546 results on '"Lai, Dongbing"'
Search Results
152. Genome wide association study for anthracycline-induced congestive heart failure.
- Author
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Gardner, Laura, primary, Shen, Fei, additional, Radovich, Milan, additional, Li, Lang, additional, Miller, Kathy, additional, Jiang, Guanglong, additional, Lai, Dongbing, additional, O'Neill, Anne M., additional, Sparano, Joseph A., additional, Davidson, Nancy E., additional, Cameron, David A., additional, Gradus-Pizlo, Irmina, additional, Mastouri, Ronald, additional, Suter, Thomas M., additional, Foroud, Tatiana, additional, Sledge, George W., additional, and Schneider, Bryan P., additional
- Published
- 2016
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153. A multivariate finite mixture latent trajectory model with application to dementia studies
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Lai, Dongbing, primary, Xu, Huiping, additional, Koller, Daniel, additional, Foroud, Tatiana, additional, and Gao, Sujuan, additional
- Published
- 2016
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154. Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians
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Kim, Sungeun, primary, Nho, Kwangsik, additional, Ramanan, Vijay K., additional, Lai, Dongbing, additional, Foroud, Tatiana M., additional, Lane, Katie, additional, Murrell, Jill R., additional, Gao, Sujuan, additional, Hall, Kathleen S., additional, Unverzagt, Frederick W., additional, Baiyewu, Olusegun, additional, Ogunniyi, Adesola, additional, Gureje, Oye, additional, Kling, Mitchel A., additional, Doraiswamy, P. Murali, additional, Kaddurah-Daouk, Rima, additional, Hendrie, Hugh C., additional, and Saykin, Andrew J., additional
- Published
- 2016
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155. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
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Farlow, Janice L., Lin, Hai, Sauerbeck, Laura, Lai, Dongbing, Koller, Daniel L., Pugh, Elizabeth, Hetrick, Kurt, Ling, Hua, Kleinloog, Rachel, van der Vlies, Pieter, Deelen, Patrick, Swertz, Morris A., Verweij, Bon H., Regli, Luca, Rinkel, Gabriel J. E., Ruigrok, Ynte M., Doheny, Kimberly, Liu, Yunlong, Broderick, Joseph, Foroud, Tatiana, FIA Study Investigators, Farlow, Janice L., Lin, Hai, Sauerbeck, Laura, Lai, Dongbing, Koller, Daniel L., Pugh, Elizabeth, Hetrick, Kurt, Ling, Hua, Kleinloog, Rachel, van der Vlies, Pieter, Deelen, Patrick, Swertz, Morris A., Verweij, Bon H., Regli, Luca, Rinkel, Gabriel J. E., Ruigrok, Ynte M., Doheny, Kimberly, Liu, Yunlong, Broderick, Joseph, Foroud, Tatiana, and FIA Study Investigators
- Published
- 2015
156. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm
- Author
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ZL Cerebrovasculaire Ziekten Medisch, Brain, Circulatory Health, Neurologie, Farlow, Janice L., Lin, Hai, Sauerbeck, Laura, Lai, Dongbing, Koller, Daniel L., Pugh, Elizabeth, Hetrick, Kurt, Ling, Hua, Kleinloog, Rachel, van der Vlies, Pieter, Deelen, Patrick, Swertz, Morris A., Verweij, Bon H., Regli, Luca, Rinkel, Gabriel J. E., Ruigrok, Ynte M., Doheny, Kimberly, Liu, Yunlong, Broderick, Joseph, Foroud, Tatiana, FIA Study Investigators, ZL Cerebrovasculaire Ziekten Medisch, Brain, Circulatory Health, Neurologie, Farlow, Janice L., Lin, Hai, Sauerbeck, Laura, Lai, Dongbing, Koller, Daniel L., Pugh, Elizabeth, Hetrick, Kurt, Ling, Hua, Kleinloog, Rachel, van der Vlies, Pieter, Deelen, Patrick, Swertz, Morris A., Verweij, Bon H., Regli, Luca, Rinkel, Gabriel J. E., Ruigrok, Ynte M., Doheny, Kimberly, Liu, Yunlong, Broderick, Joseph, Foroud, Tatiana, and FIA Study Investigators
- Published
- 2015
157. Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199
- Author
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Schneider, Bryan P., primary, Li, Lang, additional, Radovich, Milan, additional, Shen, Fei, additional, Miller, Kathy D., additional, Flockhart, David A., additional, Jiang, Guanglong, additional, Vance, Gail, additional, Gardner, Laura, additional, Vatta, Matteo, additional, Bai, Shaochun, additional, Lai, Dongbing, additional, Koller, Daniel, additional, Zhao, Fengmin, additional, O'Neill, Anne, additional, Smith, Mary Lou, additional, Railey, Elda, additional, White, Carol, additional, Partridge, Ann, additional, Sparano, Joseph, additional, Davidson, Nancy E., additional, Foroud, Tatiana, additional, and Sledge, George W., additional
- Published
- 2015
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158. HEART FAILURE PREDICTS COGNITIVE DYSFUNCTION AFTER ADJUSTING FOR APOE FACTORS
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Jung, Miyeon J., Apostolova, Liana G., Gao, Sujuan, Burney, Heather, Lai, Dongbing, Saykin, Andrew J., and Pressler, Susan J.
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- 2018
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159. Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders
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Walters, Raymond K., Polimanti, Renato, Johnson, Emma C., McClintick, Jeanette N., Adams, Mark J., Adkins, Amy E., Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M., Bigdeli, Tim B., Chen, Li-Shiun, Clarke, Toni-Kim, Chou, Yi-Ling, Degenhardt, Franziska, Docherty, Anna R., Edwards, Alexis C., Fontanillas, Pierre, Foo, Jerome C., Fox, Louis, Frank, Josef, Giegling, Ina, Gordon, Scott, Hack, Laura M., Hartmann, Annette M., Hartz, Sarah M., Heilmann-Heimbach, Stefanie, Herms, Stefan, Hodgkinson, Colin, Hoffmann, Per, Jan Hottenga, Jouke, Kennedy, Martin A., Alanne-Kinnunen, Mervi, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S., Mbarek, Hamdi, McIntosh, Andrew M., McQueen, Matthew B., Meyers, Jacquelyn L., Milaneschi, Yuri, Palviainen, Teemu, Pearson, John F., Peterson, Roseann E., Ripatti, Samuli, Ryu, Euijung, Saccone, Nancy L., Salvatore, Jessica E., Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T., Wedow, Robbee, Wetherill, Leah, Wills, Amanda G., Boardman, Jason D., Chen, Danfeng, Choi, Doo-Sup, Copeland, William E., Culverhouse, Robert C., Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W., Elson, Sarah L., Frye, Mark A., Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T., Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D., Nurnberger, John I., Palotie, Aarno, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A., Soyka, Michael, Treutlein, Jens, Witt, Stephanie, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E., Boden, Joseph M., Boomsma, Dorret I., Bierut, Laura J., Brown, Sandra A., Bucholz, Kathleen K., Cichon, Sven, Costello, E. Jane, de Wit, Harriet, Diazgranados, Nancy, Dick, Danielle M., Eriksson, Johan G., Farrer, Lindsay A., Foroud, Tatiana M., Gillespie, Nathan A., Goate, Alison M., Goldman, David, Grucza, Richard A., Hancock, Dana B., Harris, Kathleen Mullan, Heath, Andrew C., Hesselbrock, Victor, Hewitt, John K., Hopfer, Christian J., Horwood, John, Iacono, William, Johnson, Eric O., Kaprio, Jaakko A., Karpyak, Victor M., Kendler, Kenneth S., Kranzler, Henry R., Krauter, Kenneth, Lichtenstein, Paul, Lind, Penelope A., McGue, Matt, MacKillop, James, Madden, Pamela A. F., Maes, Hermine H., Magnusson, Patrik, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Nelson, Elliot C., Nöthen, Markus M., Palmer, Abraham A., Pedersen, Nancy L., Penninx, Brenda W. J. H., Porjesz, Bernice, Rice, John P., Rietschel, Marcella, Riley, Brien P., Rose, Richard, Rujescu, Dan, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C., Tarter, Ralph E., Vanyukov, Michael M., Vrieze, Scott, Wall, Tamara L., Whitfield, John B., Zhao, Hongyu, Neale, Benjamin M., Gelernter, Joel, Edenberg, Howard J., and Agrawal, Arpana
- Abstract
Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n= 46,568; African, n= 6,280). Independent, genome-wide significant effects of different ADH1Bvariants were identified in European (rs1229984; P= 9.8 × 10–13) and African ancestries (rs2066702; P= 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
- Published
- 2018
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160. Steroid Pathway Genes and Neonatal Respiratory Distress After Betamethasone Use in Anticipated Preterm Birth
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Haas, David M., primary, Lai, Dongbing, additional, Sharma, Sunita, additional, Then, Jenny, additional, Kho, Alvin, additional, Flockhart, David A., additional, Tantisira, Kelan, additional, and Foroud, Tatiana, additional
- Published
- 2015
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161. P3-011: Genome-wide association of plasma homocysteine in the indianapolis-ibadan dementia study cohort
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Kim, Sungeun, primary, Lai, Dongbing, additional, Lane, Katie, additional, Ramanan, Vijay K., additional, Murrell, Jill R., additional, Gao, Sujuan, additional, Hall, Kathleen S., additional, Foroud, Tatiana M., additional, Baiyewu, Olusegun, additional, Ogunniyi, Adesola, additional, Gureje, Oye, additional, Hendrie, Hugh C., additional, and Saykin, Andrew J., additional
- Published
- 2015
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162. Meta-analysis of genome-wide studies identifiesWNT16andESR1SNPs associated with bone mineral density in premenopausal women
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Koller, Daniel L, primary, Zheng, Hou-Feng, additional, Karasik, David, additional, Yerges-Armstrong, Laura, additional, Liu, Ching-Ti, additional, McGuigan, Fiona, additional, Kemp, John P, additional, Giroux, Sylvie, additional, Lai, Dongbing, additional, Edenberg, Howard J, additional, Peacock, Munro, additional, Czerwinski, Stefan A, additional, Choh, Audrey C, additional, McMahon, George, additional, St Pourcain, Beate, additional, Timpson, Nicholas J, additional, Lawlor, Debbie A, additional, Evans, David M, additional, Towne, Bradford, additional, Blangero, John, additional, Carless, Melanie A, additional, Kammerer, Candace, additional, Goltzman, David, additional, Kovacs, Christopher S, additional, Prior, Jerilynn C, additional, Spector, Tim D, additional, Rousseau, Francois, additional, Tobias, Jon H, additional, Akesson, Kristina, additional, Econs, Michael J, additional, Mitchell, Braxton D, additional, Richards, J Brent, additional, Kiel, Douglas P, additional, and Foroud, Tatiana, additional
- Published
- 2013
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163. Haplotype Association Mapping In 33 Inbred Mouse Strains Identifies Genetic Regions Contributing To Chronic Hypoxia-Induced Pulmonary Hypertension
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Nichols, William C., primary, Koller, Daniel, additional, Pauciulo, Michael W., additional, Hale, Philip, additional, Pastura, Patricia, additional, Tolentino, Chelsea, additional, Lai, Dongbing, additional, Aronow, Bruce, additional, Le Cras, Timothy D., additional, and Foroud, Tatiana, additional
- Published
- 2012
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164. Fine Mapping Quantitative Trait Loci that Influence Alcohol Preference Behavior in the High and Low Alcohol Preferring (HAP and LAP) Mice
- Author
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Bice, Paula J., primary, Lai, Dongbing, additional, Zhang, Lili, additional, and Foroud, Tatiana, additional
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- 2010
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165. Replication of previous genome-wide association studies of bone mineral density in premenopausal American women
- Author
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Ichikawa, Shoji, primary, Koller, Daniel L, additional, Padgett, Leah R, additional, Lai, Dongbing, additional, Hui, Siu L, additional, Peacock, Munro, additional, Foroud, Tatiana, additional, and Econs, Michael J, additional
- Published
- 2010
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166. Association of Adenylate Cyclase 10 (ADCY10) Polymorphisms and Bone Mineral Density in Healthy Adults
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Ichikawa, Shoji, primary, Koller, Daniel L., additional, Curry, Leah R., additional, Lai, Dongbing, additional, Xuei, Xiaoling, additional, Edenberg, Howard J., additional, Hui, Siu L., additional, Peacock, Munro, additional, Foroud, Tatiana, additional, and Econs, Michael J., additional
- Published
- 2008
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167. Identification of a Linkage Disequilibrium Block in Chromosome 1q Associated With BMD in Premenopausal White Women
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Ichikawa, Shoji, primary, Koller, Daniel L, additional, Curry, Leah R, additional, Lai, Dongbing, additional, Xuei, Xiaoling, additional, Pugh, Elizabeth W, additional, Tsai, Ya-Yu, additional, Doheny, Kimberly F, additional, Edenberg, Howard J, additional, Hui, Siu L, additional, Foroud, Tatiana, additional, Peacock, Munro, additional, and Econs, Michael J, additional
- Published
- 2008
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168. Human ALOX12, but Not ALOX15, Is Associated With BMD in White Men and Women
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Ichikawa, Shoji, primary, Koller, Daniel L, additional, Johnson, Michelle L, additional, Lai, Dongbing, additional, Xuei, Xiaoling, additional, Edenberg, Howard J, additional, Klein, Robert F, additional, Orwoll, Eric S, additional, Hui, Siu L, additional, Foroud, Tatiana M, additional, Peacock, Munro, additional, and Econs, Michael J, additional
- Published
- 2006
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169. Contribution of the LRP5 Gene to Normal Variation in Peak BMD in Women
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Koller, Daniel L, primary, Ichikawa, Shoji, additional, Johnson, Michelle L, additional, Lai, Dongbing, additional, Xuei, Xiaoling, additional, Edenberg, Howard J, additional, Conneally, P Michael, additional, Hui, Siu L, additional, Johnston, C Conrad, additional, Peacock, Munro, additional, Foroud, Tatiana, additional, and Econs, Michael J, additional
- Published
- 2005
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170. Contribution of the LRP5 Gene to Normal Variation in Peak BMD in Women
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Koller, Daniel L, primary, Ichikawa, Shoji, additional, Johnson, Michelle L, additional, Lai, Dongbing, additional, Xuei, Xiaoling, additional, Edenberg, Howard J, additional, Conneally, P Michael, additional, Hui, Siu L, additional, Johnston, C Conrad, additional, Peacock, Munro, additional, Foroud, Tatiana, additional, and Econs, Michael J, additional
- Published
- 2004
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171. False Positive Rates in Association Studies as a Function of Degree of Stratification
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Koller, Daniel L, primary, Peacock, Munro, additional, Lai, Dongbing, additional, Foroud, Tatiana, additional, and Econs, Michael J, additional
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- 2004
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172. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms
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van ’t Hof, Femke N. G., Ruigrok, Ynte M., Lee, Cue Hyunkyu, Ripke, Stephan, Anderson, Graig, de Andrade, Mariza, Baas, Annette F., Blankensteijn, Jan D., Böttinger, Erwin P., Bown, Matthew J., Broderick, Joseph, Bijlenga, Philippe, Carrell, David S., Crawford, Dana C., Crosslin, David R., Ebeling, Christian, Eriksson, Johan G., Fornage, Myriam, Foroud, Tatiana, von und zu Fraunberg, Mikael, Friedrich, Christoph M., Gaál, Emília I., Gottesman, Omri, Guo, Dong‐Chuan, Harrison, Seamus C., Hernesniemi, Juha, Hofman, Albert, Inoue, Ituro, Jääskeläinen, Juha E., Jones, Gregory T., Kiemeney, Lambertus A. L. M., Kivisaari, Riku, Ko, Nerissa, Koskinen, Seppo, Kubo, Michiaki, Kullo, Iftikhar J., Kuivaniemi, Helena, Kurki, Mitja I., Laakso, Aki, Lai, Dongbing, Leal, Suzanne M., Lehto, Hanna, LeMaire, Scott A., Low, Siew‐Kee, Malinowski, Jennifer, McCarty, Catherine A., Milewicz, Dianna M., Mosley, Thomas H., Nakamura, Yusuke, Nakaoka, Hirofumi, Niemelä, Mika, Pacheco, Jennifer, Peissig, Peggy L., Pera, Joanna, Rasmussen‐Torvik, Laura, Ritchie, Marylyn D., Rivadeneira, Fernando, van Rij, Andre M., Santos‐Cortez, Regie Lyn P., Saratzis, Athanasios, Slowik, Agnieszka, Takahashi, Atsushi, Tromp, Gerard, Uitterlinden, André G., Verma, Shefali S., Vermeulen, Sita H., Wang, Gao T., Han, Buhm, Rinkel, Gabriël J. E., de Bakker, Paul I. W., Verissimo, Ana, Wright, Benjamin J., Bumpstead, Suzannah, Gretarsdottir, Solveig, Badger, Stephen A., Child, Anne H., Clough, Rachel E., Cockerill, Gillian, Hafez, Hany, Scott, D. Julian A., Futers, Simon, Sohrabi, Soroush, Smith, Alberto, Thompson, Matthew M., van Bockxmeer, Frank M., Matthiasson, Stefan E., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Teijink, Joep A. W., Wijmenga, Cisca, de Graaf, Jacqueline, Kiemeney, Lambertus A., Palmen, Jutta, Smith, Andrew J., Lindholt, Jes S., Bradley, Declan T., Waltham, Matthew, Edkins, Sarah, Gwilliam, Rhian, Hunt, Sarah E., Potter, Simon, Golledge, Jonathan, Eriksson, Per, Norman, Paul E., Powell, Janet T., Stefansson, Kari, Thompson, John R., Humphries, Steve E., Sayers, Robert D., Deloukas, Panos, Samani, Nilesh J., Phillip, L. Victoria, Hill, Geraldine B., Williams, Michael J. A., Thomson, Ian A., Krysa, Jo, Wilkins, Gerard T., Merriman, Tony R., Vasudevan, Thodor M., Lewis, David R., Blair, Ross D., and Hill, Andrew A.
- Subjects
abdominal aortic aneurysm ,genome wide association study ,intracranial aneurysm ,thoracic aortic aneurysm ,Inflammation ,Vascular Biology ,Ischemic Stroke - Abstract
Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and Results: We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.
- Published
- 2016
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173. Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women.
- Author
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Koller, Daniel L, Zheng, Hou-Feng, Karasik, David, Yerges-Armstrong, Laura, Liu, Ching-Ti, McGuigan, Fiona, Kemp, John P, Giroux, Sylvie, Lai, Dongbing, Edenberg, Howard J, Peacock, Munro, Czerwinski, Stefan A, Choh, Audrey C, McMahon, George, St Pourcain, Beate, Timpson, Nicholas J, Lawlor, Debbie A, Evans, David M, Towne, Bradford, and Blangero, John
- Abstract
Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts ( n = 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p = 1.7 × 10
−9 ) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p = 1.3 × 10−8 ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n = 5597 for femoral neck; n = 4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant ( WNT16 joint p = 1.3 × 10−11 ; ESR1/C6orf97 joint p = 1.4 × 10−10 ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 ( p < 1 × 10−5 ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2013 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]- Published
- 2013
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174. Identification of a Linkage Disequilibrium Block in Chromosome lq Associated With BMD in Premenopausal White Women.
- Author
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Ichikawa, Shoji, Koller, Daniel L, Curry, Leah R, Lai, Dongbing, Xuei, Xiaoling, Pugh, Elizabeth W, Ya-Yu Tsai, Doheny, Kimberly F, Edenberg, Howard J, Hui, Siu L, Tatiana Foroud, Peacock, Munro, and Econs, Michael J
- Abstract
The article discusses a study concerning the age-related skeletal disease osteoporosis. A characteristics of the disease is the reduction in bone strength due to loss of bone mass density (BMD). Low BMD can lead to the risk of fractures from minor trauma. A two-stage genotyping approach was used to identify possible gene linkage of chromosome 1q to BMD levels in U.S. white premenopausal women. An in-depth analysis of the study results are presented.
- Published
- 2008
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175. ERRATUM: Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans.
- Author
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Wetherill, Leah, Lai, Dongbing, Johnson, Emma C., Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K., Dick, Danielle M., Hariri, Ahmad R., Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L., Nurnberger, John I., Schuckit, Marc, Scott, Denise M., Taylor, Robert E., Tischfield, Jay, Porjesz, Bernice, and Goate, Alison M.
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LOCUS (Genetics) , *DRUG addiction , *SINGLE nucleotide polymorphisms , *ALCOHOL - Published
- 2019
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176. Alcohol‐Preferring Rats Show Decreased Corticotropin‐Releasing Hormone‐2 Receptor Expression and Differences in HPAActivation Compared to Alcohol‐Nonpreferring Rats
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Yong, Weidong, Spence, John Paul, Eskay, Robert, Fitz, Stephanie D., Damadzic, Ruslan, Lai, Dongbing, Foroud, Tatiana, Carr, Lucinda G., Shekhar, Anantha, Chester, Julia A., Heilig, Markus, and Liang, Tiebing
- Published
- 2014
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177. Contribution of the LRP5Gene to Normal Variation in Peak BMD in Women
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Koller, Daniel L, Ichikawa, Shoji, Johnson, Michelle L, Lai, Dongbing, Xuei, Xiaoling, Edenberg, Howard J, Conneally, P Michael, Hui, Siu L, Johnston, C Conrad, Peacock, Munro, Foroud, Tatiana, and Econs, Michael J
- Abstract
The role of the LRP5gene in rare BMD‐related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5in our sample.
- Published
- 2005
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178. Genome-wide association studies of the self-rating of effects of ethanol (SRE).
- Author
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Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma C., Schwandt, Melanie, Ramchandani, Vijay A., Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R. Dayne, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia V., Nurnberger, John, Tischfield, Jay, Goate, Alison, and Edenberg, Howard J.
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ALCOHOLISM , *ALCOHOL drinking , *SELF-evaluation , *NON-coding RNA , *RNA analysis - Abstract
The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders. [ABSTRACT FROM AUTHOR]
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- 2020
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179. High Polygenic Risk Scores Are Associated With Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk
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Nurnberger, John I., Wang, Yumin, Zang, Yong, Lai, Dongbing, Wetherill, Leah, Edenberg, Howard J., Aliev, Fazil, Plawecki, Martin H., Chorlian, David, Chan, Grace, Bucholz, Kathleen, Bauer, Lance, Kamarajan, Chella, Salvatore, Jessica E., Kapoor, Manav, Hesselbrock, Victor, Dick, Danielle, Bierut, Laura, McCutcheon, Vivia, Meyers, Jacquelyn L., Porjesz, Bernice, Kramer, John, Kuperman, Samuel, Kinreich, Sivan, Anokhin, Andrey P., Porjesz, B., Hesselbrock, V., Foroud, T., Agrawal, A., Dick, D., Hesselbrock, V., Edenburg, H.J., Foroud, T., Nurnberger, J., Liu, Y., Kuperman, S., Kramer, J., Porjesz, B., Meyers, J., Kamarajan, C., Pandey, A., Bierut, L., Rice, J., Bucholz, K., Agrawal, A., Schuckit, M., Tischfield, J., Brooks, A., Hart, R., Almasy, L., Dick, D., Salvatore, J., Goate, A., Kapoor, M., Slesinger, P., Scott, D., Bauer, L., Wetherill, L., Xuei, X., Lai, D., O’Connor, S., Plawecki, M., Zang, Y., Acion, L., Chan, G., Chorlian, D.B., Zhang, J., Kinreich, S., Pandey, G., Chao, M., Anokhin, A., McCutcheon, V., Saccone, S., Aliev, F., Barr, P., Chin, H., and Parsian, A.
- Abstract
Genome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations.
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- 2021
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180. Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans.
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Wetherill, Leah, Lai, Dongbing, Johnson, Emma C., Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K., Dick, Danielle M., Hariri, Ahmad R., Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L., Nurnberger, John I., Schuckit, Marc, Scott, Denise M., Taylor, Robert E., Tischfield, Jay, Porjesz, Bernice, and Goate, Alison M.
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DRUG addiction , *SINGLE nucleotide polymorphisms , *SUBSTANCE abuse , *ALCOHOL , *GENETIC markers , *NEUROGENETICS - Abstract
Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome‐wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European‐Americans (EA; 2927 cases) and 3132 African‐Americans (AA: 1315 cases) participating in the family‐based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome‐wide significant (GWS; P < 5E‐08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion‐deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans‐ancestral meta‐analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward‐related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non‐European samples with distinct patterns of substance use may lead to the identification of novel ancestry‐specific genetic markers of risk. [ABSTRACT FROM AUTHOR]
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- 2019
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181. Genome‐wide association studies of alcohol dependence, DSM‐IV criterion count and individual criteria.
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Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin E., Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn L., Anokhin, Andrey P., Bennett, David A., Bucholz, Kathleen K., Chang, Katharine K., De Jager, Philip L., Dick, Danielle M., Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John I., Raj, Towfique, Schuckit, Marc, and Scott, Denise M.
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ALCOHOLIC beverages , *ALCOHOL , *FUNCTIONAL magnetic resonance imaging - Abstract
Genome‐wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM‐IV AD (primary analysis), DSM‐IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans‐ancestral meta‐analyses combined these results with data from 3175 (585 families) African‐American (AA) individuals from COGA. In the EA GWAS, three loci were genome‐wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E−11) and Desire to cut drinking (P = 1.21E−11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E−09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E−08). In the trans‐ancestral meta‐analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome‐wide significant: rs61826952 (chromosome 1, DSM‐IV AD, P = 8.42E−11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E−08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%‐1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss − gain; P =.0037) and reward‐related ventral striatum reactivity (P =.008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability. [ABSTRACT FROM AUTHOR]
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- 2019
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182. Association of Adiposity Genetic Variants With Menarche Timing in 92,105 Women of European Descent
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He, Chunyan, Corre, Tanguy, Mangino, Massimo, Uitterlinden, André G., Strachan, David P., Hu, Frank B., Franceschini, Nora, Murabito, Joanne M., Cousminer, Diana L., Hunter, David J., Boyd, Heather A., Willemsen, Gonneke, Mihailov, Evelin, Carola Zillikens, M., Chasman, Daniel I., Rudan, Igor, Harris, Tamara B., Hayward, Caroline, Yerges-Armstrong, Laura M., Fernández-Rhodes, Lindsay, Oostra, Ben, Launer, Lenore, Buring, Julie E., Montgomery, Grant W., Gudnason, Vilmundur, Lin, Peng, Widen, Elisabeth, Lunetta, Kathryn L., Kraft, Peter, Van Duijn, Cornelia M., Elks, Cathy E., Tao, Ran, McArdle, Patrick F., Ridker, Paul M., Toniolo, Daniela, Byrne, Enda M., Rose, Lynda M., Ong, Ken K., Hofman, Albert, Porcu, Eleonora, Martin, Nicholas G., Bierut, Laura J., Stöckl, Doris, Feenstra, Bjarke, Broer, Linda, Murray, Anna, Zhai, Guangju, Rivadeneira, Fernando, Lai, Dongbing, Warrington, Nicole M., Spector, Tim D., Vollenweider, Peter, Poole, Charles, Hottenga, Jouke Jan, Crisponi, Laura, Visser, Jenny A., Wilson, James F., Koller, Daniel L., Perry, John R.B., Dreyfus, Jill G., Polasek, Ozren, Pennell, Craig E., Fisher, Sherri L., Boomsma, Dorret I., Kutalik, Zoltán, Albrecht, Eva, Grallert, Harald, Smith, Albert V., North, Kari E., Gieger, Christian, Stolk, Lisette, Esko, Tõnu, Metspalu, Andres, Demerath, Ellen W., and Hirschhorn, Joel N.
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2. Zero hunger ,3. Good health - Abstract
Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)2), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970–2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9–17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
183. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
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Erzurumluoglu, A Mesut, Liu, Mengzhen, Jackson, Victoria E, Barnes, Daniel R, Datta, Gargi, Melbourne, Carl A, Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C, Asselbergs, Folkert W, Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, De Boer, Rudolf A, De Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul DP, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renström, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, Van Der Leij, Andries R, Van Der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin NA, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, Understanding Society Scientific Group, EPIC-CVD, Van Der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, and Howson, Joanna MM
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Europe ,Male ,Databases, Factual ,Genetic Loci ,Smoking ,Humans ,Exome ,Female ,Polymorphism, Single Nucleotide ,United Kingdom ,3. Good health ,Biological Specimen Banks - Abstract
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
184. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
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Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L., Brazel, David M, Chambers, John C., Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P., De Boer, Rudolf A., De Leeuw, Christiaan A., Dennis, Joe G., Dominiczak, Anna F., Dunning, Alison M., Easton, Douglas F., Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D., Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J., Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R., Harris, Sarah E., Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G., Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L., Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S., Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian’an, Madden, Pamela A. F., Mangino, Massimo, Marioni, Riccardo E., Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G., McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J., Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D. P., Pistis, Giorgio, Polderman, Tinca J., Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renström, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J., Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A., Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A., Starr, John M., Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M., Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J., Tindle, Hilary A., Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, Van Der Leij, Andries R, Van Der Meer, Peter, Varga, Tibor V., Verweij, Niek, Völzke, Henry, Wareham, Nicholas J., Warren, Helen R., Weir, David R., Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J., Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J., Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W., Frayling, Tim M., Frossard, Philippe, Hall, Ian P., Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J. Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B., Nordestgaard, Børge Grønne, Palmer, Colin N. A., Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, Van Der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S., Wain, Louise V., Abecasis, Goncalo R., Danesh, John, Tobin, Martin D., Vrieze, Scott, Liu, Dajiang J., and Howson, Joanna M. M.
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631/208 ,45 ,45/43 ,article ,692/699/476/5 ,3. Good health - Abstract
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
185. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
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Brazel, David M, Jiang, Yu, Hughey, Jordan M, Turcot, Valérie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J Dylan, Liu, MengZhen, CHD Exome+ Consortium, Consortium For Genetics Of Smoking Behaviour, Barnes, Daniel R, Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A Mesut, Faul, Jessica D, Haessler, Jeff, Hammerschlag, Anke R, Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, De Leeuw, Christiaan A, Loukola, Anu, Mangino, Massimo, Melbourne, Carl A, Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B, Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G, Martin, Nicholas G, Polderman, Tinca J, Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H Steven, Smith, Jennifer A, Tardif, Jean-Claude, Tindle, Hilary A, Van Der Leij, Andries R, Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P, Foroud, Tatiana, Howson, Joanna MM, Kardia, Sharon LR, Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, McGue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D, Weir, David R, Kaprio, Jaakko, Abecasis, Gonçalo R, Liu, Dajiang J, and Vrieze, Scott
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Nicotine ,Alcohol Drinking ,Genotype ,Smoking ,Genetic Variation ,Polymorphism, Single Nucleotide ,3. Good health ,Heritability ,Phenotype ,Tobacco ,Databases, Genetic ,Behavioral genetics ,GWAS ,Humans ,Exome ,Genetic Predisposition to Disease ,Alcohol ,Genome-Wide Association Study ,Oligonucleotide Array Sequence Analysis - Abstract
BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
186. Genome-wide association of plasma homocysteine in the indianapolis-ibadan dementia study cohort.
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Kim, Sungeun, Lai, Dongbing, Lane, Katie, Ramanan, Vijay K., Murrell, Jill R., Gao, Sujuan, Hall, Kathleen S., Foroud, Tatiana M., Baiyewu, Olusegun, Ogunniyi, Adesola, Gureje, Oye, Hendrie, Hugh C., and Saykin, Andrew J.
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- 2015
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187. Do personality characteristics predict future alcohol problems after considering current demography, substance use, and alcohol response?
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Schuckit, Marc A., Smith, Tom L., Danko, George, Bucholz, Kathleen K., Hesselbrock, Victor, Hesselbrock, Michie, Kuperman, Samuel, Kramer, John, Nurnberger, John I., Lai, Dongbing, Chan, Grace, Kamarajan, Chella, Kuo, Sally, Dick, Danielle M., Tear, Jake, Mendoza, Lee Anne, Edenberg, Howard J., and Porjesz, Bernice
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PSYCHOLOGY of alcoholism , *SUBSTANCE abuse , *CANNABIS (Genus) , *INTERVIEWING , *REGRESSION analysis , *QUESTIONNAIRES , *DEMOGRAPHY , *PERSONALITY assessment , *LONGITUDINAL method - Abstract
Background: Several personality traits predict future alcohol problems but also relate to demographic and substance‐related variables that themselves correlate with later adverse alcohol outcomes. Few prospective studies have evaluated whether personality measures predict alcohol problems after considering current demographic and substance‐related variables. Methods: Data from 414 drinkers without alcohol use disorder (AUD) from the Collaborative Study on the Genetics of Alcoholism (average age 20, 44% male) were followed over an average of 9 years. Time 1 (baseline) demography, AUD family history (FH), substance use and problems, and psychiatric histories were gathered using a standardized interview; the Level of Response (LR) to alcohol was measured by the Self‐Report of the Effects of alcohol (SRE) questionnaire; and seven personality dimensions were extracted from the NEO Five‐Factor Personality, Barratt, and Zuckerman scales. Analyses involved product–moment correlations of each baseline measure with the highest number of DSM‐IV AUD criteria endorsed in any follow‐up period, and hierarchical regression analyses evaluated whether the personality domains added significantly to the prediction of the outcome after adjusting for other baseline variables. Results: Significant correlations with the outcome were observed for baseline age, sex, length of follow‐up, AUD family history, past cannabis use, and all alcohol‐related baseline variables, including SRE‐based LR, but not prior mood or anxiety disorders. All personality characteristics except extraversion also correlated with outcomes. A hierarchical regression analysis that included all relevant personality scores together demonstrated significant contributions to the prediction of future alcohol problems for demographics in Step 1; demographics and most baseline alcohol items, including response level, in Step 2; and cannabis use in Step 3; after which demographics, LR, baseline alcohol problems, cannabis use, and higher sensation seeking added significantly in Step 4. Regression for each personality domain separately revealed significant contributions to Step 4 for all personality domains except openness. Lower levels of response to alcohol added significantly to all regression analyses. Conclusions: Most tested personality scores and lower levels of response to alcohol contributed to predictions of later alcohol problems even after considering baseline demographic and substance use measures. [ABSTRACT FROM AUTHOR]
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- 2023
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188. Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.
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Gaddis, Nathan, Mathur, Ravi, Marks, Jesse, Zhou, Linran, Quach, Bryan, Waldrop, Alex, Levran, Orna, Agrawal, Arpana, Randesi, Matthew, Adelson, Miriam, Jeffries, Paul W., Martin, Nicholas G., Degenhardt, Louisa, Montgomery, Grant W., Wetherill, Leah, Lai, Dongbing, Bucholz, Kathleen, Foroud, Tatiana, Porjesz, Bernice, and Runarsdottir, Valgerdur
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OPIOID abuse , *GENOME-wide association studies , *GENETIC correlations , *STRUCTURAL equation modeling , *CONSORTIA - Abstract
Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10–9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits. [ABSTRACT FROM AUTHOR]
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- 2022
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189. Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use.
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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 Jr., John I., Pandey, Gayathri, Plawecki, Martin H., Sanchez-Roige, Sandra, Waldman, Irwin, Palmer, Abraham A., and Dick, Danielle M.
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SUBSTANCE abuse , *EXTERNALIZING behavior , *TEENAGERS , *PATH analysis (Statistics) , *PEERS , *AT-risk youth - 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. [ABSTRACT FROM AUTHOR]
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- 2021
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190. Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease
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Paul Cannon, Laurie J. Ozelius, James E. Tomkins, Nir Giladi, Owen A. Ross, Emil K. Gustavsson, Avi Orr Urtreger, Ali Samii, Tae-Hwi Schwantes-An, Sayantan Das, Haydeh Payami, Claudia Schulte, Eduardo Tolosa, Timothy Lynch, Eden R. Martin, Matthew J. Farrer, Brian K. Fiske, Pierre Fontanillas, Eric Molho, Ryan J. Uitti, Babak Alipanahi, Dolores Vilas, Jan O. Aasly, Dongbing Lai, Richard H. Myers, William K. Scott, Gary W. Beecham, Jordan Follett, Thomas Gasser, John Q. Trojanowski, Zbigniew K. Wszolek, Jeanne C. Latourelle, Caroline M. Tanner, Joanne Trinh, Alexis Brice, Lorraine N. Clark, Roy N. Alcalay, Karen Marder, Susan Bressman, Deborah Raymond, Tatiana Foroud, Connie Marras, Kathrin Brockman, Birgitt Schüle, Cory Y. McLean, Rachel Saunders-Pullman, Ekaterina Rogaeva, Daniela Berg, Cyrus P. Zabetian, Stefano Goldwurm, Karen Nuytemans, Mark R. Cookson, Helen Mejia-Santana, Jeffery M. Vance, Christine Klein, Naomi P. Visanji, J. William Langston, Michael P. Rogers, Anthony E. Lang, Anat Mirelman, Vivianna M. Van Deerlin, Lai, Dongbing [0000-0001-7803-580X], Brockman, Kathrin [0000-0002-7515-8596], Klein, Christine [0000-0003-2102-3431], Ross, Owen A [0000-0003-4813-756X], Visanji, Naomi P [0000-0001-5968-7845], Zabetian, Cyrus P [0000-0002-7739-4306], Mirelman, Anat [0000-0002-1520-2292], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,Aging ,Parkinson's disease ,Penetrance ,Disease ,Neurodegenerative ,medicine.disease_cause ,0302 clinical medicine ,genetics [Parkinson Disease] ,2.1 Biological and endogenous factors ,Aetiology ,Research Articles ,Genetics ,Mutation ,Parkinson's Disease ,Parkinson Disease ,Middle Aged ,LRRK2 ,Neurology ,Neurological ,Female ,Research Article ,Genotype ,Clinical Sciences ,Biology ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,23andMe Research Team ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Chromosome 12 ,Aged ,Linkage (software) ,Neurology & Neurosurgery ,Prevention ,Human Genome ,Neurosciences ,medicine.disease ,nervous system diseases ,Brain Disorders ,030104 developmental biology ,Chromosome 3 ,genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] ,Neurology (clinical) ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Objective The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genome-wide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these two proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value = 1.1E-07; age-at-onset top variant: P-value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. This article is protected by copyright. All rights reserved.
- Published
- 2021
191. Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder.
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Green N, Gao H, Chu X, Yuan Q, McGuire P, Lai D, Jiang G, Xuei X, Reiter J, Stevens J, Sutherland G, Goate A, Pang Z, Slesinger P, Hart RP, Tischfield JA, Agrawal A, Wang Y, Duren Z, Edenberg HJ, and Liu Y
- Abstract
Alcohol use disorder (AUD) is likely associated with complex transcriptional alterations in addiction-relevant brain regions. We characterize AUD-associated differences in cell type-specific gene expression and chromatin accessibility in the caudate nucleus by conducting a single-nucleus RNA-seq assay and a single-nucleus RNA-seq + ATAC-seq (multiome) assay on caudate tissue from 143 human postmortem brains (74 with AUD). We identified 17 cell types. AUD was associated with a higher proportion of microglia in an activated state and more astrocytes in a reactive state. There was widespread evidence for differentially expressed genes across cell types with the most identified in oligodendrocytes and astrocytes, including genes involved in immune response and synaptic regulation, many of which appeared to be regulated in part by JUND and OLIG2 . Microglia-astrocyte communication via interleukin-1 beta, and microglia-astrocyte-oligodendrocyte interaction via transforming growth factor beta 1 were increased in individuals with AUD. Expression quantitative trait loci analysis revealed potential driver genes of AUD, including ADAL, that may protect against AUD in medium spiny neurons and interneurons. This work provides a thorough profile of the effects of AUD in the human brain and identifies several promising genes for further study.
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- 2024
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192. Unsupervised representation learning on high-dimensional clinical data improves genomic discovery and prediction.
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Yun T, Cosentino J, Behsaz B, McCaw ZR, Hill D, Luben R, Lai D, Bates J, Yang H, Schwantes-An TH, Zhou Y, Khawaja AP, Carroll A, Hobbs BD, Cho MH, McLean CY, and Hormozdiari F
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- Humans, Multifactorial Inheritance genetics, Genetic Predisposition to Disease, Unsupervised Machine Learning, Genomics methods, Deep Learning, Polymorphism, Single Nucleotide, Genome-Wide Association Study methods
- Abstract
Although high-dimensional clinical data (HDCD) are increasingly available in biobank-scale datasets, their use for genetic discovery remains challenging. Here we introduce an unsupervised deep learning model, Representation Learning for Genetic Discovery on Low-Dimensional Embeddings (REGLE), for discovering associations between genetic variants and HDCD. REGLE leverages variational autoencoders to compute nonlinear disentangled embeddings of HDCD, which become the inputs to genome-wide association studies (GWAS). REGLE can uncover features not captured by existing expert-defined features and enables the creation of accurate disease-specific polygenic risk scores (PRSs) in datasets with very few labeled data. We apply REGLE to perform GWAS on respiratory and circulatory HDCD-spirograms measuring lung function and photoplethysmograms measuring blood volume changes. REGLE replicates known loci while identifying others not previously detected. REGLE are predictive of overall survival, and PRSs constructed from REGLE loci improve disease prediction across multiple biobanks. Overall, REGLE contain clinically relevant information beyond that captured by existing expert-defined features, leading to improved genetic discovery and disease prediction., (© 2024. The Author(s).)
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- 2024
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193. Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations.
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Lai D, Zhang M, Green N, Abreu M, Schwantes-An TH, Parker C, Zhang S, Jin F, Sun A, Zhang P, Edenberg H, Liu Y, and Foroud T
- Abstract
Genetic risks for substance use disorders (SUDs) are due to both SUD-specific and SUD-shared genes. We performed the largest multivariate analyses to date to search for SUD-shared genes using samples of European (EA), African (AA), and Latino (LA) ancestries. By focusing on variants having cross-SUD and cross-ancestry concordant effects, we identified 45 loci. Through gene-based analyses, gene mapping, and gene prioritization, we identified 250 SUD-shared genes. These genes are highly expressed in amygdala, cortex, hippocampus, hypothalamus, and thalamus, primarily in neuronal cells. Cross-SUD concordant variants explained ~ 50% of the heritability of each SUD in EA. The top 5% individuals having the highest polygenic scores were approximately twice as likely to have SUDs as others in EA and LA. Polygenic scores had higher predictability in females than in males in EA. Using real-world data, we identified five drugs targeting identified SUD-shared genes that may be repurposed to treat SUDs., Competing Interests: Competing interests The authors declare no competing interests.
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- 2024
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194. Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.
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Hop PJ, Lai D, Keagle PJ, Baron DM, Kenna BJ, Kooyman M, Shankaracharya, Halter C, Straniero L, Asselta R, Bonvegna S, Soto-Beasley AI, Wszolek ZK, Uitti RJ, Isaias IU, Pezzoli G, Ticozzi N, Ross OA, Veldink JH, Foroud TM, Kenna KP, and Landers JE
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- Humans, Female, Male, Pedigree, Middle Aged, Mutation, Exome genetics, Exome Sequencing, Case-Control Studies, Aged, Parkinson Disease genetics, rab GTP-Binding Proteins genetics, Genetic Predisposition to Disease, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics
- Abstract
Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified
1,2 . To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32 encodes a small GTPase known to interact with LRRK2 (refs.3,4 ). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD-LRRK2 kinase activity5-7 -and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk., (© 2024. The Author(s).)- Published
- 2024
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195. Decoding the Role of Secondary Motor Cortex Neuronal Ensembles during Cocaine Self-Administration: Insights from Longitudinal in vivo Calcium Imaging via Miniscopes.
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Chen Y, Fu H, Korada A, Lange MA, Rayanki C, Montgomery JMF, Lu T, Lai D, Fang S, Guo C, and Ma YY
- Abstract
Recent findings in our lab demonstrated that the risk of cocaine relapse is closely linked to the hyperexcitability of cortical pyramidal neurons in the secondary motor cortex (M2), noticeable 45 days after cocaine intravenous self-administration (IVSA). The present study was designed to explore the underlying mechanisms of neuronal alterations in M2. Our hypothesis was that M2 neurons were affected directly by cocaine taking behaviors. This hypothesis was tested by monitoring individual neuronal activity in M2 using MiniScopes for in vivo Ca
2+ imaging in C57BL/6J mice when they had access to cocaine IVSA as a reinforcement (RNF) contingent to active lever press (ALP) but not to inactive lever press (ILP). With support of our established pipeline to processing Ca2+ imaging data, the current study was designed to monitor M2 neuronal ensembles at the single-neuron level in real time with high temporal resolution and high throughput in each IVSA session and longitudinally among multiple IVSA sessions. Specifically, five consecutive 1-hr daily IVSA sessions were used to model the initial cocaine taking behaviors. Besides detailed analyses of IVSA events (ALP, ILP, and RNF), the data from Ca2+ imaging recordings in M2 were analyzed by (1) comparing neuronal activation within a daily IVSA session (i.e., the first vs. the last 15 min) and between different daily sessions (i.e., the first vs. the last IVSA day), (2) associating Ca2+ transients with individual IVSA events, and (3) correlating Ca2+ transients with the cumulative effects of IVSA events. Our data demonstrated that M2 neurons are exquisitely sensitive to and significantly affected by concurrent operant behaviors and the history of drug exposure, which in turn sculpt the upcoming operant behaviors and the response to drugs. As critical nodes of the reward loop, M2 neurons appear to be the governing center orchestrating the establishment of addiction-like behaviors.- Published
- 2024
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196. Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with an alcohol use disorder.
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Barr PB, Neale Z, Chatzinakos C, Schulman J, Mullins N, Zhang J, Chorlian DB, Kamarajan C, Kinreich S, Pandey AK, Pandey G, Saenz de Viteri S, Acion L, Bauer L, Bucholz KK, Chan G, Dick DM, Edenberg HJ, Foroud T, Goate A, Hesselbrock V, Johnson EC, Kramer J, Lai D, Plawecki MH, Salvatore JE, Wetherill L, Agrawal A, Porjesz B, and Meyers JL
- Abstract
Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; mean age: 38). Within participants with an AUD diagnosis, we explored risk across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning for lifetime suicide attempt. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22 - 1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with an AUD who report a lifetime suicide attempt appear to experience greater levels of trauma, have more severe comorbidities, and carry polygenic risk for a variety of psychiatric problems. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders., Competing Interests: Disclosures The authors do not have any conflicts of interest to report.
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- 2024
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197. Association of Heart Failure With Cognitive Decline and Development of Mild Cognitive Impairment and Dementia.
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Jung M, Apostolova LG, Gao S, Burney HN, Lai D, Saykin AJ, and Pressler SJ
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- Humans, Female, Male, Aged, Retrospective Studies, Aged, 80 and over, Heart Failure complications, Heart Failure epidemiology, Cognitive Dysfunction epidemiology, Dementia epidemiology, Dementia complications
- Abstract
Background: Incidence of cognitive impairment and its consequences have not been fully examined in heart failure (HF)., Objective: The aim of this study was to examine associations of HF with cognitive decline, frequencies and risks of, and time-to-develop mild cognitive impairment (MCI) or dementia during 15-year follow-up., Methods: For this retrospective cohort study, data were retrieved from the National Alzheimer's Coordinating Center. Cognitive decline was assessed using the Uniform Data Set neuropsychological battery. Development of MCI and dementia was assessed using clinically diagnosed cognitive status., Results: Compared with participants without HF (n = 12 904), participants with HF (n = 256) had more decline in attention, executive function, and memory while controlling for covariates including apolipoprotein E4. Participants with HF developed MCI or dementia more frequently (44.9% vs 34.4%), developed dementia faster from normal cognition, and had a lower risk of dementia from MCI after controlling for covariates (hazard ratio, 0.71) than participants without HF., Conclusions: Heart failure was associated with accelerated cognitive decline., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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198. Functional Analysis of G6PD Variants Associated With Low G6PD Activity in the All of Us Research Program.
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Powell NR, Geck RC, Lai D, Shugg T, Skaar TC, and Dunham M
- Abstract
Glucose-6-phosphate dehydrogenase (G6PD) protects red blood cells against oxidative damage through regeneration of NADPH. Individuals with G6PD polymorphisms (variants) that produce an impaired G6PD enzyme are usually asymptomatic, but at risk of hemolytic anemia from oxidative stressors, including certain drugs and foods. Prevention of G6PD deficiency-related hemolytic anemia is achievable through G6PD genetic testing or whole-genome sequencing (WGS) to identify affected individuals who should avoid hemolytic triggers. However, accurately predicting the clinical consequence of G6PD variants is limited by over 800 G6PD variants which remain of uncertain significance. There also remains significant variability in which deficiency-causing variants are included in pharmacogenomic testing arrays across institutions: many panels only include c.202G>A, even though dozens of other variants can also cause G6PD deficiency. Here, we seek to improve G6PD genotype interpretation using data available in the All of Us Research Program and using a yeast functional assay. We confirm that G6PD coding variants are the main contributor to decreased G6PD activity, and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed if only the c.202G>A variant were tested for. We expand clinical interpretation for G6PD variants of uncertain significance; reporting that c.595A>G, known as G6PD Dagua or G6PD Açores, and the newly identified variant c.430C>G, reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that five missense variants of uncertain significance are unlikely to lead to G6PD deficiency, since they were seen in hemi- or homozygous individuals without a reduction in G6PD activity. We also applied the new WHO guidelines and were able to classify two synonymous variants as WHO class C. We anticipate these results will improve the accuracy, and prompt increased use, of G6PD genetic tests through a more complete clinical interpretation of G6PD variants. As the All of Us data increases from 245,000 to 1 million participants, and additional functional assays are carried out, we expect this research to serve as a template to enable complete characterization of G6PD deficiency genotypes. With an increased number of interpreted variants, genetic testing of G6PD will be more informative for preemptively identifying individuals at risk for drug- or food-induced hemolytic anemia.
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- 2024
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199. Utilizing multimodal AI to improve genetic analyses of cardiovascular traits.
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Zhou Y, Cosentino J, Yun T, Biradar MI, Shreibati J, Lai D, Schwantes-An TH, Luben R, McCaw Z, Engmann J, Providencia R, Schmidt AF, Munroe P, Yang H, Carroll A, Khawaja AP, McLean CY, Behsaz B, and Hormozdiari F
- Abstract
Electronic health records, biobanks, and wearable biosensors contain multiple high-dimensional clinical data (HDCD) modalities (e.g., ECG, Photoplethysmography (PPG), and MRI) for each individual. Access to multimodal HDCD provides a unique opportunity for genetic studies of complex traits because different modalities relevant to a single physiological system (e.g., circulatory system) encode complementary and overlapping information. We propose a novel multimodal deep learning method, M-REGLE, for discovering genetic associations from a joint representation of multiple complementary HDCD modalities. We showcase the effectiveness of this model by applying it to several cardiovascular modalities. M-REGLE jointly learns a lower representation (i.e., latent factors) of multimodal HDCD using a convolutional variational autoencoder, performs genome wide association studies (GWAS) on each latent factor, then combines the results to study the genetics of the underlying system. To validate the advantages of M-REGLE and multimodal learning, we apply it to common cardiovascular modalities (PPG and ECG), and compare its results to unimodal learning methods in which representations are learned from each data modality separately, but the downstream genetic analyses are performed on the combined unimodal representations. M-REGLE identifies 19.3% more loci on the 12-lead ECG dataset, 13.0% more loci on the ECG lead I + PPG dataset, and its genetic risk score significantly outperforms the unimodal risk score at predicting cardiac phenotypes, such as atrial fibrillation (Afib), in multiple biobanks.
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- 2024
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200. Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci.
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Strom NI, Gerring ZF, Galimberti M, Yu D, Halvorsen MW, Abdellaoui A, Rodriguez-Fontenla C, Sealock JM, Bigdeli T, Coleman JR, Mahjani B, Thorp JG, Bey K, Burton CL, Luykx JJ, Zai G, Alemany S, Andre C, Askland KD, Banaj N, Barlassina C, Nissen JB, Bienvenu OJ, Black D, Bloch MH, Boberg J, Børte S, Bosch R, Breen M, Brennan BP, Brentani H, Buxbaum JD, Bybjerg-Grauholm J, Byrne EM, Cabana-Dominguez J, Camarena B, Camarena A, Cappi C, Carracedo A, Casas M, Cavallini MC, Ciullo V, Cook EH, Crosby J, Cullen BA, De Schipper EJ, Delorme R, Djurovic S, Elias JA, Estivill X, Falkenstein MJ, Fundin BT, Garner L, German C, Gironda C, Goes FS, Grados MA, Grove J, Guo W, Haavik J, Hagen K, Harrington K, Havdahl A, Höffler KD, Hounie AG, Hucks D, Hultman C, Janecka M, Jenike E, Karlsson EK, Kelley K, Klawohn J, Krasnow JE, Krebs K, Lange C, Lanzagorta N, Levey D, Lindblad-Toh K, Macciardi F, Maher B, Mathes B, McArthur E, McGregor N, McLaughlin NC, Meier S, Miguel EC, Mulhern M, Nestadt PS, Nurmi EL, O'Connell KS, Osiecki L, Ousdal OT, Palviainen T, Pedersen NL, Piras F, Piras F, Potluri S, Rabionet R, Ramirez A, Rauch S, Reichenberg A, Riddle MA, Ripke S, Rosário MC, Sampaio AS, Schiele MA, Skogholt AH, Sloofman LGSG, Smit J, Soler AM, Thomas LF, Tifft E, Vallada H, van Kirk N, Veenstra-VanderWeele J, Vulink NN, Walker CP, Wang Y, Wendland JR, Winsvold BS, Yao Y, Zhou H, Agrawal A, Alonso P, Berberich G, Bucholz KK, Bulik CM, Cath D, Denys D, Eapen V, Edenberg H, Falkai P, Fernandez TV, Fyer AJ, Gaziano JM, Geller DA, Grabe HJ, Greenberg BD, Hanna GL, Hickie IB, Hougaard DM, Kathmann N, Kennedy J, Lai D, Landén M, Le Hellard S, Leboyer M, Lochner C, McCracken JT, Medland SE, Mortensen PB, Neale BM, Nicolini H, Nordentoft M, Pato M, Pato C, Pauls DL, Piacentini J, Pittenger C, Posthuma D, Ramos-Quiroga JA, Rasmussen SA, Richter MA, Rosenberg DR, Ruhrmann S, Samuels JF, Sandin S, Sandor P, Spalletta G, Stein DJ, Stewart SE, Storch EA, Stranger BE, Turiel M, Werge T, Andreassen OA, Børglum AD, Walitza S, Hveem K, Hansen BK, Rück CP, Martin NG, Milani L, Mors O, Reichborn-Kjennerud T, Ribasés M, Kvale G, Mataix-Cols D, Domschke K, Grünblatt E, Wagner M, Zwart JA, Breen G, Nestadt G, Kaprio J, Arnold PD, Grice DE, Knowles JA, Ask H, Verweij KJ, Davis LK, Smit DJ, Crowley JJ, Scharf JM, Stein MB, Gelernter J, Mathews CA, Derks EM, and Mattheisen M
- Abstract
Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6 , DALRD3 , CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder., Competing Interests: Chris German is employed by and hold stock or stock options in 23andMe, Inc. Erika L. Nurmi is on the Scientific Advisory Board for Myriad Genetics and Medical Advisory Board for Tourette Association of America and received Clinical trial funding from Emalex and Octapharma Pharmaceuticals. Jeremy Veenstra-VanderWeele has served on advisory boards or consulted with Roche, Novartis, and SynapDx; received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, Forest, Janssen, Acadia, Yamo, and MapLight; received stipends for editorial work from Wiley and Springer. Jens R. Wendland is a current employee and shareholder of Takeda Pharmaceuticals and a past employee and shareholder of F. Hoffmann-La Roche, Pfizer and Nestle Health Science. Cynthia M. Bulik reports: Pearson (author, royalty recipient).Peter Falkai reports no conflict of interest regarding this study and reports to have received financial support and Advisory Board: Richter, Recordati, Boehringer-Ingelheim, Otsuka, Janssen and Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. Ian B. Hickie is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney, Australia. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. Professor Hickie has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca, Janssen Cilag) projects focused on the identification and better management of anxiety and depression. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. Benjamin M. Neale is a member of the scientific advisory board at Deep Genomics and Neumora. Christopher Pittenger consults and/or receives research support from Biohaven Pharmaceuticals, Freedom Biosciences, Ceruvia Lifesciences, Transcend Therapeutics, UCB BioPharma, and F-Prime Capital Partners. He owns equity in Alco Therapeutics. These relationships are not related to the current work. Dan J. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. Eric A. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He was formerly a consultant for Brainsway and Biohaven Pharmaceuticals in the past 12 months. He owns stock less than $5000 in NView/Proem for distribution related to the YBOCS scales. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley. Ole A. Andreasson reports to be a consultant to Cortechs.ai, Precision Health AS, speakers honorarium from Otsuka, Lundbeck, Sunovion, Janssen. Anders D. Børglum has received speaker fee from Lundbeck. David Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, and personal fees for editorial work from Elsevier, all unrelated to the current work. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, Otsuka, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). Joel Gelernter is paid for editorial work by the journal Complex Psychiatry. Pino Alonso has received funding from Biohaven, Boston Scientific, Medtronic. All other authors report no conflicts of interest.
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- 2024
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