Browsing by Author "Vilar-Ribó, Laura"

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    A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals
    (Elsevier, 2024) Jennings, Mariela V.; Martínez-Magaña, José Jaime; Courchesne-Krak, Natasia S.; Cupertino, Renata B.; Vilar-Ribó, Laura; Bianchi, Sevim B.; Hatoum, Alexander S.; Atkinson, Elizabeth G.; Giusti-Rodriguez, Paola; Montalvo-Ortiz, Janitza L.; Gelernter, Joel; Soler Artigas, María; 23andMe, Inc. Research Team; Elson, Sarah L.; Edenberg, Howard J.; Fontanillas, Pierre; Palmer, Abraham A.; Sanchez-Roige, Sandra; Biochemistry and Molecular Biology, School of Medicine
    Background: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. Methods: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. Findings: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. Interpretation: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine.
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    Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
    (Elsevier, 2022-02-01) 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; Artigas, María Soler; Van der Auwera, Sandra; 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; 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.; Weickert, Cynthia Shannon; 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; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Eating Disorders Working Group of the Psychiatric Genomics Consortium; German Borderline Genomics Consortium; MVP Suicide Exemplar Workgroup; VA Million Veteran Program; Medical and Molecular Genetics, School of Medicine
    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.
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    GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors
    (American Psychiatric Association, 2023) Docherty, Anna R.; Mullins, Niamh; Ashley-Koch, Allison E.; Qin, Xuejun; Coleman, Jonathan R. I.; Shabalin, Andrey; Kang, JooEun; Murnyak, Balasz; Wendt, Frank; Adams, Mark; Campos, Adrian I.; DiBlasi, Emily; Fullerton, Janice M.; Kranzler, Henry R.; Bakian, Amanda V.; Monson, Eric T.; Rentería, Miguel E.; Walss-Bass, Consuelo; Andreassen, Ole A.; Behera, Chittaranjan; Bulik, Cynthia M.; Edenberg, Howard J.; Kessler, Ronald C.; Mann, J. John; Nurnberger, John I., Jr.; Pistis, Giorgio; Streit, Fabian; Ursano, Robert J.; Polimanti, Renato; Dennis, Michelle; Garrett, Melanie; Hair, Lauren; Harvey, Philip; Hauser, Elizabeth R.; Hauser, Michael A.; Huffman, Jennifer; Jacobson, Daniel; Madduri, Ravi; McMahon, Benjamin; Oslin, David W.; Trafton, Jodie; Awasthi, Swapnil; Berrettini, Wade H.; Bohus, Martin; Chang, Xiao; Chen, Hsi-Chung; Chen, Wei J.; Christensen, Erik D.; Crow, Scott; Duriez, Philibert; Edwards, Alexis C.; Fernández-Aranda, Fernando; Galfalvy, Hanga; Gandal, Michael; Gorwood, Philip; Guo, Yiran; Hafferty, Jonathan D.; Hakonarson, Hakon; Halmi, Katherine A.; Hishimoto, Akitoyo; Jain, Sonia; Jamain, Stéphane; Jiménez-Murcia, Susana; Johnson, Craig; Kaplan, Allan S.; Kaye, Walter H.; Keel, Pamela K.; Kennedy, James L.; Kim, Minsoo; Klump, Kelly L.; Levey, Daniel F.; Li, Dong; Liao, Shih-Cheng; Lieb, Klaus; Lilenfeld, Lisa; Marshall, Christian R.; Mitchell, James E.; Okazaki, Satoshi; Otsuka, Ikuo; Pinto, Dalila; Powers, Abigail; Ramoz, Nicolas; Ripke, Stephan; Roepke, Stefan; Rozanov, Vsevolod; Scherer, Stephen W.; Schmahl, Christian; Sokolowski, Marcus; Starnawska, Anna; Strober, Michael; Su, Mei-Hsin; Thornton, Laura M.; Treasure, Janet; Ware, Erin B.; Watson, Hunna J.; Witt, Stephanie H.; Woodside, D. Blake; Yilmaz, Zeynep; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Alda, Martin; Alfredsson, Lars; Appadurai, Vivek; Artigas, María Soler; Van der Auwera, Sandra; 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.; Braff, David L.; Bryant, Richard; Budde, Monika; Byrne, Enda M.; Cahn, Wiepke; Castelao, Enrique; Cervilla, Jorge A.; Chaumette, Boris; Corvin, Aiden; Craddock, Nicholas; Djurovic, Srdjan; Foo, Jerome C.; Forstner, Andreas J.; Frye, Mark; Gatt, Justine M.; Giegling, Ina; Grabe, Hans J.; Green, Melissa J.; Grevet, Eugenio H.; Grigoroiu-Serbanescu, Maria; Gutierrez, Blanca; Guzman-Parra, Jose; Hamshere, Marian L.; Hartmann, Annette M.; 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; Krebs, Marie-Odile; Landén, Mikael; Leboyer, Marion; Lee, Phil H.; Levinson, Douglas F.; Liao, Calwing; Lissowska, Jolanta; Mayoral, Fermin; McElroy, Susan L.; McGrath, Patrick; McGuffin, Peter; McQuillin, Andrew; Mehta, Divya; Melle, Ingrid; Mitchell, Philip B.; Molina, Esther; Morken, Gunnar; Nievergelt, Caroline; Nöthen, Markus M.; O'Donovan, Michael C.; Ophoff, Roel A.; Owen, Michael J.; Pato, Carlos; Pato, Michele T.; Penninx, Brenda W. J. H.; 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.; Sanders, Alan R.; Schofield, Peter R.; Schulze, Thomas G.; Scott, Laura J.; Serretti, Alessandro; Shi, Jianxin; Sirignano, Lea; Sklar, Pamela; Smeland, Olav B.; Smoller, Jordan W.; Sonuga-Barke, Edmund J. S.; Trzaskowski, Maciej; Tsuang, Ming T.; Turecki, Gustavo; Vilar-Ribó, Laura; Vincent, John B.; Völzke, Henry; Walters, James T. R.; Weickert, Cynthia Shannon; Weickert, Thomas W.; Weissman, Myrna M.; Williams, Leanne M.; Wray, Naomi R.; Zai, Clement C.; Agerbo, Esben; Børglum, Anders D.; Breen, Gerome; Demontis, Ditte; Erlangsen, Annette; Gelernter, Joel; Glatt, Stephen J.; Hougaard, David M.; Hwu, Hai-Gwo; Kuo, Po-Hsiu; Lewis, Cathryn M.; Li, Qingqin S.; Liu, Chih-Min; Martin, Nicholas G.; McIntosh, Andrew M.; Medland, Sarah E.; Mors, Ole; Nordentoft, Merete; Olsen, Catherine M.; Porteous, David; Smith, Daniel J.; Stahl, Eli A.; Stein, Murray B.; Wasserman, Danuta; Werge, Thomas; Whiteman, David C.; Willour, Virginia; VA Million Veteran Program (MVP); MVP Suicide Exemplar Workgroup; Suicide Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Eating Disorder Working Group of the Psychiatric Genomics Consortium; German Borderline Genomics Consortium; Coon, Hilary; Beckham, Jean C.; Kimbrel, Nathan A.; Ruderfer, Douglas M.; Psychiatry, School of Medicine
    Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.