimfeld, Kaili; van Donkelaar, Marjolein; Liao, Zhijie; Jansen, Philip R.; Andlauer, Till F. M.; Bates, Timothy C.; Bernard, Manon; Blokland, Kirsten; Bonte, Milene; Borglum, Anders D.; Bourgeron, Thomas; Brandeis, Daniel; Ceronihh, Fabiola; Csepe, Valeria; Dale, Philip S.; de Jong, Peter F.; DeFries, John C.; Demonet, Jean-Francois; Demontis, Ditte; Feng, Yu; Gordon, Scott D.; Guger, Sharon L.; Hayiou-Thomas, Marianna E.; Hernandez-Cabrera, Juan A.; Hottenga, Jouke-Jan; Hulme, Charles; Kere, Juha; Kerr, Elizabeth N.; Koomar, Tanner; Landerl, Karin; Leonard, Gabriel T.; Lovett, Maureen W.; Lyytinen, Heikki; Martin, Nicholas G.; Martinelli, Angela; Maurer, Urs; Michaelson, Jacob J.; Moll, Kristina; Monaco, Anthony P.; Morgan, Angela T.; Nothen, Markus M.; Pausova, Zdenka; Pennell, Craig E.; Pennington, Bruce F.; Price, Kaitlyn M.; Rajagopal, Veera M.; Ramus, Franck; Richer, Louis; Simpson, Nuala H.; Smith, Shelley D.; Snowling, Margaret J.; Stein, John; Struguuu, Lisa J.; Talcott, Joel B.; Tiemeier, Henning; van der Schroeff, Marc P.; Verhoef, Ellen; Watkins, Kate E.; Wilkinson, Margaret; Wright, Margaret J.; Barr, Cathy L.; Boomsma, Dorret; Carreiras, Manuel; Franken, Marie-Christine J.; Gruen, Jeffrey R.; Luciano, Michelle; Muller-Myhsok, Bertram; Newbury, Dianne F.; Olson, Richard K.; Paracchini, Silvia; Paus, Tomas; Plomin, Robert; Reilly, Sheena; Schulte-Korn, Gerd; Tomblin, J. Bruce; Bergen, Elsjevan; Whitehouse, Andrew J. O.; Willcutt, Erik G.; St Pourcain, Beate; Francks, Clyde; Fisher, Simon E. (2022)
    The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 x 10(-8)) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.
  • Antikainen, Anni A. V.; Sandholm, Niina; Tregouet, David-Alexandre; Charmet, Romain; McKnight, Amy Jayne; Ahluwalia, Tarunveer S.; Syreeni, Anna; Valo, Erkka; Forsblom, Carol; Gordin, Daniel; Harjutsalo, Valma; Hadjadj, Samy; Maxwell, Alexander P.; Rossing, Peter; Groop, Per-Henrik (2021)
    Aims Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D. Methods and results We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) =1.32, P = 1.50 x 10(-8)], and rs6055069 on DEFB127 promoter (OR= 4.17, P= 2.35 x 10(-9)), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P <1 x 10(-6)), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P=4.21 x 10(-7)). Conclusion While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on beta-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation. [GRAPHICS] .
  • GENIE Consortium; Sandholm, Niina; Cole, Joanne B.; Nair, Viji; Forsblom, Carol; Valo, Erkka; Harjutsalo, Valma; Groop, Leif; Groop, Per-Henrik; Tuomilehto, Jaakko (2022)
    Aims/hypothesis Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. Methods We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. Results The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR9.3x10(-9)). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p Conclusions/interpretation Altogether, the results point to novel genes contributing to the pathogenesis of DKD. Data availability The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages (;;
  • Kanoni, Stavroula; Graham, Sarah E.; Wang, Yuxuan; Surakka, Ida; Ramdas, Shweta; Zhu, Xiang; Clarke, Shoa L.; Bhatti, Konain Fatima; Vedantam, Sailaja; Winkler, Thomas W.; Locke, Adam E.; Marouli, Eirini; Zajac, Greg J.M.; Wu, Kuan Han H.; Ntalla, Ioanna; Hui, Qin; Klarin, Derek; Hilliard, Austin T.; Wang, Zeyuan; Xue, Chao; Thorleifsson, Gudmar; Helgadottir, Anna; Gudbjartsson, Daniel F.; Holm, Hilma; Olafsson, Isleifur; Hwang, Mi Yeong; Han, Sohee; Akiyama, Masato; Sakaue, Saori; Terao, Chikashi; Kanai, Masahiro; Zhou, Wei; Brumpton, Ben M.; Rasheed, Humaira; Havulinna, Aki S.; Veturi, Yogasudha; Pacheco, Jennifer Allen; Rosenthal, Elisabeth A.; Lingren, Todd; Feng, Qi Ping; Kullo, Iftikhar J.; Narita, Akira; Takayama, Jun; Martin, Hilary C.; Hunt, Karen A.; Trivedi, Bhavi; Haessler, Jeffrey; Giulianini, Franco; Bradford, Yuki; Miller, Jason E.; Campbell, Archie; Lin, Kuang; Millwood, Iona Y.; Rasheed, Asif; Hindy, George; Faul, Jessica D.; Zhao, Wei; Weir, David R.; Turman, Constance; Huang, Hongyan; Graff, Mariaelisa; Choudhury, Ananyo; Sengupta, Dhriti; Mahajan, Anubha; Brown, Michael R.; Zhang, Weihua; Yu, Ketian; Schmidt, Ellen M.; Pandit, Anita; Gustafsson, Stefan; Yin, Xianyong; Luan, Jian’an; Zhao, Jing Hua; Matsuda, Fumihiko; Jang, Hye Mi; Yoon, Kyungheon; Medina-Gomez, Carolina; Pitsillides, Achilleas; Hottenga, Jouke Jan; Wood, Andrew R.; Ji, Yingji; Gao, Zishan; Haworth, Simon; Yousri, Noha A.; Mitchell, Ruth E.; Chai, Jin Fang; Aadahl, Mette; Bjerregaard, Anne A.; Yao, Jie; Manichaikul, Ani; Hwu, Chii Min; Hung, Yi Jen; Warren, Helen R.; Ramirez, Julia; Bork-Jensen, Jette; Kårhus, Line L.; Goel, Anuj; Sabater-Lleal, Maria; Noordam, Raymond; Mauro, Pala; Matteo, Floris; McDaid, Aaron F.; Marques-Vidal, Pedro; Wielscher, Matthias; Trompet, Stella; Sattar, Naveed; Møllehave, Line T.; Munz, Matthias; Zeng, Lingyao; Huang, Jianfeng; Yang, Bin; Poveda, Alaitz; Kurbasic, Azra; Lamina, Claudia; Forer, Lukas; Scholz, Markus; Galesloot, Tessel E.; Bradfield, Jonathan P.; Ruotsalainen, Sanni E.; Daw, EWarwick W.; Zmuda, Joseph M.; Mitchell, Jonathan S.; Fuchsberger, Christian; Christensen, Henry; Brody, Jennifer A.; Vazquez-Moreno, Miguel; Feitosa, Mary F.; Wojczynski, Mary K.; Wang, Zhe; Preuss, Michael H.; Mangino, Massimo; Christofidou, Paraskevi; Verweij, Niek; Benjamins, Jan W.; Engmann, Jorgen; Tsao, Noah L.; Verma, Anurag; Slieker, Roderick C.; Lo, Ken Sin; Zilhao, Nuno R.; Le, Phuong; Kleber, Marcus E.; Delgado, Graciela E.; Huo, Shaofeng; Ikeda, Daisuke D.; Iha, Hiroyuki; Yang, Jian; Liu, Jun; Demirkan, Ayşe; Leonard, Hampton L.; Marten, Jonathan; Frank, Mirjam; Schmidt, Börge; Smyth, Laura J.; Cañadas-Garre, Marisa; Wang, Chaolong; Nakatochi, Masahiro; Wong, Andrew; Hutri-Kähönen, Nina; Sim, Xueling; Xia, Rui; Huerta-Chagoya, Alicia; Fernandez-Lopez, Juan Carlos; Lyssenko, Valeriya; Nongmaithem, Suraj S.; Bayyana, Swati; Stringham, Heather M.; Irvin, Marguerite R.; Oldmeadow, Christopher; Kim, Han Na; Ryu, Seungho; Timmers, Paul R.H.J.; Arbeeva, Liubov; Dorajoo, Rajkumar; Lange, Leslie A.; Prasad, Gauri; Lorés-Motta, Laura; Pauper, Marc; Long, Jirong; Li, Xiaohui; Theusch, Elizabeth; Takeuchi, Fumihiko; Spracklen, Cassandra N.; Loukola, Anu; Bollepalli, Sailalitha; Warner, Sophie C.; Wang, Ya Xing; Wei, Wen B.; Nutile, Teresa; Ruggiero, Daniela; Sung, Yun Ju; Chen, Shufeng; Liu, Fangchao; Yang, Jingyun; Kentistou, Katherine A.; Banas, Bernhard; Nardone, Giuseppe Giovanni; Meidtner, Karina; Bielak, Lawrence F.; Smith, Jennifer A.; Hebbar, Prashantha; Farmaki, Aliki Eleni; Hofer, Edith; Lin, Maoxuan; Concas, Maria Pina; Vaccargiu, Simona; van der Most, Peter J.; Pitkänen, Niina; Cade, Brian E.; van der Laan, Sander W.; Chitrala, Kumaraswamy Naidu; Weiss, Stefan; Bentley, Amy R.; Doumatey, Ayo P.; Adeyemo, Adebowale A.; Lee, Jong Young; Petersen, Eva R.B.; Nielsen, Aneta A.; Choi, Hyeok Sun; Nethander, Maria; Freitag-Wolf, Sandra; Southam, Lorraine; Rayner, Nigel W.; Wang, Carol A.; Lin, Shih Yi; Wang, Jun Sing; Couture, Christian; Lyytikäinen, Leo Pekka; Nikus, Kjell; Cuellar-Partida, Gabriel; Vestergaard, Henrik; Hidalgo, Bertha; Giannakopoulou, Olga; Cai, Qiuyin; Obura, Morgan O.; van Setten, Jessica; Li, Xiaoyin; Liang, Jingjing; Tang, Hua; Terzikhan, Natalie; Shin, Jae Hun; Jackson, Rebecca D.; Reiner, Alexander P.; Martin, Lisa Warsinger; Chen, Zhengming; Li, Liming; Kawaguchi, Takahisa; Thiery, Joachim; Bis, Joshua C.; Launer, Lenore J.; Li, Huaixing; Nalls, Mike A.; Raitakari, Olli T.; Ichihara, Sahoko; Wild, Sarah H.; Nelson, Christopher P.; Campbell, Harry; Jäger, Susanne; Nabika, Toru; Al-Mulla, Fahd; Niinikoski, Harri; Braund, Peter S.; Kolcic, Ivana; Kovacs, Peter; Giardoglou, Tota; Katsuya, Tomohiro; de Kleijn, Dominique; de Borst, Gert J.; Kim, Eung Kweon; Adams, Hieab H.H.; Ikram, M. Arfan; Zhu, Xiaofeng; Asselbergs, Folkert W.; Kraaijeveld, Adriaan O.; Beulens, Joline W.J.; Shu, Xiao Ou; Rallidis, Loukianos S.; Pedersen, Oluf; Hansen, Torben; Mitchell, Paul; Hewitt, Alex W.; Kähönen, Mika; Pérusse, Louis; Bouchard, Claude; Tönjes, Anke; Chen, Yii Der Ida; Pennell, Craig E.; Mori, Trevor A.; Lieb, Wolfgang; Franke, Andre; Ohlsson, Claes; Mellström, Dan; Cho, Yoon Shin; Lee, Hyejin; Yuan, Jian Min; Koh, Woon Puay; Rhee, Sang Youl; Woo, Jeong Taek; Heid, Iris M.; Stark, Klaus J.; Zimmermann, Martina E.; Völzke, Henry; Homuth, Georg; Evans, Michele K.; Zonderman, Alan B.; Polasek, Ozren; Pasterkamp, Gerard; Hoefer, Imo E.; Redline, Susan; Pahkala, Katja; Oldehinkel, Albertine J.; Snieder, Harold; Biino, Ginevra; Schmidt, Reinhold; Schmidt, Helena; Bandinelli, Stefania; Dedoussis, George; Thanaraj, Thangavel Alphonse; Kardia, Sharon L.R.; Peyser, Patricia A.; Kato, Norihiro; Schulze, Matthias B.; Girotto, Giorgia; Böger, Carsten A.; Jung, Bettina; Joshi, Peter K.; Bennett, David A.; De Jager, Philip L.; Lu, Xiangfeng; Mamakou, Vasiliki; Brown, Morris; Caulfield, Mark J.; Munroe, Patricia B.; Guo, Xiuqing; Ciullo, Marina; Jonas, Jost B.; Samani, Nilesh J.; Kaprio, Jaakko; Pajukanta, Päivi; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Adair, Linda S.; Bechayda, Sonny Augustin; de Silva, H. Janaka; Wickremasinghe, Ananda R.; Krauss, Ronald M.; Wu, Jer Yuarn; Zheng, Wei; Hollander, Anneke Iden; Bharadwaj, Dwaipayan; Correa, Adolfo; Wilson, James G.; Lind, Lars; Heng, Chew Kiat; Nelson, Amanda E.; Golightly, Yvonne M.; Wilson, James F.; Penninx, Brenda; Kim, Hyung Lae; Attia, John; Scott, Rodney J.; Rao, D. C.; Arnett, Donna K.; Hunt, Steven C.; Walker, Mark; Koistinen, Heikki A.; Chandak, Giriraj R.; Mercader, Josep M.; Costanzo, Maria C.; Jang, Dongkeun; Burtt, Noël P.; Villalpando, Clicerio Gonzalez; Orozco, Lorena; Fornage, Myriam; Tai, EShyong S.; van Dam, Rob M.; Lehtimäki, Terho; Chaturvedi, Nish; Yokota, Mitsuhiro; Liu, Jianjun; Reilly, Dermot F.; McKnight, Amy Jayne; Kee, Frank; Jöckel, Karl Heinz; McCarthy, Mark I.; Palmer, Colin N.A.; Vitart, Veronique; Hayward, Caroline; Simonsick, Eleanor; van Duijn, Cornelia M.; Jin, Zi Bing; Qu, Jia; Hishigaki, Haretsugu; Lin, Xu; März, Winfried; Gudnason, Vilmundur; Tardif, Jean Claude; Lettre, Guillaume; Hart, Leen M.‘t; Elders, Petra J.M.; Damrauer, Scott M.; Kumari, Meena; Kivimaki, Mika; van der Harst, Pim; Spector, Tim D.; Loos, Ruth J.F.; Province, Michael A.; Parra, Esteban J.; Cruz, Miguel; Psaty, Bruce M.; Brandslund, Ivan; Pramstaller, Peter P.; Rotimi, Charles N.; Christensen, Kaare; Ripatti, Samuli; Widén, Elisabeth; Hakonarson, Hakon; Grant, Struan F.A.; Kiemeney, Lambertus A.L.M.; de Graaf, Jacqueline; Loeffler, Markus; Kronenberg, Florian; Gu, Dongfeng; Erdmann, Jeanette; Schunkert, Heribert; Franks, Paul W.; Linneberg, Allan; Jukema, J. Wouter; Khera, Amit V.; Männikkö, Minna; Jarvelin, Marjo Riitta; Kutalik, Zoltan; Francesco, Cucca; Mook-Kanamori, Dennis O.; van Dijk, Ko Willems; Watkins, Hugh; Strachan, David P.; Grarup, Niels; Sever, Peter; Poulter, Neil; Chuang, Lee Ming; Rotter, Jerome I.; Dantoft, Thomas M.; Karpe, Fredrik; Neville, Matt J.; Timpson, Nicholas J.; Cheng, Ching Yu; Wong, Tien Yin; Khor, Chiea Chuen; Li, Hengtong; Sabanayagam, Charumathi; Peters, Annette; Gieger, Christian; Hattersley, Andrew T.; Pedersen, Nancy L.; Magnusson, Patrik K.E.; Boomsma, Dorret I.; Willemsen, Allegonda H.M.; Cupples, LAdrienne A.; van Meurs, Joyce B.J.; Ghanbari, Mohsen; Gordon-Larsen, Penny; Huang, Wei; Kim, Young Jin; Tabara, Yasuharu; Wareham, Nicholas J.; Langenberg, Claudia; Zeggini, Eleftheria; Kuusisto, Johanna; Laakso, Markku; Ingelsson, Erik; Abecasis, Goncalo; Chambers, John C.; Kooner, Jaspal S.; de Vries, Paul S.; Morrison, Alanna C.; Hazelhurst, Scott; Ramsay, Michèle; North, Kari E.; Daviglus, Martha; Kraft, Peter; Martin, Nicholas G.; Whitfield, John B.; Abbas, Shahid; Saleheen, Danish; Walters, Robin G.; Holmes, Michael V.; Black, Corri; Smith, Blair H.; Baras, Aris; Justice, Anne E.; Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.; Kooperberg, Charles; Tamiya, Gen; Yamamoto, Masayuki; van Heel, David A.; Trembath, Richard C.; Wei, Wei Qi; Jarvik, Gail P.; Namjou, Bahram; Hayes, M. Geoffrey; Ritchie, Marylyn D.; Jousilahti, Pekka; Salomaa, Veikko; Hveem, Kristian; Åsvold, Bjørn Olav; Kubo, Michiaki; Kamatani, Yoichiro; Okada, Yukinori; Murakami, Yoshinori; Kim, Bong Jo; Thorsteinsdottir, Unnur; Stefansson, Kari; Zhang, Jifeng; Chen, YEugene E.; Ho, Yuk Lam; Lynch, Julie A.; Rader, Daniel J.; Tsao, Philip S.; Chang, Kyong Mi; Cho, Kelly; O’Donnell, Christopher J.; Gaziano, John M.; Wilson, Peter W.F.; Frayling, Timothy M.; Hirschhorn, Joel N.; Kathiresan, Sekar; Mohlke, Karen L.; Sun, Yan V.; Morris, Andrew P.; Boehnke, Michael; Brown, Christopher D.; Natarajan, Pradeep; Deloukas, Panos; Willer, Cristen J.; Assimes, Themistocles L.; Peloso, Gina M. (2022)
    Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
  • Santos-Cortez, R.L.P.; Bhutta, M.F.; Earl, J.P.; Hafrén, Lena; Jennings, M.; Mell, J.C.; Pichichero, M.E.; Ryan, A.F.; Tateossian, Hilda; Ehrlich, G.D. (2020)
    Objective: To review the most recent advances in human and bacterial genomics as applied to pathogenesis and clinical management of otitis media. Data sources: PubMed articles published since the last meeting in June 2015 up to June 2019. Review methods: A panel of experts in human and bacterial genomics of otitis media was formed. Each panel member reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019, discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members. Conclusion: Trans-disciplinary approaches applying pan-omic technologies to identify human susceptibility to otitis media and to understand microbial population dynamics, patho-adaptation and virulence mechanisms are crucial to the development of novel, personalized therapeutics and prevention strategies for otitis media. Implications for practice: In the future otitis media prevention strategies may be augmented by mucosal immunization, combination vaccines targeting multiple pathogens, and modulation of the middle ear microbiome. Both treatment and vaccination may be tailored to an individual's otitis media phenotype as defined by molecular profiles obtained by using rapidly developing techniques in microbial and host genomics. © 2020 Elsevier B.V.
  • Dahlstrom, Emma; Sandholm, Niina (2017)
    Purpose of Review Diabetic complications affecting the kidneys, retina, nerves, and the cardiovasculature are the major causes of morbidity and mortality in diabetes. This paper aims to review the current understanding of the genetic basis of these complications, based on recent findings especially from genome-wide association studies. Recent Findings Variants in or near AFF3, RGMA-MCTP2, SP3-CDCA7, GLRA3, CNKSR3, and UMOD have reached genome-wide significance (p value <5 x 10(-8)) for association with diabetic kidney disease, and recently, GRB2 was reported to be associated at genome-wide significance with diabetic retinopathy. While some loci affecting cardiovascular disease in the general population have been replicated in diabetes, GLUL affects the risk of cardiovascular disease specifically in diabetic subjects. Summary Genetic findings are emerging for diabetic complications, although the studies remain relatively small compared to those for type 1 and type 2 diabetes. In addition to pinpointing specific loci, the studies also reveal biological information on correlated traits and pathways.
  • Lehtonen, Leevi (Helsingin yliopisto, 2021)
    Sex differences can be found in most human phenotypes, and they play an important role in human health and disease. Females and males have different sex chromosomes, which are known to cause sex differences, as are differences in the concentration of sex hormones such as testosterone, estradiol and progesterone. However, the role of the autosomes has remained more debated. The primary aim of this thesis is to assess the magnitude and relevance of human sex-specific genetic architecture in the autosomes. This is done by calculating sex-specific heritability estimates and genetic correlation estimates between females and males, as well as comparing these to sex differences on the phenotype level. Additionally, the heritability and genetic correlation estimates are compared between two populations, in order to assess the magnitude of sex differences compared to differences between populations. The analyses in this thesis are based on sex-stratified genome-wide association study (GWAS) data from 48 phenotypes in the UK Biobank (UKB), which contains genotype data from approximately 500 000 individuals as well as thousands of phenotype measurements. A replication of the analyses using three phenotypes was also made on data from the FinnGen project, with a dataset from approximately 175 000 individuals. The 48 phenotypes used in this study range from biomarkers such as serum testosterone and albumin levels to general traits such as height and blood pressure. The heritability and genetic correlation estimates were calculated using linkage disequilibrium score regression (LDSC). LDSC fits a linear regression model between test statistic values of GWAS variants and linkage disequilibrium (LD) scores calculated from a reference population. For most phenotypes, the heritability and genetic correlation results show little evidence of sex differences. Serum testosterone level and waist-to-hip ratio are exceptions to this, showing strong evidence of sex differences both on the genetic and the phenotype level. However, the overall correlation between phenotype level sex differences and sex differences in heritability or genetic correlation estimates is low. The replication in the FinnGen dataset for height, weight and body mass index (BMI), showed that for these traits the differences in heritability estimates and genetic correlations between the Finnish and UK populations are comparable or larger than the differences found between males and females.