Browsing by Subject "Genome-wide association"

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    Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium
    (Cambridge University Press, 2019-05) Polimanti, Renato; Peterson, Roseann E.; Ong, Jue-Sheng; MacGregor, Stuart; Edwards, Alexis C.; Clarke, Toni-Kim; Frank, Josef; Gerring, Zachary; Gillespie, Nathan A.; Lind, Penelope A.; Maes, Hermine H.; Martin, Nicholas G.; Mbarek, Hamdi; Medland, Sarah E.; Streit, Fabian; Agrawal, Arpana; Edenberg, Howard J.; Kendler, Kenneth S.; Lewis, Cathryn M.; Sullivan, Patrick F.; Wray, Naomi R.; Gelernter, Joel; Derks, Eske M.; Biochemistry and Molecular Biology, School of Medicine
    BACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
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    Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy
    (Wiley, 2020-09) Chua, Katherina C.; Xiong, Chenling; Ho, Carol; Mushiroda, Taisei; Jiang, Chen; Mulkey, Flora; Lai, Dongbing; Schneider, Bryan P.; Rashkin, Sara R.; Witte, John S.; Friedman, Paula N.; Ratain, Mark J.; McLeod, Howard L.; Rugo, Hope S.; Shulman, Lawrence N.; Kubo, Michiaki; Owzar, Kouros; Kroetz, Deanna L.; Medical and Molecular Genetics, School of Medicine
    Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 – 0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 – 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.
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    Genome-wide Network-assisted Association and Enrichment Study of Amyloid Imaging Phenotype in Alzheimer's Disease
    (Bentham Science, 2019) Li, Jin; Chen, Feng; Zhang, Qiushi; Meng, Xianglian; Yao, Xiaohui; Risacher, Shannon L.; Yan, Jingwen; Saykin, Andrew J.; Liang, Hong; Shen, Li; Radiology and Imaging Sciences, School of Medicine
    Background: The etiology of Alzheimer's disease remains poorly understood at the mechanistic level, and genome-wide network-based genetics have the potential to provide new insights into the disease mechanisms. Objective: The study aimed to explore the collective effects of multiple genetic association signals on an AV-45 PET measure, which is a well-known Alzheimer's disease biomarker, by employing a network assisted strategy. Methods: First, we took advantage of a dense module search algorithm to identify modules enriched by genetic association signals in a protein-protein interaction network. Next, we performed statistical evaluation to the modules identified by dense module search, including a normalization process to adjust the topological bias in the network, a replication test to ensure the modules were not found randomly , and a permutation test to evaluate unbiased associations between the modules and amyloid imaging phenotype. Finally, topological analysis, module similarity tests and functional enrichment analysis were performed for the identified modules. Results: We identified 24 consensus modules enriched by robust genetic signals in a genome-wide association analysis. The results not only validated several previously reported AD genes (APOE, APP, TOMM40, DDAH1, PARK2, ATP5C1, PVRL2, ELAVL1, ACTN1 and NRF1), but also nominated a few novel genes (ABL1, ABLIM2) that have not been studied in Alzheimer's disease but have shown associations with other neurodegenerative diseases. Conclusion: The identified genes, consensus modules and enriched pathways may provide important clues to future research on the neurobiology of Alzheimer's disease and suggest potential therapeutic targets.
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    Shared Genetic Risk between Eating Disorder and Substance Use-Related Phenotypes: Evidence from Genome-Wide Association Studies
    (Wiley, 2021) Munn-Chernoff, Melissa A.; Johnson, Emma C.; Chou, Yi-Ling; Coleman, Jonathan R.I.; Thornton, Laura M.; Walters, Raymond K.; Yilmaz, Zeynep; Baker, Jessica H.; Hübel, Christopher; Gordon, Scott; Medland, Sarah E.; Watson, Hunna J.; Gaspar, Héléna A.; Bryois, Julien; Hinney, Anke; Leppä, Virpi M.; Mattheisen, Manuel; Ripke, Stephan; Yao, Shuyang; Giusti-Rodríguez, Paola; Hanscombe, Ken B.; Adan, Roger A.H.; Alfredsson, Lars; Ando, Tetsuya; Andreassen, Ole A.; Berrettini, Wade H.; Boehm, Ilka; Boni, Claudette; Perica, Vesna Boraska; Buehren, Katharina; Burghardt, Roland; Cassina, Matgteo; Cichon, Sven; Clementi, Maurizio; Cone, Roger D.; Courtet, Philippe; Crow, Scott; Crowley, James J.; Danner, Unna N.; Davis, Oliver S.P.; de Zwaan, Martina; Dedoussis, George; Degortes, Daniela; DeSocio, Janiece E.; Dick, Danielle M.; Dikeos, Dimitris; Dina, Christian; Dmitrzak-Weglarz, Monika; Docampo, Elisa; Duncan, Laramie E.; Egberts, Karin; Ehrlich, Stefan; Escaramís, Geòrgia; Esko, Tõnu; Estivill, Xavier; Farmer, Anne; Favaro, Angela; Fernández-Aranda, Fernando; Fichter, Manfred M.; Fischer, Krista; Föcker, Manuel; Foretova, Lenka; Forstner, Andreas J.; Forzan, Monica; Franklin, Christopher S.; Gallinger, Steven; Giegling, Ina; Giuranna, Johanna; Gonidakis, Fragiskos; Gorwood, Philip; Gratacos Mayora, Monica; Guillaume, Sébastien; Guo, Yiran; Hakonarson, Hakon; Hatzikotoulas, Konstantinos; Hauser, Joanna; Hebebrand, Johannes; Helder, Sietske G.; Herms, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Huckins, Laura M.; Hudson, James I.; Imgart, Hartmut; Inoko, Hidetoshi; Janout, Vladimir; Jiménez-Murcia, Susana; Julià, Antonio; Kalsi, Gursharan; Kaminská, Deborah; Karhunen, Leila; Karwautz, Andreas; Kas, Martien J.H.; Kennedy, James L.; Keski-Rahkonen, Anna; Kiezebrink, Kirsty; Kim, Youl-Ri; Klump, Kelly L.; Knudsen, Gun Peggy S.; La Via, Maria C.; Le Hellard, Stephanie; Levitan, Robert D.; Li, Dong; Lilenfeld, Lisa; Lin, Bochao Danae; Lissowska, Jolanta; Luykx, Jurjen; Magistretti, Pierre J.; Maj, Mario; Mannik, Katrin; Marsal, Sara; Marshall, Christian R.; Mattingsdal, Morten; McDevitt, Sara; McGuffin, Peter; Metspalu, Andres; Meulenbelt, Ingrid; Micali, Nadia; Mitchell, Karen; Monteleone, Alessio Maria; Monteleone, Palmiero; Nacmias, Benedetta; Navratilova, Marie; Ntalla, Ioanna; O’Toole, Julie K.; Ophoff, Roel A.; Padyukov, Leonid; Palotie, Aarno; Pantel, Jacques; Papezova, Hana; Pinto, Dalila; Rabionet, Raquel; Raevuori, Anu; Ramoz, Nicolas; Reichborn-Kjennerud, Ted; Ricca, Valdo; Ripatti, Samuli; Ritschel, Franziska; Roberts, Marion; Rotondo, Alessandro; Rujescu, Dan; Rybakowski, Filip; Santonastaso, Paolo; Scherag, André; Scherer, Stephen W.; Schmidt, Ulrike; Schork, Nicholas J.; Schosser, Alexandra; Seitz, Jochen; Slachtova, Lenka; Slagboom, P. Eline; Slof-Op’t Landt, Margarita C.T.; Slopien, Agnieszka; Sorbi, Sandro; Świątkowska, Beata; Szatkiewicz, Jin P.; Tachmazidou, Ioanna; Tenconi, Elena; Tortorella, Alfonso; Tozzi, Federica; Treasure, Janet; Tsitsika, Artemis; Tyszkiewicz-Nwafor, Marta; Tziouvas, Konstantinos; van Elburg, Annemarie A.; van Furth, Eric F.; Wagner, Gudrun; Walton, Esther; Widen, Elisabeth; Zeggini, Eleftheria; Zerwas, Stephanie; Zipfel, Stephan; Bergen, Andrew W.; Boden, Joseph M.; Brandt, Harry; Crawford, Steven; Halmi, Katherine A.; Horwood, L. John; Johnson, Craig; Kaplan, Allan S.; Kaye, Walter H.; Mitchell, James; Olsen, Catherine M.; Pearson, John F.; Pedersen, Nancy L.; Strober, Michael; Werge, Thomas; Whiteman, David C.; Woodside, D. Blake; Stuber, Garret D.; Grove, Jakob; Henders, Anjali K.; Larsen, Janne T.; Parker, Richard; Petersen, Liselotte V.; Jordan, Jennifer; Kennedy, Martin A.; Birgegård, Andreas; Lichtenstein, Paul; Norring, Claes; Landén, Mikael; Mortensen, Preben Bo; Polimanti, Renato; 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; Degenhardt, Franziska; Docherty, Anna R.; Edwards, Alexis C.; Foo, Jerome C.; Fox, Louis; Frank, Josef; Hack, Laura M.; Hartmann, Annette M.; Hartz, Sarah M.; Heilmann-Heimbach, Stefanie; Hodgkinson, Colin; Hoffmann, Per; Hottenga, Jouke-Jan; Konte, Bettina; Lahti, Jari; Lahti-Pulkkinen, Marius; Lai, Dongbing; Ligthart, Lannie; Loukola, Anu; Maher, Marion S.; Mbarek, Hamdi; McIntosh, Andrew M.; McQueen, Matthew B.; Meyers, Jacquelyn L.; Milaneschi, Yuri; Palviainen, Teemu; Peterson, Roseann E.; 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.; Zhou, Hang; Boardman, Jason D.; Chen, Danfeng; Choi, Doo-Sup; Copeland, William E.; Culverhouse, Robert C.; Dahmen, Norbert; Degenhardt, Louisa; Domingue, Benjamin W.; Frye, Mark A.; Gäbel, Wolfgang; Hayward, Caroline; Ising, Marcus; Keyes, Margaret; Kiefer, Falk; Koller, Gabrielle; Kramer, John; Kuperman, Samuel; Lucae, Susanne; Lynskey, Michael T.; Maier, Wolfgang; Mann, Karl; Männistö, Satu; Müller-Myhsok, Bertram; Murray, Alison D.; Nurnberger, John I.; Preuss, Ulrich; Räikkönen, Katri; Reynolds, Maureen D.; Ridinger, Monika; Scherbaum, Norbert; Schuckit, Marc A.; Soyka, Michael; Treutlein, Jens; Witt, Stephanie H.; Wodarz, Norbert; Zill, Peter; Adkins, Daniel E.; Boomsma, Dorret I.; Bierut, Laura J.; Brown, Sandra A.; Bucholz, Kathleen K.; Costello, E. Jane; de Wit, Harriet; Diazgranados, Nancy; Eriksson, Johan G.; Farrer, Lindsay A.; Foroud, Tatiana M.; Gillespie, Nathan A.; Goate, Alison M.; Goldman, David; Grucza, Richard A.; Hancock, Dana B.; Mullan Harris, Kathleen; Hesselbrock, Victor; Hewitt, John K.; Hopfer, Christian; Iacono, William G.; Johnson, Eric O.; Karpyak, Victor M.; Kendler, Kenneth S.; Kranzler, Henry R.; Krauter, Kenneth; Lind, Penelope A.; McGue, Matt; MacKillop, James; Madden, Pamela A.F.; Maes, Hermine H.; Magnusson, Patrik K.E.; Nelson, Elliot C.; Nöthen, Markus M.; Palmer, Abraham A.; Penninx, Brenda W.J.H.; Porjesz, Bernice; Rice, John P.; Rietschel, Marcella; Riley, Brien P.; Rose, Richard J.; 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.; Wade, Tracey D.; Heath, Andrew C.; Montgomery, Grant W.; Martin, Nicholas G.; Sullivan, Patrick F.; Kaprio, Jaakko; Breen, Gerome; Gelernter, Joel; Edenberg, Howard J.; Bulik, Cynthia M.; Agrawal, Arpana; Biochemistry and Molecular Biology, School of Medicine
    Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic risk between eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use, mainly abuse and dependence (twin-based genetic correlation [rg]=0.23–0.53). Analytic advances facilitate the computation of genetic correlations using summary statistics from existing genome-wide association studies (GWAS). We investigated shared genetic risk between eating disorder and substance use and disorder phenotypes using GWAS data. Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; q<0.0001), and cannabis initiation and AN with binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, smoking cessation, and cigarettes per day) and AN without binge-eating (rgs=−0.19 to −0.23; qs<0.04). The observed patterns of association between different eating disorder and substance use-related phenotypes highlights the potentially complex and substance-specific relationships between these behaviors associated with significant public health burden.