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1. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author

Munn-Chernoff, M.A. Johnson, E.C. Chou, Y.-L. Coleman, J.R.I. Thornton, L.M. Walters, R.K. Yilmaz, Z. Baker, J.H. Hübel, C. Gordon, S. Medland, S.E. Watson, H.J. Gaspar, H.A. Bryois, J. Hinney, A. Leppä, V.M. Mattheisen, M. Ripke, S. Yao, S. Giusti-Rodríguez, P. Hanscombe, K.B. Adan, R.A.H. Alfredsson, L. Ando, T. Andreassen, O.A. Berrettini, W.H. Boehm, I. Boni, C. Boraska Perica, V. Buehren, K. Burghardt, R. Cassina, M. Cichon, S. Clementi, M. Cone, R.D. Courtet, P. Crow, S. Crowley, J.J. Danner, U.N. Davis, O.S.P. de Zwaan, M. Dedoussis, G. Degortes, D. DeSocio, J.E. Dick, D.M. Dikeos, D. Dina, C. Dmitrzak-Weglarz, M. Docampo, E. Duncan, L.E. Egberts, K. Ehrlich, S. Escaramís, G. Esko, T. Estivill, X. Farmer, A. Favaro, A. Fernández-Aranda, F. Fichter, M.M. Fischer, K. Föcker, M. Foretova, L. Forstner, A.J. Forzan, M. Franklin, C.S. Gallinger, S. Giegling, I. Giuranna, J. Gonidakis, F. Gorwood, P. Gratacos Mayora, M. Guillaume, S. Guo, Y. Hakonarson, H. Hatzikotoulas, K. Hauser, J. Hebebrand, J. Helder, S.G. Herms, S. Herpertz-Dahlmann, B. Herzog, W. Huckins, L.M. Hudson, J.I. Imgart, H. Inoko, H. Janout, V. Jiménez-Murcia, S. Julià, A. Kalsi, G. Kaminská, D. Karhunen, L. Karwautz, A. Kas, M.J.H. Kennedy, J.L. Keski-Rahkonen, A. Kiezebrink, K. Kim, Y.-R. Klump, K.L. Knudsen, G.P.S. La Via, M.C. Le Hellard, S. Levitan, R.D. Li, D. Lilenfeld, L. Lin, B.D. Lissowska, J. Luykx, J. Magistretti, P.J. Maj, M. Mannik, K. Marsal, S. Marshall, C.R. Mattingsdal, M. McDevitt, S. McGuffin, P. Metspalu, A. Meulenbelt, I. Micali, N. Mitchell, K. Monteleone, A.M. Monteleone, P. Nacmias, B. Navratilova, M. Ntalla, I. O'Toole, J.K. Ophoff, R.A. Padyukov, L. Palotie, A. Pantel, J. Papezova, H. Pinto, D. Rabionet, R. Raevuori, A. Ramoz, N. Reichborn-Kjennerud, T. Ricca, V. Ripatti, S. Ritschel, F. Roberts, M. Rotondo, A. Rujescu, D. Rybakowski, F. Santonastaso, P. Scherag, A. Scherer, S.W. Schmidt, U. Schork, N.J. Schosser, A. Seitz, J. Slachtova, L. Slagboom, P.E. Slof-Op't Landt, M.C.T. Slopien, A. Sorbi, S. Świątkowska, B. Szatkiewicz, J.P. Tachmazidou, I. Tenconi, E. Tortorella, A. Tozzi, F. Treasure, J. Tsitsika, A. Tyszkiewicz-Nwafor, M. Tziouvas, K. van Elburg, A.A. van Furth, E.F. Wagner, G. Walton, E. Widen, E. Zeggini, E. Zerwas, S. Zipfel, S. Bergen, A.W. Boden, J.M. Brandt, H. Crawford, S. Halmi, K.A. Horwood, L.J. Johnson, C. Kaplan, A.S. Kaye, W.H. Mitchell, J. Olsen, C.M. Pearson, J.F. Pedersen, N.L. Strober, M. Werge, T. Whiteman, D.C. Woodside, D.B. Grove, J. Henders, A.K. Larsen, J.T. Parker, R. Petersen, L.V. Jordan, J. Kennedy, M.A. Birgegård, A. Lichtenstein, P. Norring, C. Landén, M. Mortensen, P.B. Polimanti, R. McClintick, J.N. Adkins, A.E. Aliev, F. Bacanu, S.-A. Batzler, A. Bertelsen, S. Biernacka, J.M. Bigdeli, T.B. Chen, L.-S. Clarke, T.-K. Degenhardt, F. Docherty, A.R. Edwards, A.C. Foo, J.C. Fox, L. Frank, J. Hack, L.M. Hartmann, A.M. Hartz, S.M. Heilmann-Heimbach, S. Hodgkinson, C. Hoffmann, P. Hottenga, J.-J. Konte, B. Lahti, J. Lahti-Pulkkinen, M. Lai, D. Ligthart, L. Loukola, A. Maher, B.S. Mbarek, H. McIntosh, A.M. McQueen, M.B. Meyers, J.L. Milaneschi, Y. Palviainen, T. Peterson, R.E. Ryu, E. Saccone, N.L. Salvatore, J.E. Sanchez-Roige, S. Schwandt, M. Sherva, R. Streit, F. Strohmaier, J. Thomas, N. Wang, J.-C. Webb, B.T. Wedow, R. Wetherill, L. Wills, A.G. Zhou, H. Boardman, J.D. Chen, D. Choi, D.-S. Copeland, W.E. Culverhouse, R.C. Dahmen, N. Degenhardt, L. Domingue, B.W. Frye, M.A. Gäebel, W. Hayward, C. Ising, M. Keyes, M. Kiefer, F. Koller, G. Kramer, J. Kuperman, S. Lucae, S. Lynskey, M.T. Maier, W. Mann, K. Männistö, S. Müller-Myhsok, B. Murray, A.D. Nurnberger, J.I. Preuss, U. Räikkönen, K. Reynolds, M.D. Ridinger, M. Scherbaum, N. Schuckit, M.A. Soyka, M. Treutlein, J. Witt, S.H. Wodarz, N. Zill, P. Adkins, D.E. Boomsma, D.I. Bierut, L.J. Brown, S.A. Bucholz, K.K. Costello, E.J. de Wit, H. Diazgranados, N. Eriksson, J.G. Farrer, L.A. Foroud, T.M. Gillespie, N.A. Goate, A.M. Goldman, D. Grucza, R.A. Hancock, D.B. Harris, K.M. Hesselbrock, V. Hewitt, J.K. Hopfer, C.J. Iacono, W.G. Johnson, E.O. Karpyak, V.M. Kendler, K.S. Kranzler, H.R. Krauter, K. Lind, P.A. McGue, M. MacKillop, J. Madden, P.A.F. Maes, H.H. Magnusson, P.K.E. Nelson, E.C. Nöthen, M.M. Palmer, A.A. Penninx, B.W.J.H. Porjesz, B. Rice, J.P. Rietschel, M. Riley, B.P. Rose, R.J. Shen, P.-H. Silberg, J. Stallings, M.C. Tarter, R.E. Vanyukov, M.M. Vrieze, S. Wall, T.L. Whitfield, J.B. Zhao, H. Neale, B.M. Wade, T.D. Heath, A.C. Montgomery, G.W. Martin, N.G. Sullivan, P.F. Kaprio, J. Breen, G. Gelernter, J. Edenberg, H.J. Bulik, C.M. Agrawal, A.

Subjects
mental disorders
Abstract

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors. © 2020 Society for the Study of Addiction

Published
2021

2. Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits

Author

Quach, B.C., Bray, M.J., Gaddis, N.C., Liu, M., Palviainen, T., Minica, C.C., Zellers, S., Sherva, R., Aliev, F., Nothnagel, M., Young, K.A., Marks, J., Young, H., Guo, Y., Waldrop, A., Sey, N., Landi, M.T., McNeil, D.W., Farrer, L.A., Markunas, C.A., Vink, J.M., Hottenga, J.J., Iacono, W.G., Kranzler, H.R., Saccone, N.L., Neale, M.C., Madden, P.A.F., Rietschel, M., Marazita, M.L., McGue, M.K., Won, H., Winterer, G., Grucza, R.A., Dick, D.M., Gelernter, J., Caporaso, N.E., Baker, T.B., Boomsma, D.I., Kaprio, J., Hokanson, J.E., Vrieze, S., Bierut, L.J., Johnson, E.O., Hancock, D.B., Quach, B.C., Bray, M.J., Gaddis, N.C., Liu, M., Palviainen, T., Minica, C.C., Zellers, S., Sherva, R., Aliev, F., Nothnagel, M., Young, K.A., Marks, J., Young, H., Guo, Y., Waldrop, A., Sey, N., Landi, M.T., McNeil, D.W., Farrer, L.A., Markunas, C.A., Vink, J.M., Hottenga, J.J., Iacono, W.G., Kranzler, H.R., Saccone, N.L., Neale, M.C., Madden, P.A.F., Rietschel, M., Marazita, M.L., McGue, M.K., Won, H., Winterer, G., Grucza, R.A., Dick, D.M., Gelernter, J., Caporaso, N.E., Baker, T.B., Boomsma, D.I., Kaprio, J., Hokanson, J.E., Vrieze, S., Bierut, L.J., Johnson, E.O., and Hancock, D.B.

Abstract

Contains fulltext : 276901.pdf (Publisher’s version ) (Open Access), Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking

Published
2020

4. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Author

Schijven, D., Chen, C.-Y., Morey, R.A., Vermetten, E., Sanchez, S.E., Maihofer, A.X., Jett, M., Dale, A.M., Ratanatharathorn, A., McGlinchey, R.E., McLaughlin, K.A., Polimanti, R., Roberts, A.L., Williams, M.A., Nievergelt, C.M., Atkinson, E.G., Mors, O., Brashear, M., Gordon, S.D., Trapido, E., Haas, M., Lawford, B.R., Kimbrel, N.A., Sponheim, S.R., Daskalakis, N.P., Duncan, L.E., Rung, A., Orcutt, H.K., Pietrzak, R.H., Bustamante, A.C., Bisson, J.I., Koenen, K.C., McLean, S.A., Ripke, S., Kremen, W.S., Maples-Keller, J., Marmar, C., Sheerin, C.M., Calabrese, J.R., Andersen, S.B., Seligowski, A.V., Feeny, N.C., Polusny, M.A., Qin, X.-J., Daly, M.J., Ashley-Koch, A.E., Morris, C.P., Liberzon, I., Erbes, C.R., King, A.P., Zhao, H., Forbes, D., Jakovljevic, M., van den Heuvel, L.L., Peters, E.S., Evans, A., Boks, M.P., Aiello, A.E., Hougaard, D.M., Roy-Byrne, P., Bierut, L.J., Kranzler, H.R., Vinkers, C.H., Peterson, A.L., Wolf, C., Deckert, J., Linnstaedt, S.D., Stein, D.J., Levey, D.F., Almli, L.M., Martin, N.G., Williamson, D.E., Flory, J.D., Børglum, A.D., Guffanti, G., Stein, M.B., Lori, A., Khan, A., Baker, D.G., Ressler, K.J., Torres, K., Seedat, S., Andreassen, O.A., Neale, B.M., Werge, T., Mehta, D., Austin, S.B., Breen, G., Beckham, J.C., Geuze, E., Miller, M.W., Mortensen, P.B., Coleman, J.R.I., Provost, A.C., Norman, S.B., Garrett, M.E., McLeay, S., Van Hooff, M., Bolger, E.A., Franz, C.E., Luykx, J.J., Maurer, D., Wolff, J.D., Martin, A.R., Young, K.A., Lewis, C.E., Zoellner, L.A., Dennis, M.F., Delahanty, D.L., O’Donnell, M., Heath, A.C., Saccone, N.L., Domschke, K., Logue, M.W., Ursano, R.J., Smith, A.K., Rothbaum, A.O., Rutten, B.P.F., Harnal, S., Panizzon, M.S., Uddin, M., Babiat, D., Bryant, R.A., Gelernter, J., Smoller, J.W., Klengel, T., Bybjerg-Grauholm, J., Choi, K.W., Jovanovic, T., Caldas-de-Almeida, J.M., Nelson, E.C., Mavissakalian, M.R., Johnson, E.O., Hammamieh, R, Milberg, W.P., Nordentoft, M., Gillespie, C., Amstadter, A.B., Bradley, B., Teicher, M.H., Arbisi, P.A., Lebois, L.A.M., Hauser, M.A., Dzubur-Kulenovic, A., Hemmings, S.M.J., Gelaye, B., Sumner, J.A., Uka, A.G., Young, R.M.D., Voisey, J., Wang, Y., Galea, S., Wang, Z., Jones, I., Peverill, M., Disner, S.G., Seng, J.S., Kessler, R.C., Junglen, A.G., Wolf, E.J., Lugonja, B., Dalvie, S., Koen, N., Rice, J.P., Rothbaum, B.O., Thompson, W.K., Ruggiero, K., Karstoft, K.-I., Farrer, L.A., Stevens, J.S., Silove, D., Avdibegovic, E., Risbrough, V.B., Lyons, M.J., Bækvad-Hansen, M., and McFarlane, A.

Abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations. © 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2019
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5. Collaborative meta-Analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

Author

Culverhouse, R.C. Saccone, N.L. Horton, A.C. Ma, Y. Anstey, K.J. Banaschewski, T. Burmeister, M. Cohen-Woods, S. Etain, B. Fisher, H.L. Goldman, N. Guillaume, S. Horwood, J. Juhasz, G. Lester, K.J. Mandelli, L. Middeldorp, C.M. Olié, E. Villafuerte, S. Air, T.M. Araya, R. Bowes, L. Burns, R. Byrne, E.M. Coffey, C. Coventry, W.L. Gawronski, K.A.B. Glei, D. Hatzimanolis, A. Hottenga, J.-J. Jaussent, I. Jawahar, C. Jennen-Steinmetz, C. Kramer, J.R. Lajnef, M. Little, K. Zu Schwabedissen, H.M. Nauck, M. Nederhof, E. Petschner, P. Peyrot, W.J. Schwahn, C. Sinnamon, G. Stacey, D. Tian, Y. Toben, C. Van Der Auwera, S. Wainwright, N. Wang, J.-C. Willemsen, G. Anderson, I.M. Arolt, V. Aslund, C. Bagdy, G. Baune, B.T. Bellivier, F. Boomsma, D.I. Courtet, P. Dannlowski, U. De Geus, E.J.C. Deakin, J.F.W. Easteal, S. Eley, T. Fergusson, D.M. Goate, A.M. Gonda, X. Grabe, H.J. Holzman, C. Johnson, E.O. Kennedy, M. Laucht, M. Martin, N.G. Munafò, M.R. Nilsson, K.W. Oldehinkel, A.J. Olsson, C.A. Ormel, J. Otte, C. Patton, G.C. Penninx, B.W.J.H. Ritchie, K. Sarchiapone, M. Scheid, J.M. Serretti, A. Smit, J.H. Stefanis, N.C. Surtees, P.G. Völzke, H. Weinstein, M. Whooley, M. Nurnberger, J.I., Jr. Breslau, N. Bierut, L.J.

Abstract

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-Analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-Analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-Analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Published
2018

6. Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence

Author

Hancock, D.B., Guo, Y., Reginsson, G.W., Gaddis, N.C., Lutz, S.M., Sherva, R., Loukola, A., Minica, C.C., Markunas, C.A., Han, Y., Young, K.A., Gudbjartsson, D.F., Gu, F., McNeil, D.W., Qaiser, B., Glasheen, C., Olson, S., Landi, M.T., Madden, P.A.F., Farrer, L.A., Vink, J.M., Saccone, N.L., Neale, M.C., Kranzler, H.R., McKay, J., Hung, R.J., Amos, C.I., Marazita, M.L., Boomsma, D.I., Baker, T.B., Gelernter, J., Kaprio, J., Caporaso, N.E., Thorgeirsson, T.E., Hokanson, J.E., Bierut, L.J., Stefansson, K., Johnson, E.O., Hancock, D.B., Guo, Y., Reginsson, G.W., Gaddis, N.C., Lutz, S.M., Sherva, R., Loukola, A., Minica, C.C., Markunas, C.A., Han, Y., Young, K.A., Gudbjartsson, D.F., Gu, F., McNeil, D.W., Qaiser, B., Glasheen, C., Olson, S., Landi, M.T., Madden, P.A.F., Farrer, L.A., Vink, J.M., Saccone, N.L., Neale, M.C., Kranzler, H.R., McKay, J., Hung, R.J., Amos, C.I., Marazita, M.L., Boomsma, D.I., Baker, T.B., Gelernter, J., Kaprio, J., Caporaso, N.E., Thorgeirsson, T.E., Hokanson, J.E., Bierut, L.J., Stefansson, K., and Johnson, E.O.

Abstract

Item does not contain fulltext, Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 [times] 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 [times] 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 [times] 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 [times] 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Published
2018

7. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

Author

Culverhouse, R C, Saccone, N.L., Horton, A C, Ma, Y, Anstey, K J, Banaschewski, T., Burmeister, M., Cohen-Woods, Sarah, Etain, B., Fisher, H L, Goldman, N, Guillaume, S, Horwood, J., Juhasz, G, Lester, K J, Mandelli, L, Middeldorp, C M, Olié, E, Villafuerte, S., Air, T M, Araya, R., Bowes, L, Burns, M.R., Byrne, Enda M, Coffey, J.C., Coventry, W.L., Gawronski, K A B, Glei, D, Hatzimanolis, A, Hottenga, J-J, Jaussent, I, Jawahar, C, Jennen-Steinmetz, C, Kramer, J R, Lajnef, M, Little, K, Meyer zu Schwabedissen, H., Nauck, M., Nederhof, E., Petschner, P, Peyrot, Wouter J, Schwahn, C, Sinnamon, G, Stacey, D., Tian, Y, Toben, C, Van der Auwera, Sandra, Wainwright, N.W., Wang, J-C, Willemsen, G, Anderson, I M, Arolt, V., Åslund, C, Bagdy, G, Baune, Bernard T, Bellivier, F., Boomsma, D I, Courtet, P, Dannlowski, Udo, de Geus, E J C, Deakin, J F W, Easteal, S, Eley, T.C., Fergusson, D.M., Goate, A.M., Gonda, X, Grabe, Hans J, Holzman, C, Johnson, E.O., Kennedy, D.M., Laucht, M, Martin, Nicholas G, Munafò, Marcus R, Nilsson, K.W., Oldehinkel, Albertine J, Olsson, C A, Ormel, J., Otte, C., Patton, G C, Penninx, B W J H, Ritchie, K, Sarchiapone, M., Scheid, J M, Serretti, A, Smit, J H, Stefanis, N C, Surtees, P G, Völzke, H., Weinstein, M, Whooley, M.A., Nurnberger, J.I., Breslau, N., Bierut, L.J., Culverhouse, R C, Saccone, N.L., Horton, A C, Ma, Y, Anstey, K J, Banaschewski, T., Burmeister, M., Cohen-Woods, Sarah, Etain, B., Fisher, H L, Goldman, N, Guillaume, S, Horwood, J., Juhasz, G, Lester, K J, Mandelli, L, Middeldorp, C M, Olié, E, Villafuerte, S., Air, T M, Araya, R., Bowes, L, Burns, M.R., Byrne, Enda M, Coffey, J.C., Coventry, W.L., Gawronski, K A B, Glei, D, Hatzimanolis, A, Hottenga, J-J, Jaussent, I, Jawahar, C, Jennen-Steinmetz, C, Kramer, J R, Lajnef, M, Little, K, Meyer zu Schwabedissen, H., Nauck, M., Nederhof, E., Petschner, P, Peyrot, Wouter J, Schwahn, C, Sinnamon, G, Stacey, D., Tian, Y, Toben, C, Van der Auwera, Sandra, Wainwright, N.W., Wang, J-C, Willemsen, G, Anderson, I M, Arolt, V., Åslund, C, Bagdy, G, Baune, Bernard T, Bellivier, F., Boomsma, D I, Courtet, P, Dannlowski, Udo, de Geus, E J C, Deakin, J F W, Easteal, S, Eley, T.C., Fergusson, D.M., Goate, A.M., Gonda, X, Grabe, Hans J, Holzman, C, Johnson, E.O., Kennedy, D.M., Laucht, M, Martin, Nicholas G, Munafò, Marcus R, Nilsson, K.W., Oldehinkel, Albertine J, Olsson, C A, Ormel, J., Otte, C., Patton, G C, Penninx, B W J H, Ritchie, K, Sarchiapone, M., Scheid, J M, Serretti, A, Smit, J H, Stefanis, N C, Surtees, P G, Völzke, H., Weinstein, M, Whooley, M.A., Nurnberger, J.I., Breslau, N., and Bierut, L.J.

Abstract

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.Molecular Psychiat

Published
2018
Full Text
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8. A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder

Author

Morey, R.A., Garrett, M.E., Roberts, A.L., Ratanatharathorn, A., Kessler, R.C., Gelernter, J., Dalvie, S., Hauser, M.A., Almli, L.M., Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup, Smoller, J.W., Baker, D.G., Ashley-Koch, A.E., Chen, C.-Y., Nugent, N.R., Rice, J.P., Farrer, L.A., Miller, M.W., Aiello, A.E., Nievergelt, C.M., Duncan, L.E., Bierut, L.J., Bradley, B., Wildman, D.E., Daly, M.J., Koen, N., Polimanti, R., Amstadter, A.B., Ressler, K.J., Galea, S., King, A., Bisson, J., Guffanti, G., Sumner, J.A., Kimbrel, N.A., Johnson, E.O., Maihofer, A.X., Ripke, S., Kranzler, H.R., Yehuda, R., Koenen, K.C., Ursano, R.J., Beckham, J.C., Uddin, M., Gelernter, J.E., Liberzon, I., Zhao, H., Saccone, N.L., Stein, M.B., Martin, A.R., Stein, D.J., and Logue, M.W.

Abstract

Background: The nature and underlying mechanisms of the observed increased vulnerability to posttraumatic stress disorder (PTSD) in women are unclear. Methods: We investigated the genetic overlap of PTSD with anthropometric traits and reproductive behaviors and functions in women. The analysis was conducted using female-specific summary statistics from large genome-wide association studies (GWAS) and a cohort of 3577 European American women (966 PTSD cases and 2611 trauma-exposed controls). We applied a high-resolution polygenic score approach and Mendelian randomization analysis to investigate genetic correlations and causal relationships. Results: We observed an inverse association of PTSD with genetically determined anthropometric traits related to body shape, independent of body mass index (BMI). The top association was related to BMI-adjusted waist circumference (WCadj; R = -0.079, P < 0.001, Q = 0.011). We estimated a relative decrease of 64.6% (95% confidence interval = 27.5-82.7) in the risk of PTSD per 1-SD increase in WCadj. MR-Egger regression intercept analysis showed no evidence of pleiotropic effects in this association (Ppleiotropy = 0.979). We also observed associations of genetically determined WCadj with age at first sexual intercourse and number of sexual partners (P = 0.013 and P < 0.001, respectively). Conclusions: There is a putative causal relationship between genetically determined female body shape and PTSD, which could be mediated by evolutionary mechanisms involved in human sexual behaviors.

Published
2017
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9. Multilocus measures for linkage disequilibrium

Author

Rice, J.P., Saccone, N.L., and Kwok, P.-Y.

Subjects
Human genetics -- Research, Genetic disorders -- Research, Linkage (Genetics) -- Physiological aspects, Biological sciences
Published
2001

12. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Author

Polderman, T.J.C., Stefansson, K., Zuccolo, L., Wall, T.L., Stan����kov��, A., Zhan, X., Hunter, D.J., Davila-Velderrain, J., Palviainen, T., Brazel, D.M., 23andMe Research Team, Haller, T., Chen, F., Jiang, Y., Johnson, E.O., Rose, R.J., Martin, N.G., Wedow, R., Rice, J.P., Boehnke, M., Jorgenson, E., Posthuma, D., Haessler, J., Kellis, M., Young, K.A., Jansen, P.R., Bjornsdottir, G., Kardia, S.L.R., Metspalu, A., Chen, C., Eaton, C.B., Madden, P.A.F., Gillespie, N.A., McGue, M., Choquet, H., McMahon, G., Jang, S.-K., Faul, J.D., Nielsen, J.B., Fritsche, L.G., Yin, J., Cucca, F., Medland, S.E., Vrieze, S., Thorgeirsson, T.E., Loukola, A., Reginsson, G.W., Tian, C., Orr��, V., HUNT All-In Psychiatry, Iacono, W.G., Gordon, S.D., Kraft, P., Fiorillo, E., Reiner, A.P., Willer, C.J., Boomsma, D.I., Munaf��, M.R., Tyrfingsson, T., Kaprio, J., Laakso, M., Zajac, G.J.M., Willemsen, G., Hickie, I.B., Runarsdottir, V., Li, Y., Hottenga, J.-J., McQueen, M.B., Ehringer, M.A., Zhou, W., Smith, J.A., Taylor, A.E., Tindle, H.A., Kooperberg, C., Boardman, J.D., Lee, J.J., McGuire, D., Zhao, W., Mulas, A., Cornelis, M.C., Lind, P.A., Hveem, K., Weisner, C., Datta, G., Gudbjartsson, D.F., Lutz, S.M., M��gi, R., Hewitt, J.K., Turman, C., Thai, K.K., Stallings, M.C., Kamatani, Y., Hopfer, C.J., David, S.P., Young, H., Rimm, E., Bierut, L.J., Ling, Y., Foerster, J.R., Harris, K.M., Davies, G.E., Krauter, K.S., Matoba, N., Abecasis, G., Esko, T., Keller, M.C., Whitfield, J.B., Liu, D.J., Huang, H., Stitzel, J.A., Liu, M., Peters, U., Saccone, N.L., Docherty, A.R., Pandit, A., Stefansson, H., Hokanson, J.E., Heath, A.C., Okada, Y., Weir, D.R., and Mohlke, K.L.

Subjects
3. Good health
Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

13. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

Author

Lucy Bowes, Richard Burns, Alex Hatzimanolis, Gonneke Willemsen, Martin A. Kennedy, Kathryn J. Lester, Katerina A.B. Gawronski, Udo Dannlowski, Alison Goate, Carolyn Coffey, Matthias Nauck, David Stacey, Ricardo Araya, Frank Bellivier, Cecilia Åslund, Catherine Toben, Catharine Jawahar, Karen Ritchie, Emilie Olié, Gyorgy Bagdy, Nicholas G. Martin, Robert Culverhouse, Isabelle Jaussent, Peter Petschner, Eric O. Johnson, Nancy L. Saccone, Sandra Villafuerte, Mohamed Lajnef, John I. Nurnberger, Volker Arolt, Laura Mandelli, Philippe Courtet, Henry Völzke, Yinjiao Ma, Craig A. Olsson, Y. Tian, Bernhard T. Baune, Keriann Little, Wouter J. Peyrot, Nicholas W.J. Wainwright, Helen L. Fisher, Brenda W.J.H. Penninx, Manfred Laucht, E.J.C. de Geus, Jan Smit, Sébastien Guillaume, J. M. Scheid, S Van der Auwera, Christian Schwahn, Hans-Jörgen Grabe, Kent W. Nilsson, Xenia Gonda, Dana A. Glei, Gabriella Juhasz, Bruno Etain, C. Holzman, Maxine Weinstein, Thalia C. Eley, Kaarin J. Anstey, Marco Sarchiapone, John Francis William Deakin, Naomi Breslau, P. G. Surtees, John Kramer, J-J Hottenga, Enda M. Byrne, Marcus R. Munafò, Christine Jennen-Steinmetz, Laura J. Bierut, Albertine J. Oldehinkel, Noreen Goldman, Dorret I. Boomsma, Simon Easteal, Margit Burmeister, John Horwood, George C Patton, Tobias Banaschewski, David M. Fergusson, Amy C. Horton, Mary A. Whooley, J. C. Wang, Esther Nederhof, H. M. Zu Schwabedissen, Grant C.B. Sinnamon, Christian Otte, Sarah Cohen-Woods, Ian M. Anderson, William L. Coventry, Tracy Air, Christel M. Middeldorp, Nicholas C. Stefanis, Alessandro Serretti, Johan Ormel, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, roussel, pascale, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de psychiatrie adulte, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital La Colombière, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fondation FondaMental [Créteil], Hopital Saint-Louis [AP-HP] (AP-HP), Culverhouse, R.C., Saccone, N.L., Horton, A.C., Ma, Y., Anstey, K.J., Banaschewski, T., Burmeister, M., Cohen-Woods, S., Etain, B., Fisher, H.L., Goldman, N., Guillaume, S., Horwood, J., Juhasz, G., Lester, K.J., Mandelli, L., Middeldorp, C.M., Olié, E., Villafuerte, S., Air, T.M., Araya, R., Bowes, L., Burns, R., Byrne, E.M., Coffey, C., Coventry, W.L., Gawronski, K.A.B., Glei, D., Hatzimanolis, A., Hottenga, J.-J., Jaussent, I., Jawahar, C., Jennen-Steinmetz, C., Kramer, J.R., Lajnef, M., Little, K., Zu Schwabedissen, H.M., Nauck, M., Nederhof, E., Petschner, P., Peyrot, W.J., Schwahn, C., Sinnamon, G., Stacey, D., Tian, Y., Toben, C., Van Der Auwera, S., Wainwright, N., Wang, J.-C., Willemsen, G., Anderson, I.M., Arolt, V., Aslund, C., Bagdy, G., Baune, B.T., Bellivier, F., Boomsma, D.I., Courtet, P., Dannlowski, U., De Geus, E.J.C., Deakin, J.F.W., Easteal, S., Eley, T., Fergusson, D.M., Goate, A.M., Gonda, X., Grabe, H.J., Holzman, C., Johnson, E.O., Kennedy, M., Laucht, M., Martin, N.G., Munafò, M.R., Nilsson, K.W., Oldehinkel, A.J., Olsson, C.A., Ormel, J., Otte, C., Patton, G.C., Penninx, B.W.J.H., Ritchie, K., Sarchiapone, M., Scheid, J.M., Serretti, A., Smit, J.H., Stefanis, N.C., Surtees, P.G., Völzke, H., Weinstein, M., Whooley, M., Nurnberger, J.I., Breslau, N., Bierut, L.J., Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Etudes des Combustibles (DEC), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, China Jiliang University (CJLU), Psychiatry, and APH - Digital Health

Subjects
DISORDER, Netherlands Twin Register (NTR), SAMPLE, [SDV]Life Sciences [q-bio], Brain and Behaviour, 0302 clinical medicine, Cooperative Behavior, Gene–environment interaction, Depression (differential diagnoses), Serotonin Plasma Membrane Transport Proteins, RISK, Depression, Tobacco and Alcohol, Interaction hypothesis, Life Change Event, Justice and Strong Institutions, 3. Good health, [SDV] Life Sciences [q-bio], ENVIRONMENT INTERACTION, Psychiatry and Mental health, Meta-analysis, Psychology, Serotonin Plasma Membrane Transport Protein, Molecular Biology, Cellular and Molecular Neuroscience, Psychiatry and Mental Health, Human, Clinical psychology, SDG 16 - Peace, LIFE EVENTS, Genotype, POLYMORPHISM 5-HTTLPR, Stress, Article, CHILDHOOD MALTREATMENT, Life Change Events, 03 medical and health sciences, Journal Article, Humans, Genetic Predisposition to Disease, Risk factor, Depressive Disorder, SEROTONIN TRANSPORTER GENE, Stressor, SDG 16 - Peace, Justice and Strong Institutions, MAJOR DEPRESSION, 030227 psychiatry, 5-HTTLPR, Behavioral medicine, COHORT PROFILE, Psychological, Gene-Environment Interaction, Stress, Psychological, 030217 neurology & neurosurgery
Abstract

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.44.

Published
2018
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