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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266/pdf/nihms-1584390.pdf
Accepted manuscript
DOI
- https://doi.org/10.1111/adb.12880
Final published version
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- Emma C Johnson, Washington University St. Louis ,
- Yi-Ling Chou, Washington University St. Louis ,
- Jonathan R I Coleman, King's College London ,
- Laura M Thornton, University of North Carolina ,
- Raymond K Walters, Harvard University ,
- Zeynep Yilmaz
- Jessica H Baker, University of North Carolina ,
- Christopher Hübel
- Scott Gordon, QIMR Berghofer Medical Research Institute ,
- Sarah E Medland, QIMR Berghofer Medical Research Institute ,
- Hunna J Watson, University of North Carolina ,
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- Julien Bryois, Karolinska Institutet ,
- Anke Hinney, University of Duisburg-Essen ,
- Virpi M Leppä, Karolinska Institutet ,
- Manuel Mattheisen, Stockholm County Council, Karolinska Institutet, University of Würzburg ,
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- Shuyang Yao, Karolinska Institutet ,
- Paola Giusti-Rodríguez, University of North Carolina ,
- Ken B Hanscombe, King's College London ,
- Roger A H Adan, Utrecht University ,
- Lars Alfredsson, Karolinska Institutet ,
- Tetsuya Ando, National Institute of Mental Health, National Institutes of Health ,
- Ole A Andreassen, University of Oslo ,
- Wade H Berrettini, University of Pennsylvania ,
- Ilka Boehm, Technische Universität Dresden ,
- Claudette Boni, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. ,
- Vesna Boraska Perica, Wellcome Sanger Institute ,
- Katharina Buehren, RWTH Aachen University ,
- Roland Burghardt, Klinikum Frankfurt/Oder ,
- Matteo Cassina, University of Padova ,
- Sven Cichon, University of Basel ,
- Maurizio Clementi, University of Padova ,
- Roger D Cone, University of Michigan, Ann Arbor ,
- Philippe Courtet, Universite de Montpellier ,
- Scott Crow, University of Minnesota ,
- James J Crowley, University of North Carolina ,
- Unna N Danner, Altrecht Mental Health Institute ,
- Oliver S P Davis, University of Bristol ,
- Martina de Zwaan, Hannover Medical School ,
- George Dedoussis, Harokopio University ,
- Daniela Degortes, University of Padova ,
- Janiece E DeSocio, College of Nursing, Seattle University, Seattle, WA, USA. ,
- Danielle M Dick, Virginia Commonwealth University ,
- Dimitris Dikeos, University of Athens ,
- Christian Dina, L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France. ,
- Monika Dmitrzak-Weglarz, University of Medical Sciences Poznan ,
- Elisa Docampo, Barcelona Institute of Science and Technology ,
- Laramie E Duncan, Stanford University ,
- Karin Egberts, University of Würzburg ,
- Stefan Ehrlich, Technische Universität Dresden ,
- Geòrgia Escaramís, Barcelona Institute of Science and Technology ,
- Tõnu Esko, University of Tartu ,
- Xavier Estivill, Barcelona Institute of Science and Technology ,
- Anne Farmer, King's College London ,
- Angela Favaro, University of Padova ,
- Fernando Fernández-Aranda, University Hospital Bellvitge-IDIBELL and CIBEROBN ,
- Manfred M Fichter, Ludwig Maximilian University ,
- Krista Fischer, University of Tartu ,
- Manuel Föcker, University of Münster ,
- Lenka Foretova, Masaryk Memorial Cancer Institute ,
- Andreas J Forstner, University of Basel ,
- Monica Forzan, University of Padova ,
- Christopher S Franklin, Wellcome Sanger Institute ,
- Steven Gallinger, University of Toronto ,
- Ina Giegling, Martin Luther University Halle-Wittenberg ,
- Johanna Giuranna, University of Duisburg-Essen ,
- Fragiskos Gonidakis, University of Athens ,
- Philip Gorwood, INSERM 1266, Institute of Psychiatry and Neuroscience of Paris, Paris, France. ,
- Monica Gratacos Mayora, Barcelona Institute of Science and Technology ,
- Sébastien Guillaume, Universite de Montpellier ,
- Yiran Guo, Childrens Hosp Philadelphia, University of Pennsylvania, Childrens Hospital of Philadelphia, Div Neurol ,
- Hakon Hakonarson, Childrens Hosp Philadelphia, University of Pennsylvania, Childrens Hospital of Philadelphia, Div Neurol, University of Pennsylvania ,
- Konstantinos Hatzikotoulas, Wellcome Sanger Institute ,
- Joanna Hauser, University of Medical Sciences Poznan ,
- Johannes Hebebrand, University of Duisburg-Essen ,
- Sietske G Helder, King's College London ,
- Stefan Herms, University of Basel ,
- Beate Herpertz-Dahlmann, RWTH Aachen University ,
- Wolfgang Herzog, Heidelberg University ,
- Laura M Huckins, Wellcome Sanger Institute ,
- James I Hudson, Harvard University ,
- Hartmut Imgart, Eating Disorders Unit ,
- Hidetoshi Inoko, Tokai Univ, Tokai University, Sch Med, Dept Orthopaed Surg ,
- Vladimir Janout, Palacký University Olomouc ,
- Susana Jiménez-Murcia, University Hospital Bellvitge-IDIBELL and CIBEROBN ,
- Antonio Julià, Vall d'Hebron Research Institute ,
- Gursharan Kalsi, King's College London ,
- Deborah Kaminská, Charles Darwin University ,
- Leila Karhunen, University of Eastern Finland ,
- Andreas Karwautz, Medical University of Vienna ,
- Martien J H Kas, Utrecht University ,
- James L Kennedy, University of Toronto ,
- Anna Keski-Rahkonen, University of Helsinki ,
- Kirsty Kiezebrink, University of Aberdeen ,
- Youl-Ri Kim, Inje University ,
- Kelly L Klump, Michigan State University ,
- Gun Peggy S Knudsen, Norwegian Institute of Public Health ,
- Maria C La Via, University of North Carolina ,
- Stephanie Le Hellard, University of Bergen ,
- Robert D Levitan, University of Toronto ,
- Dong Li, Childrens Hosp Philadelphia, University of Pennsylvania, Childrens Hospital of Philadelphia, Div Neurol ,
- Lisa Lilenfeld, The Chicago School of Professional Psychology ,
- Bochao Danae Lin, Utrecht University ,
- Jolanta Lissowska, Maria Sklodowska-Curie Institute of Oncology ,
- Jurjen Luykx, Utrecht University ,
- Pierre J Magistretti, King Abdullah University of Science and Technology ,
- Mario Maj, University of Campania Luigi Vanvitelli ,
- Katrin Mannik, University of Tartu ,
- Sara Marsal, Vall d'Hebron Research Institute ,
- Christian R Marshall, The Hospital for Sick Children ,
- Morten Mattingsdal, University of Oslo ,
- Sara McDevitt, University College Cork ,
- Peter McGuffin, King's College London ,
- Andres Metspalu, University of Tartu ,
- Ingrid Meulenbelt, Leiden University ,
- Nadia Micali, University of Geneva ,
- Karen Mitchell, National Center for PTSD Executive Division ,
- Alessio Maria Monteleone, University of Campania Luigi Vanvitelli ,
- Palmiero Monteleone, University of Salerno ,
- Benedetta Nacmias, University of Florence ,
- Marie Navratilova, Masaryk Memorial Cancer Institute ,
- Ioanna Ntalla, Harokopio University ,
- Julie K O'Toole, Kartini Clinic ,
- Roel A Ophoff, University of California at Los Angeles ,
- Leonid Padyukov, Karolinska Institutet ,
- Aarno Palotie, Broad Institute ,
- Jacques Pantel, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. ,
- Hana Papezova, Charles Darwin University ,
- Dalila Pinto, Icahn School of Medicine at Mount Sinai ,
- Raquel Rabionet, Saint Joan de Déu Research Institute ,
- Anu Raevuori, University of Helsinki ,
- Nicolas Ramoz, INSERM 1266, Institute of Psychiatry and Neuroscience of Paris, Paris, France. ,
- Ted Reichborn-Kjennerud, Norwegian Institute of Public Health ,
- Valdo Ricca, University of Florence ,
- Samuli Ripatti, University of Helsinki ,
- Franziska Ritschel, Technische Universität Dresden ,
- Marion Roberts, King's College London ,
- Alessandro Rotondo, University of Pisa ,
- Dan Rujescu, Martin Luther University Halle-Wittenberg ,
- Filip Rybakowski, University of Medical Sciences Poznan ,
- Paolo Santonastaso, University of Padova ,
- André Scherag, Jena University Hospital ,
- Stephen W Scherer, The Hospital for Sick Children ,
- Ulrike Schmidt, King's College London ,
- Nicholas J Schork, J. Craig Venter Institute (JCVI) ,
- Alexandra Schosser, Medical University of Vienna ,
- Jochen Seitz, RWTH Aachen University ,
- Lenka Slachtova, Charles Darwin University ,
- P Eline Slagboom, Leiden University ,
- Margarita C T Slof-Op't Landt, Center for Eating Disorders Ursula ,
- Agnieszka Slopien, University of Medical Sciences Poznan ,
- Sandro Sorbi, University of Florence ,
- Beata Świątkowska, Nofer Institute of Occupational Medicine ,
- Jin P Szatkiewicz, University of North Carolina ,
- Ioanna Tachmazidou, Wellcome Sanger Institute ,
- Elena Tenconi, University of Padova ,
- Alfonso Tortorella, Department of Psychiatry, University of Naples SUN, Naples, Italy. ,
- Federica Tozzi, Department of Psychological and Brain Sciences ,
- Janet Treasure, King's College London ,
- Artemis Tsitsika, University of Athens ,
- Marta Tyszkiewicz-Nwafor, University of Medical Sciences Poznan ,
- Konstantinos Tziouvas, University of Athens ,
- Annemarie A van Elburg, Altrecht Mental Health Institute ,
- Eric F van Furth, Center for Eating Disorders Ursula ,
- Gudrun Wagner, Medical University of Vienna ,
- Esther Walton, Technische Universität Dresden ,
- Elisabeth Widen, University of Helsinki ,
- Eleftheria Zeggini, Wellcome Sanger Institute ,
- Stephanie Zerwas, University of North Carolina ,
- Stephan Zipfel, Tübingen University Hospital ,
- Andrew W Bergen, BioRealm LLC ,
- Joseph M Boden, University of Otago ,
- Harry Brandt, The Center for Eating Disorders at Sheppard Pratt, 6501 N. Charles Street, Baltimore, MD 21204, USA. ,
- Steven Crawford, The Center for Eating Disorders at Sheppard Pratt, 6501 N. Charles Street, Baltimore, MD 21204, USA. ,
- Katherine A Halmi, Weill Cornell Med Qatar, Weill Cornell Medical College Qatar ,
- L John Horwood, University of Otago ,
- Craig Johnson, Eating Recovery Center ,
- Allan S Kaplan, University of Toronto ,
- Walter H Kaye, University of California at San Diego ,
- James Mitchell, University of North Dakota ,
- Catherine M Olsen, QIMR Berghofer Medical Research Institute ,
- John F Pearson, University of Otago ,
- Nancy L Pedersen, Karolinska Institutet ,
- Michael Strober, University of California at Los Angeles ,
- Thomas Werge, University of Copenhagen ,
- David C Whiteman, QIMR Berghofer Medical Research Institute ,
- D Blake Woodside, University of Toronto ,
- Jakob Grove
- Anjali K Henders, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au. ,
- Janne T Larsen
- Richard Parker, QIMR Berghofer Medical Research Institute ,
- Liselotte V Petersen
- Jennifer Jordan, University of Otago ,
- Martin A Kennedy, University of Otago ,
- Andreas Birgegård, Karolinska Institutet ,
- Paul Lichtenstein, Karolinska Institutet ,
- Claes Norring, Karolinska Institutet ,
- Mikael Landén, Karolinska Institutet ,
- Preben Bo Mortensen
- Renato Polimanti, Yale University ,
- Jeanette N McClintick, Indiana University School of Medicine, South Bend, Indiana ,
- Amy E Adkins, Virginia Commonwealth University ,
- Fazil Aliev, Virginia Commonwealth University ,
- Silviu-Alin Bacanu, Virginia Commonwealth University ,
- Anthony Batzler, Psychiatric Genomics and Pharmacogenomics Program ,
- Sarah Bertelsen, Icahn School of Medicine at Mount Sinai ,
- Joanna M Biernacka, Department of Health Sciences Research, Mayo Clinic. ,
- Tim B Bigdeli, State University of New York Downstate Medical Center ,
- Li-Shiun Chen, Washington University St. Louis ,
- Toni-Kim Clarke, University of Edinburgh ,
- Franziska Degenhardt, University of Bonn ,
- Anna R Docherty, University of Utah ,
- Alexis C Edwards, Virginia Commonwealth University ,
- Jerome C Foo, Heidelberg University ,
- Louis Fox, Washington University St. Louis ,
- Josef Frank, Heidelberg University ,
- Laura M Hack, Stanford University ,
- Annette M Hartmann, Martin Luther University Halle-Wittenberg ,
- Sarah M Hartz, Washington University St. Louis ,
- Stefanie Heilmann-Heimbach, University of Bonn ,
- Colin Hodgkinson, Laboratory for Neurogenetics, National Institutes for Health, Bethesda, USA. ,
- Per Hoffmann, University of Basel ,
- Jouke-Jan Hottenga, Amsterdam Public Health Research Institute ,
- Bettina Konte, Martin Luther University Halle-Wittenberg ,
- Jari Lahti, University of Turku ,
- Marius Lahti-Pulkkinen, University of Helsinki ,
- Dongbing Lai, Indiana University School of Medicine, South Bend, Indiana ,
- Lannie Ligthart, Amsterdam Public Health Research Institute ,
- Anu Loukola, University of Helsinki ,
- Brion S Maher, Johns Hopkins University ,
- Hamdi Mbarek, Amsterdam Public Health Research Institute ,
- Andrew M McIntosh, University of Edinburgh ,
- Matthew B McQueen, University of Colorado Boulder ,
- Jacquelyn L Meyers, SUNY-Downstate Medical Center,
- Yuri Milaneschi, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands. ,
- Teemu Palviainen, University of Helsinki ,
- Roseann E Peterson, Virginia Commonwealth University ,
- Euijung Ryu, Department of Health Sciences Research, Mayo Clinic. ,
- Nancy L Saccone, Washington University St. Louis ,
- Jessica E Salvatore, Virginia Commonwealth University ,
- Sandra Sanchez-Roige, University of California at San Diego ,
- Melanie Schwandt, Office of the Clinical Director , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. ,
- Richard Sherva, Boston University ,
- Fabian Streit, Heidelberg University ,
- Jana Strohmaier, Heidelberg University ,
- Nathaniel Thomas, Virginia Commonwealth University ,
- Jen-Chyong Wang, Icahn School of Medicine at Mount Sinai ,
- Bradley T Webb, Virginia Commonwealth University ,
- Robbee Wedow, Harvard University ,
- Leah Wetherill, Indiana University School of Medicine, South Bend, Indiana ,
- Amanda G Wills, University of Colorado Anschutz Medical Campus ,
- Hang Zhou, Yale University ,
- Jason D Boardman, University of Colorado Denver ,
- Danfeng Chen, Broad Institute ,
- Doo-Sup Choi, Mayo Clinic Rochester, MN ,
- William E Copeland, University of Vermont ,
- Robert C Culverhouse, Washington University St. Louis ,
- Norbert Dahmen, University Medical Centre Mainz, Mainz, Germany ,
- Louisa Degenhardt, University of New South Wales ,
- Benjamin W Domingue, University of California at San Diego ,
- Mark A Frye, University of Balamand ,
- Wolfgang Gäebel, Heinrich Heine University Düsseldorf ,
- Caroline Hayward, University of Edinburgh ,
- Marcus Ising, Max Planck Institute of Psychiatry ,
- Margaret Keyes, University of Minnesota ,
- Falk Kiefer, Heidelberg University ,
- Gabriele Koller, Ludwig Maximilian University ,
- John Kramer, University of Iowa ,
- Samuel Kuperman, University of Iowa ,
- Susanne Lucae, Max Planck Institute of Psychiatry ,
- Michael T Lynskey, King's College London ,
- Wolfgang Maier, University of Bonn ,
- Karl Mann, Heidelberg University ,
- Satu Männistö, National Institute for Health and Welfare ,
- Bertram Müller-Myhsok, Max Planck Institute of Psychiatry ,
- Alison D Murray, University of Aberdeen ,
- John I Nurnberger, Indiana University School of Medicine, South Bend, Indiana ,
- Ulrich Preuss, Martin Luther University Halle-Wittenberg ,
- Katri Räikkönen, University of Helsinki ,
- Maureen D Reynolds, University of Pittsburgh ,
- Monika Ridinger, University of Regensburg ,
- Norbert Scherbaum, University of Duisburg-Essen ,
- Marc A Schuckit, University of California at San Diego ,
- Michael Soyka, Ludwig Maximilian University ,
- Jens Treutlein, Heidelberg University ,
- Stephanie H Witt, Heidelberg University ,
- Norbert Wodarz, University of Regensburg ,
- Peter Zill, Ludwig Maximilian University ,
- Daniel E Adkins, University of Utah ,
- Dorret I Boomsma, Amsterdam Public Health Research Institute ,
- Laura J Bierut, Washington University St. Louis ,
- Sandra A Brown, University of California at San Diego ,
- Kathleen K Bucholz, Washington University St. Louis ,
- E Jane Costello, Duke University ,
- Harriet de Wit, University of Chicago ,
- Nancy Diazgranados, NIAAA Intramural Research Program ,
- Johan G Eriksson, University of Helsinki ,
- Lindsay A Farrer, Boston University ,
- Tatiana M Foroud, Indiana University School of Medicine, South Bend, Indiana ,
- Nathan A Gillespie, Virginia Commonwealth University ,
- Alison M Goate, Icahn School of Medicine at Mount Sinai ,
- David Goldman, Laboratory for Neurogenetics, National Institutes for Health, Bethesda, USA. ,
- Richard A Grucza, Washington University St. Louis ,
- Dana B Hancock, Center for Omics Discovery and Epidemiology ,
- Kathleen Mullan Harris, University of North Carolina ,
- Victor Hesselbrock, University of Connecticut ,
- John K Hewitt, University of Colorado Boulder ,
- Christian J Hopfer, University of Colorado Denver ,
- William G Iacono, University of Minnesota ,
- Eric O Johnson, Center for Omics Discovery and Epidemiology ,
- Victor M Karpyak, University of Balamand ,
- Kenneth S Kendler, Virginia Commonwealth University ,
- Henry R Kranzler, University of Pennsylvania ,
- Kenneth Krauter, University of Colorado Boulder ,
- Penelope A Lind, QIMR Berghofer Medical Research Institute ,
- Matt McGue, University of Minnesota ,
- James MacKillop, Firestone Institute for Respiratory Health, Department of Medicine, St. Joseph's Hospital Healthcare, McMaster University, Hamilton, Canada. ,
- Pamela A F Madden, Washington University St. Louis ,
- Hermine H Maes, Virginia Commonwealth University ,
- Patrik K E Magnusson, Karolinska Institutet ,
- Elliot C Nelson, Washington University St. Louis ,
- Markus M Nöthen, University of Bonn ,
- Abraham A Palmer, University of California at San Diego ,
- Brenda W J H Penninx, VU University and GGZinGeest ,
- Bernice Porjesz, SUNY-Downstate Medical Center,
- John P Rice, Washington University St. Louis ,
- Marcella Rietschel, Heidelberg University ,
- Brien P Riley, Virginia Commonwealth University ,
- Richard J Rose, Indiana Univ, Indiana University Bloomington, Indiana University System, Dept Biol ,
- Pei-Hong Shen, Laboratory for Neurogenetics, National Institutes for Health, Bethesda, USA. ,
- Judy Silberg, Virginia Commonwealth University ,
- Michael C Stallings, University of Colorado Boulder ,
- Ralph E Tarter, University of Pittsburgh ,
- Michael M Vanyukov, University of Pittsburgh ,
- Scott Vrieze, University of Minnesota ,
- Tamara L Wall, University of California at San Diego ,
- John B Whitfield, QIMR Berghofer Medical Research Institute ,
- Hongyu Zhao, Yale University ,
- Benjamin M Neale, Harvard University ,
- Tracey D Wade, Flinders University ,
- Andrew C Heath, Washington University St. Louis ,
- Grant W Montgomery, QIMR Berghofer Medical Research Institute ,
- Nicholas G Martin, QIMR Berghofer Medical Research Institute ,
- Patrick F Sullivan, University of North Carolina ,
- Jaakko Kaprio, University of Helsinki ,
- Gerome Breen, King's College London ,
- Joel Gelernter, Yale University ,
- Howard J Edenberg, Indiana University School of Medicine, South Bend, Indiana ,
- Cynthia M Bulik, University of North Carolina ,
- Arpana Agrawal, Washington University St. Louis
- PoNE - Attitudes - social welfare - cheaters
- Department of Biomedicine - Forskning og uddannelse, Skou-bygningen
- Department of Molecular Biology and Genetics - Bioinformatics Research Centre (BiRC)
- National Centre for Register-based Research
- National Centre for Register-based Research - CIRRAU - Centre for Integrated Register-based Research
Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
| Original language | English |
|---|---|
| Article number | e12880 |
| Journal | Addiction Biology |
| Volume | 26 |
| Issue | 1 |
| Number of pages | 20 |
| ISSN | 1355-6215 |
| DOIs | |
| Publication status | Published - Jan 2021 |
- Alcoholism/genetics, Depressive Disorder, Major/genetics, Feeding and Eating Disorders/genetics, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Schizophrenia/genetics, Substance-Related Disorders/genetics, Tobacco Use Disorder/genetics
Research areas
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ID: 190441593