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1. Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes

Author

Toikumo, Sylvanus, Jennings, Mariela V, Pham, Benjamin K, Lee, Hyunjoon, Mallard, Travis T, Bianchi, Sevim B, Meredith, John J, Vilar-Ribo, Laura, Xu, Heng, Hatoum, Alexander S, Johnson, Emma C, Pazdernik, Vanessa K, Jinwala, Zeal, Pakala, Shreya R, Leger, Brittany S, Niarchou, Maria, Ehinmowo, Michael, Jenkins, Greg D, Batzler, Anthony, Pendegraft, Richard, Palmer, Abraham A, Zhou, Hang, Biernacka, Joanna M, Coombes, Brandon J, Gelernter, Joel, Xu, Ke, Hancock, Dana B, Cox, Nancy J, Smoller, Jordan W, Davis, Lea K, Justice, Amy C, Kranzler, Henry R, Kember, Rachel L, and Sanchez-Roige, Sandra

Subjects
Biomedical and Clinical Sciences, Health Sciences, Substance Misuse, Drug Abuse (NIDA only), Prevention, Tobacco, Brain Disorders, Genetics, Human Genome, Tobacco Smoke and Health, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Tobacco Use Disorder, Genetic Predisposition to Disease, Genome-Wide Association Study, United States, Male, Female, Electronic Health Records, Penn Medicine BioBank, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Published
2024

4. Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

Author

Zhou, Hang, Kember, Rachel L., Deak, Joseph D., Xu, Heng, Toikumo, Sylvanus, Yuan, Kai, Lind, Penelope A., Farajzadeh, Leila, Wang, Lu, Hatoum, Alexander S., Johnson, Jessica, Lee, Hyunjoon, Mallard, Travis T., Xu, Jiayi, Johnston, Keira J. A., Johnson, Emma C., Nielsen, Trine Tollerup, Galimberti, Marco, Dao, Cecilia, Levey, Daniel F., Overstreet, Cassie, Byrne, Enda M., Gillespie, Nathan A., Gordon, Scott, Hickie, Ian B., Whitfield, John B., Xu, Ke, Zhao, Hongyu, Huckins, Laura M., Davis, Lea K., Sanchez-Roige, Sandra, Madden, Pamela A. F., Heath, Andrew C., Medland, Sarah E., Martin, Nicholas G., Ge, Tian, Smoller, Jordan W., Hougaard, David M., Børglum, Anders D., Demontis, Ditte, Krystal, John H., Gaziano, J. Michael, Edenberg, Howard J., Agrawal, Arpana, Justice, Amy C., Stein, Murray B., Kranzler, Henry R., and Gelernter, Joel

Published
2023
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6. CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

Author

Sanchez-Roige, Sandra, Jennings, Mariela V, Thorpe, Hayley HA, Mallari, Jazlene E, van der Werf, Lieke C, Bianchi, Sevim B, Huang, Yuye, Lee, Calvin, Mallard, Travis T, Barnes, Samuel A, Wu, Jin Yi, Barkley-Levenson, Amanda M, Boussaty, Ely C, Snethlage, Cedric E, Schafer, Danielle, Babic, Zeljana, Winters, Boyer D, Watters, Katherine E, Biederer, Thomas, Mackillop, James, Stephens, David N, Elson, Sarah L, Fontanillas, Pierre, Khokhar, Jibran Y, Young, Jared W, and Palmer, Abraham A

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Social and Personality Psychology, Psychology, Pharmacology and Pharmaceutical Sciences, Behavioral and Social Science, Clinical Research, Mental Health, Human Genome, Substance Misuse, Drug Abuse (NIDA only), Genetics, Basic Behavioral and Social Science, Brain Disorders, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Good Health and Well Being, Humans, Animals, Mice, Genome-Wide Association Study, Phenotype, Impulsive Behavior, Substance-Related Disorders, Personality, Polymorphism, Single Nucleotide, Cell Adhesion Molecules, 23andMe Research Team, Clinical Sciences, Public Health and Health Services, Clinical sciences, Neurosciences, Biological psychology
Abstract

Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N = 123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N = 130,684). Because these GWAS implicated the gene CADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American). Finally, we produced Cadm2 mutant mice and used them to perform a Mouse-PheWAS ("MouseWAS") by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (~6-11%), and moderate genetic correlations (rg = 0.20-0.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such as TCF4 and PTPRF, and also identified nominal associations proximal to DRD2 and CRHR1. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.

Published
2023

7. 69. CADM2 IS IMPLICATED IN IMPULSIVE PERSONALITY AND NUMEROUS OTHER TRAITS BY GENOME- AND PHENOME-WIDE ASSOCIATION STUDIES IN HUMANS, WITH FURTHER SUPPORT FROM STUDIES OF CADM2 MUTANT MICE

Author

Sanchez-Roige, Sandra, Jennings, Mariela V, Thorpe, Hayley HA, Mallari, Jazlene, van der Werf, Lieke C, Bianchi, Sevim B, Mallard, Travis T, Watters, Katherine E, Biederer, Thomas, Team, 23andMe Research, Elson, Sarah L, Fontanillas, Pierre, Khokhar, Jibran Y, Young, Jared W, and Palmer, Abraham A

Subjects
Biological Psychology, Psychology, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Neurosciences, Biological psychology
Published
2022

8. Atypical Brain Aging and Its Association With Working Memory Performance in Major Depressive Disorder

Author

Adamson, Chris, Adler, Sophie, Alexander-Bloch, Aaron F., Anagnostou, Evdokia, Anderson, Kevin M., Areces-Gonzalez, Ariosky, Astle, Duncan E., Auyeung, Bonnie, Ayub, Muhammad, Bae, Jong Bin, Ball, Gareth, Baron-Cohen, Simon, Beare, Richard, Bedford, Saashi A., Benegal, Vivek, Bethlehem, Richard A.I., Beyer, Frauke, Blangero, John, Cábez, Manuel Blesa, Boardman, James P., Borzage, Matthew, Bosch-Bayard, Jorge F., Bourke, Niall, Bullmore, Edward T., Calhoun, Vince D., Chakravarty, Mallar M., Chen, Christina, Chertavian, Casey, Chetelat, Gaël, Chong, Yap S., Corvin, Aiden, Costantino, Manuela, Courchesne, Eric, Crivello, Fabrice, Cropley, Vanessa L., Crosbie, Jennifer, Crossley, Nicolas, Delarue, Marion, Delorme, Richard, Desrivieres, Sylvane, Devenyi, Gabriel, Di Biase, Maria A., Dolan, Ray, Donald, Kirsten A., Donohoe, Gary, Dorfschmidt, Lena, Dunlop, Katharine, Edwards, Anthony D., Elison, Jed T., Ellis, Cameron T., Elman, Jeremy A., Eyler, Lisa, Fair, Damien A., Fletcher, Paul C., Fonagy, Peter, Franz, Carol E., Galan-Garcia, Lidice, Gholipour, Ali, Giedd, Jay, Gilmore, John H., Glahn, David C., Goodyer, Ian M., Grant, P.E., Groenewold, Nynke A., Gudapati, Shreya, Gunning, Faith M., Gur, Raquel E., Gur, Ruben C., Hammill, Christopher F., Hansson, Oskar, Hedden, Trey, Heinz, Andreas, Henson, Richard N., Heuer, Katja, Hoare, Jacqueline, Holla, Bharath, Holmes, Avram J., Huang, Hao, Ipser, Jonathan, Jack, Clifford R., Jr., Jackowski, Andrea P., Jia, Tianye, Jones, David T., Jones, Peter B., Kahn, Rene S., Karlsson, Hasse, Karlsson, Linnea, Kawashima, Ryuta, Kelley, Elizabeth A., Kern, Silke, Kim, Ki-Woong, Kitzbichler, Manfred G., Kremen, William S., Lalonde, François, Landeau, Brigitte, Lerch, Jason, Lewis, John D., Li, Jiao, Liao, Wei, Liston, Conor, Lombardo, Michael V., Lv, Jinglei, Mallard, Travis T., Marcelis, Machteld, Mathias, Samuel R., Mazoyer, Bernard, McGuire, Philip, Meaney, Michael J., Mechelli, Andrea, Misic, Bratislav, Morgan, Sarah E., Mothersill, David, Ortinau, Cynthia, Ossenkoppele, Rik, Ouyang, Minhui, Palaniyappan, Lena, Paly, Leo, Pan, Pedro M., Pantelis, Christos, Park, Min Tae M., Paus, Tomas, Pausova, Zdenka, Paz-Linares, Deirel, Binette, Alexa Pichet, Pierce, Karen, Qian, Xing, Qiu, Anqi, Raznahan, Armin, Rittman, Timothy, Rodrigue, Amanda, Rollins, Caitlin K., Romero-Garcia, Rafael, Ronan, Lisa, Rosenberg, Monica D., Rowitch, David H., Salum, Giovanni A., Satterthwaite, Theodore D., Schaare, H. Lina, Schabdach, Jenna, Schachar, Russell J., Schöll, Michael, Schultz, Aaron P., Seidlitz, Jakob, Sharp, David, Shinohara, Russell T., Skoog, Ingmar, Smyser, Christopher D., Sperling, Reisa A., Stein, Dan J., Stolicyn, Aleks, Suckling, John, Sullivan, Gemma, Thyreau, Benjamin, Toro, Roberto, Traut, Nicolas, Tsvetanov, Kamen A., Turk-Browne, Nicholas B., Tuulari, Jetro J., Tzourio, Christophe, Vachon-Presseau, Étienne, Valdes-Sosa, Mitchell J., Valdes-Sosa, Pedro A., Valk, Sofie L., van Amelsvoort, Therese, Vandekar, Simon N., Vasung, Lana, Vértes, Petra E., Victoria, Lindsay W., Villeneuve, Sylvia, Villringer, Arno, Vogel, Jacob W., Wagstyl, Konrad, Wang, Yin-Shan S., Warfield, Simon K., Warrier, Varun, Westman, Eric, Westwater, Margaret L., Whalley, Heather C., White, Simon R., Witte, A. Veronica, Yang, Ning, Yeo, B.T. Thomas, Yun, Hyuk Jin, Zalesky, Andrew, Zar, Heather J., Zettergren, Anna, Zhou, Juan H., Ziauddeen, Hisham, Zimmerman, Dabriel, Zugman, Andre, Zuo, Xi-Nian N., Ho, Natalie C.W., Nogovitsyn, Nikita, Metzak, Paul, Ballester, Pedro L., Hassel, Stefanie, Rotzinger, Susan, Poppenk, Jordan, Lam, Raymond W., Taylor, Valerie H., Milev, Roumen, Frey, Benicio N., Harkness, Kate L., Addington, Jean, and Kennedy, Sidney H.

Published
2024
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9. Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes

Author

Warrier, Varun, Stauffer, Eva-Maria, Huang, Qin Qin, Wigdor, Emilie M., Slob, Eric A. W., Seidlitz, Jakob, Ronan, Lisa, Valk, Sofie L., Mallard, Travis T., Grotzinger, Andrew D., Romero-Garcia, Rafael, Baron-Cohen, Simon, Geschwind, Daniel H., Lancaster, Madeline A., Murray, Graham K., Gandal, Michael J., Alexander-Bloch, Aaron, Won, Hyejung, Martin, Hilary C., Bullmore, Edward T., and Bethlehem, Richard A. I.

Published
2023
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13. Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Author

Jami, Eshim S, Hammerschlag, Anke R, Ip, Hill F, Allegrini, Andrea G, Benyamin, Beben, Border, Richard, Diemer, Elizabeth W, Jiang, Chang, Karhunen, Ville, Lu, Yi, Lu, Qing, Mallard, Travis T, Mishra, Pashupati P, Nolte, Ilja M, Palviainen, Teemu, Peterson, Roseann E, Sallis, Hannah M, Shabalin, Andrey A, Tate, Ashley E, Thiering, Elisabeth, Vilor-Tejedor, Natàlia, Wang, Carol, Zhou, Ang, Adkins, Daniel E, Alemany, Silvia, Ask, Helga, Chen, Qi, Corley, Robin P, Ehli, Erik A, Evans, Luke M, Havdahl, Alexandra, Hagenbeek, Fiona A, Hakulinen, Christian, Henders, Anjali K, Hottenga, Jouke Jan, Korhonen, Tellervo, Mamun, Abdullah, Marrington, Shelby, Neumann, Alexander, Rimfeld, Kaili, Rivadeneira, Fernando, Silberg, Judy L, van Beijsterveldt, Catharina E, Vuoksimaa, Eero, Whipp, Alyce M, Tong, Xiaoran, Andreassen, Ole A, Boomsma, Dorret I, Brown, Sandra A, Burt, S Alexandra, Copeland, William, Dick, Danielle M, Harden, K Paige, Harris, Kathleen Mullan, Hartman, Catharina A, Heinrich, Joachim, Hewitt, John K, Hopfer, Christian, Hypponen, Elina, Jarvelin, Marjo-Riitta, Kaprio, Jaakko, Keltikangas-Järvinen, Liisa, Klump, Kelly L, Krauter, Kenneth, Kuja-Halkola, Ralf, Larsson, Henrik, Lehtimäki, Terho, Lichtenstein, Paul, Lundström, Sebastian, Maes, Hermine H, Magnus, Per, Munafò, Marcus R, Najman, Jake M, Njølstad, Pål R, Oldehinkel, Albertine J, Pennell, Craig E, Plomin, Robert, Reichborn-Kjennerud, Ted, Reynolds, Chandra, Rose, Richard J, Smolen, Andrew, Snieder, Harold, Stallings, Michael, Standl, Marie, Sunyer, Jordi, Tiemeier, Henning, Wadsworth, Sally J, Wall, Tamara L, Whitehouse, Andrew JO, Williams, Gail M, Ystrøm, Eivind, Nivard, Michel G, Bartels, Meike, and Middeldorp, Christel M

Subjects
Biological Psychology, Psychology, Serious Mental Illness, Brain Disorders, Pediatric, Human Genome, Genetics, Behavioral and Social Science, Depression, Mental Health, Mental Illness, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Mental health, Adolescent, Adult, Aggression, Anxiety, Attention Deficit Disorder with Hyperactivity, Autistic Disorder, Bipolar Disorder, Child, Child, Preschool, Genome-Wide Association Study, Humans, Loneliness, Polymorphism, Single Nucleotide, Schizophrenia, Sleep Initiation and Maintenance Disorders, depression, anxiety, repeated measures, genetic epidemiology, molecular genetics, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental & Child Psychology, Clinical sciences, Paediatrics, Applied and developmental psychology
Abstract

ObjectiveTo investigate the genetic architecture of internalizing symptoms in childhood and adolescence.MethodIn 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.ResultsThe meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.ConclusionGenetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Published
2022

14. Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

Author

Mallard, Travis T, Linnér, Richard Karlsson, Grotzinger, Andrew D, Sanchez-Roige, Sandra, Seidlitz, Jakob, Okbay, Aysu, de Vlaming, Ronald, Meddens, S Fleur W, Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics, Palmer, Abraham A, Davis, Lea K, Tucker-Drob, Elliot M, Kendler, Kenneth S, Keller, Matthew C, Koellinger, Philipp D, and Harden, K Paige

Subjects
Biological Psychology, Biological Sciences, Genetics, Psychology, Behavioral and Social Science, Brain Disorders, Depression, Schizophrenia, Mental Health, Human Genome, Mental Illness, Serious Mental Illness, Neurosciences, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Mental health, Good Health and Well Being, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
Abstract

Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree.

Published
2022

15. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author

Howe, Laurence J, Nivard, Michel G, Morris, Tim T, Hansen, Ailin F, Rasheed, Humaira, Cho, Yoonsu, Chittoor, Geetha, Ahlskog, Rafael, Lind, Penelope A, Palviainen, Teemu, van der Zee, Matthijs D, Cheesman, Rosa, Mangino, Massimo, Wang, Yunzhang, Li, Shuai, Klaric, Lucija, Ratliff, Scott M, Bielak, Lawrence F, Nygaard, Marianne, Giannelis, Alexandros, Willoughby, Emily A, Reynolds, Chandra A, Balbona, Jared V, Andreassen, Ole A, Ask, Helga, Baras, Aris, Bauer, Christopher R, Boomsma, Dorret I, Campbell, Archie, Campbell, Harry, Chen, Zhengming, Christofidou, Paraskevi, Corfield, Elizabeth, Dahm, Christina C, Dokuru, Deepika R, Evans, Luke M, de Geus, Eco JC, Giddaluru, Sudheer, Gordon, Scott D, Harden, K Paige, Hill, W David, Hughes, Amanda, Kerr, Shona M, Kim, Yongkang, Kweon, Hyeokmoon, Latvala, Antti, Lawlor, Deborah A, Li, Liming, Lin, Kuang, Magnus, Per, Magnusson, Patrik KE, Mallard, Travis T, Martikainen, Pekka, Mills, Melinda C, Njølstad, Pål Rasmus, Overton, John D, Pedersen, Nancy L, Porteous, David J, Reid, Jeffrey, Silventoinen, Karri, Southey, Melissa C, Stoltenberg, Camilla, Tucker-Drob, Elliot M, Wright, Margaret J, Hewitt, John K, Keller, Matthew C, Stallings, Michael C, Lee, James J, Christensen, Kaare, Kardia, Sharon LR, Peyser, Patricia A, Smith, Jennifer A, Wilson, James F, Hopper, John L, Hägg, Sara, Spector, Tim D, Pingault, Jean-Baptiste, Plomin, Robert, Havdahl, Alexandra, Bartels, Meike, Martin, Nicholas G, Oskarsson, Sven, Justice, Anne E, Millwood, Iona Y, Hveem, Kristian, Naess, Øyvind, Willer, Cristen J, Åsvold, Bjørn Olav, Koellinger, Philipp D, Kaprio, Jaakko, Medland, Sarah E, Walters, Robin G, Benjamin, Daniel J, Turley, Patrick, Evans, David M, Davey Smith, George, Hayward, Caroline, Brumpton, Ben, Hemani, Gibran, and Davies, Neil M

Subjects
Human Genome, Genetics, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Mental health, Generic health relevance, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Social Science Genetic Association Consortium, Within Family Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Published
2022

17. Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk

Author

Barr, Peter B, Mallard, Travis T, Sanchez-Roige, Sandra, Poore, Holly E, Linnér, Richard Karlsson, Waldman, Irwin D, Palmer, Abraham A, Harden, K Paige, and Dick, Danielle M

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Human Genome, Genetics, Underage Drinking, Prevention, Substance Misuse, Brain Disorders, Alcoholism, Alcohol Use and Health, Mental Health, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Mental health, Cardiovascular, Oral and gastrointestinal, Good Health and Well Being, Alcohol Drinking, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Substance-Related Disorders, COGA Collaborators, Clinical Sciences, Public Health and Health Services, Clinical sciences, Neurosciences, Biological psychology
Abstract

Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multivariate GWAS to tease apart variants associated with problematic alcohol use (ALCP-total) through either a shared risk for externalizing (EXT) or a problematic alcohol use-specific risk (ALCP-specific). SNPs associated with ALCP-specific were primarily related to alcohol metabolism. Genetic correlations showed ALCP-specific was predominantly associated with alcohol use and other forms of psychopathology, but not other forms of substance use. Polygenic scores for ALCP-total were associated with multiple forms of substance use, but polygenic scores for ALCP-specific were only associated with alcohol phenotypes. Polygenic scores for both ALCP-specific and EXT show different patterns of associations with alcohol misuse across development. Our results demonstrate that focusing on both shared and specific risk can better characterize pathways of risk for substance use disorders. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice.

Published
2022

18. Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts

Author

Mallard, Travis T, Savage, Jeanne E, Johnson, Emma C, Huang, Yuye, Edwards, Alexis C, Hottenga, Jouke J, Grotzinger, Andrew D, Gustavson, Daniel E, Jennings, Mariela V, Anokhin, Andrey, Dick, Danielle M, Edenberg, Howard J, Kramer, John R, Lai, Dongbing, Meyers, Jacquelyn L, Pandey, Ashwini K, Harden, Kathryn Paige, Nivard, Michel G, de Geus, Eco JC, Boomsma, Dorret I, Agrawal, Arpana, Davis, Lea K, Clarke, Toni-Kim, Palmer, Abraham A, and Sanchez-Roige, Sandra

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Mental Health, Alcoholism, Alcohol Use and Health, Substance Misuse, Brain Disorders, Human Genome, Prevention, Genetics, Cardiovascular, Oral and gastrointestinal, Mental health, Good Health and Well Being, Alcohol Drinking, Alcoholism, Genome-Wide Association Study, Humans, ALSPAC, Alcohol, Alcohol Consumption, GWAS, Genomic Structural Equation Modeling, Substance-Related and Addictive Disorders, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

ObjectiveGenome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.MethodsTo explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.ResultsThe authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.ConclusionsThis work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

Published
2022

19. Resource profile and user guide of the Polygenic Index Repository

Author

Becker, Joel, Burik, Casper AP, Goldman, Grant, Wang, Nancy, Jayashankar, Hariharan, Bennett, Michael, Belsky, Daniel W, Karlsson Linnér, Richard, Ahlskog, Rafael, Kleinman, Aaron, Hinds, David A, Caspi, Avshalom, Corcoran, David L, Moffitt, Terrie E, Poulton, Richie, Sugden, Karen, Williams, Benjamin S, Harris, Kathleen Mullan, Steptoe, Andrew, Ajnakina, Olesya, Milani, Lili, Esko, Tõnu, Iacono, William G, McGue, Matt, Magnusson, Patrik KE, Mallard, Travis T, Harden, K Paige, Tucker-Drob, Elliot M, Herd, Pamela, Freese, Jeremy, Young, Alexander, Beauchamp, Jonathan P, Koellinger, Philipp D, Oskarsson, Sven, Johannesson, Magnus, Visscher, Peter M, Meyer, Michelle N, Laibson, David, Cesarini, David, Benjamin, Daniel J, Turley, Patrick, and Okbay, Aysu

Subjects
Epidemiology, Health Sciences, 2.6 Resources and infrastructure (aetiology), Aetiology, Data Analysis, Databases, Genetic, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Polygenic score, Polygenic index, Repository, Measurement error, 23andMe Research Group, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs' prediction accuracies, we constructed them using genome-wide association studies-some not previously published-from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the 'additive SNP factor'. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available.

Published
2021

20. Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction

Author

Karlsson Linnér, Richard, Mallard, Travis T, Barr, Peter B, Sanchez-Roige, Sandra, Madole, James W, Driver, Morgan N, Poore, Holly E, de Vlaming, Ronald, Grotzinger, Andrew D, Tielbeek, Jorim J, Johnson, Emma C, Liu, Mengzhen, Rosenthal, Sara Brin, Ideker, Trey, Zhou, Hang, Kember, Rachel L, Pasman, Joëlle A, Verweij, Karin JH, Liu, Dajiang J, Vrieze, Scott, Kranzler, Henry R, Gelernter, Joel, Harris, Kathleen Mullan, Tucker-Drob, Elliot M, Waldman, Irwin D, Palmer, Abraham A, Harden, K Paige, Koellinger, Philipp D, and Dick, Danielle M

Subjects
Biological Psychology, Psychology, Opioids, Social Determinants of Health, Mental Illness, Genetics, Mental Health, Behavioral and Social Science, Basic Behavioral and Social Science, Brain Disorders, Human Genome, Drug Abuse (NIDA only), Neurosciences, Substance Misuse, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Attention Deficit Disorder with Hyperactivity, Behavior, Addictive, Behavioral Symptoms, Computational Biology, Crime, Genetic Association Studies, Genome-Wide Association Study, HIV Infections, Humans, Meta-Analysis as Topic, Multifactorial Inheritance, Multivariate Analysis, Opioid-Related Disorders, Reproducibility of Results, Self-Control, Suicide, Unemployment, COGA Collaborators, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates.

Published
2021

21. Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use

Author

Kuo, Sally I-Chun, Salvatore, Jessica E, Barr, Peter B, Aliev, Fazil, Anokhin, Andrey, Bucholz, Kathleen K, Chan, Grace, Edenberg, Howard J, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John R, Lai, Dongbing, Mallard, Travis T, Nurnberger, John I, Pandey, Gayathri, Plawecki, Martin H, Sanchez-Roige, Sandra, Waldman, Irwin, Palmer, Abraham A, and Dick, Danielle M

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Pediatric Research Initiative, Substance Misuse, Behavioral and Social Science, Genetics, Prevention, Pediatric, Basic Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adolescent, Adolescent Behavior, Child, Humans, Longitudinal Studies, Multifactorial Inheritance, Parenting, Parents, Peer Group, Risk Factors, Substance-Related Disorders, Adolescent externalizing, Polygenic score, Gene-environment interplay, Peers, Externalizing Consortium, Gene–environment interplay, Zoology, Neurosciences, Genetics & Heredity, Biomedical and clinical sciences, Health sciences
Abstract

Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene-environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; Mage = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene-environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.

Published
2021

22. The molecular genetic landscape of human brain size variation

Author

Seidlitz, Jakob, Mallard, Travis T., Vogel, Jacob W., Lee, Younga H., Warrier, Varun, Ball, Gareth, Hansson, Oskar, Hernandez, Leanna M., Mandal, Ayan S., Wagstyl, Konrad, Lombardo, Michael V., Courchesne, Eric, Glessner, Joseph T., Satterthwaite, Theodore D., Bethlehem, Richard A.I., Bernstock, Joshua D., Tasaki, Shinya, Ng, Bernard, Gaiteri, Chris, Smoller, Jordan W., Ge, Tian, Gur, Raquel E., Gandal, Michael J., and Alexander-Bloch, Aaron F.

Published
2023
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24. Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

Author

Tielbeek, Jorim J., Uffelmann, Emil, Williams, Benjamin S., Colodro-Conde, Lucía, Gagnon, Éloi, Mallard, Travis T., Levitt, Brandt E., Jansen, Philip R., Johansson, Ada, Sallis, Hannah M., Pistis, Giorgio, Saunders, Gretchen R. B., Allegrini, Andrea G., Rimfeld, Kaili, Konte, Bettina, Klein, Marieke, Hartmann, Annette M., Salvatore, Jessica E., Nolte, Ilja M., Demontis, Ditte, Malmberg, Anni L. K., Burt, S. Alexandra, Savage, Jeanne E., Sugden, Karen, Poulton, Richie, Harris, Kathleen Mullan, Vrieze, Scott, McGue, Matt, Iacono, William G., Mota, Nina Roth, Mill, Jonathan, Viana, Joana F., Mitchell, Brittany L., Morosoli, Jose J., Andlauer, Till F. M., Ouellet-Morin, Isabelle, Tremblay, Richard E., Côté, Sylvana M., Gouin, Jean-Philippe, Brendgen, Mara R., Dionne, Ginette, Vitaro, Frank, Lupton, Michelle K., Martin, Nicholas G., Castelao, Enrique, Räikkönen, Katri, Eriksson, Johan G., Lahti, Jari, Hartman, Catharina A., Oldehinkel, Albertine J., Snieder, Harold, Liu, Hexuan, Preisig, Martin, Whipp, Alyce, Vuoksimaa, Eero, Lu, Yi, Jern, Patrick, Rujescu, Dan, Giegling, Ina, Palviainen, Teemu, Kaprio, Jaakko, Harden, Kathryn Paige, Munafò, Marcus R., Morneau-Vaillancourt, Geneviève, Plomin, Robert, Viding, Essi, Boutwell, Brian B., Aliev, Fazil, Dick, Danielle M., Popma, Arne, Faraone, Stephen V., Børglum, Anders D., Medland, Sarah E., Franke, Barbara, Boivin, Michel, Pingault, Jean-Baptiste, Glennon, Jeffrey C., Barnes, J. C., Fisher, Simon E., Moffitt, Terrie E., Caspi, Avshalom, Polderman, Tinca J. C., and Posthuma, Danielle

Published
2022
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25. Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis

Author

Grotzinger, Andrew D., Mallard, Travis T., Akingbuwa, Wonuola A., Ip, Hill F., Adams, Mark J., Lewis, Cathryn M., McIntosh, Andrew M., Grove, Jakob, Dalsgaard, Søren, Lesch, Klaus-Peter, Strom, Nora, Meier, Sandra M., Mattheisen, Manuel, Børglum, Anders D., Mors, Ole, Breen, Gerome, Lee, Phil H., Kendler, Kenneth S., Smoller, Jordan W., Tucker-Drob, Elliot M., and Nivard, Michel G.

Published
2022
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26. Morphological integration of the human brain across adolescence and adulthood

Author

Nadig, Ajay, Seidlitz, Jakob, McDermott, Cassidy L., Liu, Siyuan, Bethlehem, Richard, Moore, Tyler M., Mallard, Travis T., Clasen, Liv S., Blumenthal, Jonathan D., Lalonde, François, Gur, Ruben C., Gur, Raquel E., Bullmore, Edward T., Satterthwaite, Theodore D., and Raznahan, Armin

Published
2021

28. Atypical brain aging and its association with working memory performance in major depressive disorder

Author

Ho, Natalie C.W., primary, Bethlehem, Richard AI., additional, Seidlitz, Jakob, additional, Nogovitsyn, Nikita, additional, Metzak, Paul, additional, Ballester, Pedro L., additional, Hassel, Stefanie, additional, Rotzinger, Susan, additional, Poppenk, Jordan, additional, Lam, Raymond W., additional, Taylor, Valerie H., additional, Milev, Roumen, additional, Adamson, Chris, additional, Adler, Sophie, additional, Alexander-Bloch, Aaron F., additional, Anagnostou, Evdokia, additional, Anderson, Kevin M., additional, Areces-Gonzalez, Ariosky, additional, Astle, Duncan E., additional, Auyeung, Bonnie, additional, Ayub, Muhammad, additional, Bae, Jong Bin, additional, Ball, Gareth, additional, Baron-Cohen, Simon, additional, Beare, Richard, additional, Bedford, Saashi A., additional, Benegal, Vivek, additional, Bethlehem, Richard A.I., additional, Beyer, Frauke, additional, Blangero, John, additional, Blesa Cábez, Manuel, additional, Boardman, James P., additional, Borzage, Matthew, additional, Bosch-Bayard, Jorge F., additional, Bourke, Niall, additional, Bullmore, Edward T., additional, Calhoun, Vince D., additional, Chakravarty, Mallar M., additional, Chen, Christina, additional, Chertavian, Casey, additional, Chetelat, Gaël, additional, Chong, Yap S., additional, Corvin, Aiden, additional, Costantino, Manuela, additional, Courchesne, Eric, additional, Crivello, Fabrice, additional, Cropley, Vanessa L., additional, Crosbie, Jennifer, additional, Crossley, Nicolas, additional, Delarue, Marion, additional, Delorme, Richard, additional, Desrivieres, Sylvane, additional, Devenyi, Gabriel, additional, Di Biase, Maria A., additional, Dolan, Ray, additional, Donald, Kirsten A., additional, Donohoe, Gary, additional, Dorfschmidt, Lena, additional, Dunlop, Katharine, additional, Edwards, Anthony D., additional, Elison, Jed T., additional, Ellis, Cameron T., additional, Elman, Jeremy A., additional, Eyler, Lisa, additional, Fair, Damien A., additional, Fletcher, Paul C., additional, Fonagy, Peter, additional, Franz, Carol E., additional, Galan-Garcia, Lidice, additional, Gholipour, Ali, additional, Giedd, Jay, additional, Gilmore, John H., additional, Glahn, David C., additional, Goodyer, Ian M., additional, Grant, P.E., additional, Groenewold, Nynke A., additional, Gudapati, Shreya, additional, Gunning, Faith M., additional, Gur, Raquel E., additional, Gur, Ruben C., additional, Hammill, Christopher F., additional, Hansson, Oskar, additional, Hedden, Trey, additional, Heinz, Andreas, additional, Henson, Richard N., additional, Heuer, Katja, additional, Hoare, Jacqueline, additional, Holla, Bharath, additional, Holmes, Avram J., additional, Huang, Hao, additional, Ipser, Jonathan, additional, Jack, Clifford R., additional, Jackowski, Andrea P., additional, Jia, Tianye, additional, Jones, David T., additional, Jones, Peter B., additional, Kahn, Rene S., additional, Karlsson, Hasse, additional, Karlsson, Linnea, additional, Kawashima, Ryuta, additional, Kelley, Elizabeth A., additional, Kern, Silke, additional, Kim, Ki-Woong, additional, Kitzbichler, Manfred G., additional, Kremen, William S., additional, Lalonde, François, additional, Landeau, Brigitte, additional, Lerch, Jason, additional, Lewis, John D., additional, Li, Jiao, additional, Liao, Wei, additional, Liston, Conor, additional, Lombardo, Michael V., additional, Lv, Jinglei, additional, Mallard, Travis T., additional, Marcelis, Machteld, additional, Mathias, Samuel R., additional, Mazoyer, Bernard, additional, McGuire, Philip, additional, Meaney, Michael J., additional, Mechelli, Andrea, additional, Misic, Bratislav, additional, Morgan, Sarah E., additional, Mothersill, David, additional, Ortinau, Cynthia, additional, Ossenkoppele, Rik, additional, Ouyang, Minhui, additional, Palaniyappan, Lena, additional, Paly, Leo, additional, Pan, Pedro M., additional, Pantelis, Christos, additional, Park, Min Tae M., additional, Paus, Tomas, additional, Pausova, Zdenka, additional, Paz-Linares, Deirel, additional, Pichet Binette, Alexa, additional, Pierce, Karen, additional, Qian, Xing, additional, Qiu, Anqi, additional, Raznahan, Armin, additional, Rittman, Timothy, additional, Rodrigue, Amanda, additional, Rollins, Caitlin K., additional, Romero-Garcia, Rafael, additional, Ronan, Lisa, additional, Rosenberg, Monica D., additional, Rowitch, David H., additional, Salum, Giovanni A., additional, Satterthwaite, Theodore D., additional, Schaare, H. Lina, additional, Schabdach, Jenna, additional, Schachar, Russell J., additional, Schöll, Michael, additional, Schultz, Aaron P., additional, Sharp, David, additional, Shinohara, Russell T., additional, Skoog, Ingmar, additional, Smyser, Christopher D., additional, Sperling, Reisa A., additional, Stein, Dan J., additional, Stolicyn, Aleks, additional, Suckling, John, additional, Sullivan, Gemma, additional, Thyreau, Benjamin, additional, Toro, Roberto, additional, Traut, Nicolas, additional, Tsvetanov, Kamen A., additional, Turk-Browne, Nicholas B., additional, Tuulari, Jetro J., additional, Tzourio, Christophe, additional, Vachon-Presseau, Étienne, additional, Valdes-Sosa, Mitchell J., additional, Valdes-Sosa, Pedro A., additional, Valk, Sofie L., additional, van Amelsvoort, Therese, additional, Vandekar, Simon N., additional, Vasung, Lana, additional, Vértes, Petra E., additional, Victoria, Lindsay W., additional, Villeneuve, Sylvia, additional, Villringer, Arno, additional, Vogel, Jacob W., additional, Wagstyl, Konrad, additional, Wang, Yin-Shan S., additional, Warfield, Simon K., additional, Warrier, Varun, additional, Westman, Eric, additional, Westwater, Margaret L., additional, Whalley, Heather C., additional, White, Simon R., additional, Witte, A. Veronica, additional, Yang, Ning, additional, Yeo, B.T. Thomas, additional, Yun, Hyuk Jin, additional, Zalesky, Andrew, additional, Zar, Heather J., additional, Zettergren, Anna, additional, Zhou, Juan H., additional, Ziauddeen, Hisham, additional, Zimmerman, Dabriel, additional, Zugman, Andre, additional, Zuo, Xi-Nian N., additional, Frey, Benicio N., additional, Harkness, Kate L., additional, Addington, Jean, additional, and Kennedy, Sidney H., additional

Published
2024
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29. Can polygenic scores enhance the predictive performance of clinical risk models for suicide attempts in a psychiatric emergency room setting? (Preprint)

Author

Lee, Younga Heather, primary, Zhang, Yingzhe, additional, Kennedy, Chris J, additional, Mallard, Travis T, additional, Liu, Zhaowen, additional, Vu, Phuong Linh, additional, Feng, Yen-Chen Anne, additional, Ge, Tian, additional, Petukhova, Maria V, additional, Kessler, Ronald C, additional, Nock, Matthew K, additional, and Smoller, Jordan W, additional

Published
2024
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30. Transcriptional cartography integrates multiscale biology of the human cortex

Author

Wagstyl, Konrad, primary, Adler, Sophie, additional, Seidlitz, Jakob, additional, Vandekar, Simon, additional, Mallard, Travis T, additional, Dear, Richard, additional, DeCasien, Alex R, additional, Satterthwaite, Theodore D, additional, Liu, Siyuan, additional, Vértes, Petra E, additional, Shinohara, Russell T, additional, Alexander-Bloch, Aaron, additional, Geschwind, Daniel H, additional, and Raznahan, Armin, additional

Published
2024
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31. Author Response: Transcriptional cartography integrates multiscale biology of the human cortex

Author

Wagstyl, Konrad, primary, Adler, Sophie, additional, Seidlitz, Jakob, additional, Vandekar, Simon, additional, Mallard, Travis T, additional, Dear, Richard, additional, DeCasien, Alex R, additional, Satterthwaite, Theodore D, additional, Liu, Siyuan, additional, Vértes, Petra E, additional, Shinohara, Russell T, additional, Alexander-Bloch, Aaron, additional, Geschwind, Daniel H, additional, and Raznahan, Armin, additional

Published
2024
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34. Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction

Author

Demange, Perline A., Malanchini, Margherita, Mallard, Travis T., Biroli, Pietro, Cox, Simon R., Grotzinger, Andrew D., Tucker-Drob, Elliot M., Abdellaoui, Abdel, Arseneault, Louise, van Bergen, Elsje, Boomsma, Dorret I., Caspi, Avshalom, Corcoran, David L., Domingue, Benjamin W., Harris, Kathleen Mullan, Ip, Hill F., Mitchell, Colter, Moffitt, Terrie E., Poulton, Richie, Prinz, Joseph A., Sugden, Karen, Wertz, Jasmin, Williams, Benjamin S., de Zeeuw, Eveline L., Belsky, Daniel W., Harden, K. Paige, and Nivard, Michel G.

Published
2021
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35. Executive Function and Impulsivity Predict Distinct Genetic Variance in Internalizing Problems, Externalizing Problems, Thought Disorders, and Compulsive Disorders: A Genomic Structural Equation Modeling Study

Author

Gustavson, Daniel E., primary, Morrison, Claire L., additional, Mallard, Travis T., additional, Jennings, Mariela V., additional, Fontanillas, Pierre, additional, Elson, Sarah L., additional, Palmer, Abraham A., additional, Friedman, Naomi P., additional, and Sanchez-Roige, Sandra, additional

Published
2023
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37. Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.

Author

Barr, Peter B., Bigdeli, Tim B., Meyers, Jacquelyn L., Peterson, Roseann E., Sanchez-Roige, Sandra, Mallard, Travis T., Dick, Danielle M., Harden, K. Paige, Wilkinson, Anna, Graham, David P., Nielsen, David A., Swann, Alan C., Lipsky, Rachele K., Kosten, Thomas R., Aslan, Mihaela, Harvey, Philip D., Kimbrel, Nathan A., and Beckham, Jean C.

Subjects
HEALTH behavior, AT-risk behavior, VETERANS' health, ELECTRONIC health records, VETERANS, NOSOLOGY, HEPATITIS C
Abstract

This cohort study investigates the correlates of risk for disinhibited behaviors using electronic health record data of individuals in the Million Veteran Program. Key Points: Question: What are the correlates of risk for disinhibited behaviors in the US veterans population? Findings: In this cohort study including electronic health record data of 560 824 veterans, risk for disinhibited behaviors was associated with medical outcomes across all bodily systems, including substance use disorders, suicide and self-harm, liver disease, chronic airway obstruction, and viral hepatitis C. Many of these associations were significant across ancestry and after accounting for other comorbid problems. Meaning: Results suggest that risk for disinhibited behaviors was associated with many health outcomes of particular relevance within the veteran community. Importance: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs). Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP). Design, Setting, and Participants: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020. Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt. Main Outcomes and Measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records. Results: Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C. Conclusions and Relevance: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population. [ABSTRACT FROM AUTHOR]

Published
2024
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38. MULTI-ANCESTRY PHENOME-WIDE ASSOCIATION ANALYSES OF GENETIC LIABILITY FOR PROBLEMATIC ALCOHOL USE

Author

Kember, Rachel, primary, Johnson, Jessica, additional, Johnston, Keira J.A., additional, Lee, Hyunjoon, additional, Xu, Jiayi, additional, Davis, Lea K., additional, Smoller, Jordan W., additional, Mallard, Travis T., additional, Huckins, Laura M., additional, Sanchez-Roige, Sandra, additional, Kranzler, Henry R., additional, Gelernter, Joel, additional, and Zhou, Hang, additional

Published
2023
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39. F76. GENOME-WIDE ASSOCIATION STUDY OF DELAY DISCOUNTING IN 134,935 23 AND ME PARTICIPANTS

Author

Cupertino, Renata, primary, Fontanillas, Pierre, additional, Bianchi, Sevim B., additional, Meredith, John J., additional, Pakala, Shreya, additional, Jennings, Mariela V., additional, Mallard, Travis T., additional, Niarchou, Maria, additional, Elson, Sarah L., additional, Gustavson, Daniel E., additional, Davis, Lea K., additional, Palmer, Abraham, additional, and Sanchez-Roige, Sandra, additional

Published
2023
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45. Do polygenic indices capture 'direct' effects on child externalizing behavior? Within-family analyses in two longitudinal birth cohorts

Author

Tanksley, Peter T., primary, Brislin, Sarah J, additional, Wertz, Jasmin, additional, de Vlaming, Ronald, additional, Courchesne-Krak, Natasia S, additional, Mallard, Travis T, additional, Raffington, Laurel T., additional, Karlsson Linner, Richard, additional, Koellinger, Philipp, additional, Palmer, Abraham, additional, Sanchez-Roige, Alexandra, additional, Waldman, Irwin, additional, Dick, Danielle, additional, Moffitt, Terrie E, additional, Caspi, Avshalom, additional, and Harden, K. Paige, additional

Published
2023
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46. Transcriptional Cartography Integrates Multiscale Biology of the Human Cortex

Author

Wagstyl, Konrad, primary, Adler, Sophie, additional, Seidlitz, Jakob, additional, Vandekar, Simon, additional, Mallard, Travis T., additional, Dear, Richard, additional, DeCasien, Alex R., additional, Satterthwaite, Theodore D., additional, Liu, Siyuan, additional, Vértes, Petra E., additional, Shinohara, Russell T., additional, Alexander-Bloch, Aaron, additional, Geschwind, Daniel H., additional, and Raznahan, Armin, additional

Published
2023
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48. Multi-ancestry meta-analysis of tobacco use disorders based on electronic health record data prioritizes novel candidate risk genes and reveals associations with numerous health outcomes

Author

Toikumo, Sylvanus, primary, Jennings, Mariela V, additional, Pham, Benjamin, additional, Lee, Hyunjoon, additional, Mallard, Travis T, additional, Bianchi, Sevim B, additional, Meredith, John J, additional, Vilar-Ribó, Laura, additional, Xu, Heng, additional, Hatoum, Alexander S, additional, Johnson, Emma C, additional, Pazdernik, Vanessa, additional, Jinwala, Zeal, additional, Leger, Brittany S, additional, Niarchou, Maria, additional, Ehinmowo, Michael, additional, BioBank, Penn Medicine, additional, Veteran, Million, additional, Jenkins, Greg D, additional, Batzler, Anthony, additional, Pendegraft, Richard, additional, Palmer, Abraham A, additional, Zhou, Hang, additional, Biernacka, Joanna M, additional, Coombes, Brandon J, additional, Gelernter, Joel, additional, Xu, Ke, additional, Hancock, Dana B, additional, Cox, Nancy J, additional, Smoller, Jordan W, additional, Davis, Lea K, additional, Justice, Amy C, additional, Kranzler, Henry R, additional, Kember, Rachel L, additional, and Sanchez-Roige, Sandra, additional

Published
2023
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49. Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics

Author

Williams, Camille M., primary, Poore, Holly, additional, Tanksley, Peter T., additional, Kweon, Hyeokmoon, additional, Courchesne-Krak, Natasia S., additional, Londono-Correa, Diego, additional, Mallard, Travis T., additional, Barr, Peter, additional, Koellinger, Philipp D., additional, Waldman, Irwin D., additional, Sanchez-Roige, Sandra, additional, Harden, K. Paige, additional, Palmer, Abraham A, additional, Dick, Danielle M., additional, and Linnér, Richard Karlsson, additional

Published
2023
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50. Robust estimation of cortical similarity networks from brain MRI

Author

Gates Cambridge Scholarships, Schmidt Futures, National Institute of Mental Health (US), St Catharine's College, Autism Research Trust, Junta de Andalucía, Universidad de Sevilla, National Institutes of Health (US), National Institute for Health and Care Research (US), Alan Turing Institute, Sebenius, Isaac, Seidlitz, Jakob, Warrier, Varun, Bethlehem, Richard A. I., Alexander-Bloch, Aaron, Mallard, Travis T., Romero García, Rafael, Bullmore, Edward T., Morgan, Sarah E., Gates Cambridge Scholarships, Schmidt Futures, National Institute of Mental Health (US), St Catharine's College, Autism Research Trust, Junta de Andalucía, Universidad de Sevilla, National Institutes of Health (US), National Institute for Health and Care Research (US), Alan Turing Institute, Sebenius, Isaac, Seidlitz, Jakob, Warrier, Varun, Bethlehem, Richard A. I., Alexander-Bloch, Aaron, Mallard, Travis T., Romero García, Rafael, Bullmore, Edward T., and Morgan, Sarah E.

Abstract

Structural similarity is a growing focus for magnetic resonance imaging (MRI) of connectomes. Here we propose Morphometric INverse Divergence (MIND), a new method to estimate within-subject similarity between cortical areas based on the divergence between their multivariate distributions of multiple MRI features. Compared to the prior approach of morphometric similarity networks (MSNs) on n > 11,000 scans spanning three human datasets and one macaque dataset, MIND networks were more reliable, more consistent with cortical cytoarchitectonics and symmetry and more correlated with tract-tracing measures of axonal connectivity. MIND networks derived from human T1-weighted MRI were more sensitive to age-related changes than MSNs or networks derived by tractography of diffusion-weighted MRI. Gene co-expression between cortical areas was more strongly coupled to MIND networks than to MSNs or tractography. MIND network phenotypes were also more heritable, especially edges between structurally differentiated areas. MIND network analysis provides a biologically validated lens for cortical connectomics using readily available MRI data.

Published
2023

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