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2. The genetic aetiology of cannabis use: From twin models to genome-wide association studies and beyond

Author

Verweij, K.J.H., Vink, J.M., Abdellaoui, A., Gillespie, N.A., Derks, E.M., Treur, J.L., Verweij, K.J.H., Vink, J.M., Abdellaoui, A., Gillespie, N.A., Derks, E.M., and Treur, J.L.

Abstract

Contains fulltext : 285187.pdf (Publisher’s version ) (Open Access), Cannabis is among the most widely consumed psychoactive substances worldwide. Individual differences in cannabis use phenotypes can partly be explained by genetic differences. Technical and methodological advances have increased our understanding of the genetic aetiology of cannabis use. This narrative review discusses the genetic literature on cannabis use, covering twin, linkage, and candidate-gene studies, and the more recent genome-wide association studies (GWASs), as well as the interplay between genetic and environmental factors. Not only do we focus on the insights that these methods have provided on the genetic aetiology of cannabis use, but also on how they have helped to clarify the relationship between cannabis use and co-occurring traits, such as the use of other substances and mental health disorders. Twin studies have shown that cannabis use is moderately heritable, with higher heritability estimates for more severe phases of use. Linkage and candidate-gene studies have been largely unsuccessful, while GWASs so far only explain a small portion of the heritability. Dozens of genetic variants predictive of cannabis use have been identified, located in genes such as CADM2, FOXP2, and CHRNA2. Studies that applied multivariate methods (twin models, genetic correlation analysis, polygenic score analysis, genomic structural equation modelling, Mendelian randomisation) indicate that there is considerable genetic overlap between cannabis use and other traits (especially other substances and externalising disorders) and some evidence for causal relationships (most convincingly for schizophrenia). We end our review by discussing implications of these findings and suggestions for future work.

Published
2022

3. Self-reported impact of developmental stuttering across the lifespan

Author

Boyce, J.O., Jackson, V.E., Reyk, O. van, Parker, R., Vogel, A.P., Eising, E., Horton, S.E., Gillespie, N.A., Scheffer, I.E., Amor, D.J., Hildebrand, M.S., Fisher, S.E., Martin, N.G., Reilly, S., Bahlo, M., Morgan, A.T., Boyce, J.O., Jackson, V.E., Reyk, O. van, Parker, R., Vogel, A.P., Eising, E., Horton, S.E., Gillespie, N.A., Scheffer, I.E., Amor, D.J., Hildebrand, M.S., Fisher, S.E., Martin, N.G., Reilly, S., Bahlo, M., and Morgan, A.T.

Abstract

Contains fulltext : 283563.pdf (Publisher’s version ) (Closed access)

Published
2022

4. 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

5. Associations between the CADM2 gene, substance use, risky sexual behavior, and self-control: A phenome-wide association study

Author

Arends, R.M., Pasman, J.A., Verweij, K.J.H., Derks, E.M., Gordon, S.D., Hickie, I.B., Thomas, N.S., Aliev, F., Zietsch, B.P., Zee, M.D. van der, Mitchell, B.L., Martin, N.G., Dick, D.M., Gillespie, N.A., Geus, E.J.C. de, Boomsma, D.I., Schellekens, A.F.A., Vink, J.M., Arends, R.M., Pasman, J.A., Verweij, K.J.H., Derks, E.M., Gordon, S.D., Hickie, I.B., Thomas, N.S., Aliev, F., Zietsch, B.P., Zee, M.D. van der, Mitchell, B.L., Martin, N.G., Dick, D.M., Gillespie, N.A., Geus, E.J.C. de, Boomsma, D.I., Schellekens, A.F.A., and Vink, J.M.

Abstract

Contains fulltext : 230584.pdf (Publisher’s version ) (Open Access), Risky behaviors, such as substance use and unprotected sex, are associated with various physical and mental health problems. Recent genome-wide association studies indicated that variation in the cell adhesion molecule 2 (CADM2) gene plays a role in risky behaviors and self-control. In this phenome-wide scan for risky behavior, it was tested if underlying common vulnerability could be (partly) explained by pleiotropic effects of this gene and how large the effects were. Single nucleotide polymorphism (SNP)-level and gene-level association tests within four samples (25 and Up, Spit for Science, Netherlands Twin Register, and UK Biobank and meta-analyses over all samples (combined sample of 362,018 participants) were conducted to test associations between CADM2, substance- and sex-related risk behaviors, and various measures related to self-control. We found significant associations between the CADM2 gene, various risky behaviors, and different measures of self-control. The largest effect sizes were found for cannabis use, sensation seeking, and disinhibition. Effect sizes ranged from 0.01% to 0.26% for single top SNPs and from 0.07% to 3.02% for independent top SNPs together, with sufficient power observed only in the larger samples and meta-analyses. In the largest cohort, we found indications that risk-taking proneness mediated the association between CADM2 and latent factors for lifetime smoking and regular alcohol use. This study extends earlier findings that CADM2 plays a role in risky behaviors and self-control. It also provides insight into gene-level effect sizes and demonstrates the feasibility of testing mediation. These findings present a good starting point for investigating biological etiological pathways underlying risky behaviors.

Published
2021

6. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Author

Hofer, E., Roshchupkin, G.V., Adams, H.H.H., Knol, M.J., Lin, H., Li, S., Zare, H., Ahmad, S., Armstrong, N.J., Satizabal, C.L., Bernard, M., Bis, J.C., Gillespie, N.A., Luciano, M., Mishra, A., Scholz, M., Teumer, A., Xia, R., Jian, X., Mosley, T.H., Saba, Y., Pirpamer, L., Seiler, S., Becker, J.T., Carmichael, O., Rotter, J.I., Psaty, B.M., Lopez, O.L., Amin, N., van der Lee, S.J., Yang, Q., Himali, J.J., Maillard, P., Beiser, A.S., DeCarli, C., Karama, S., Lewis, L., Harris, M., Bastin, M.E., Deary, I.J., Veronica Witte, A., Beyer, F., Loeffler, M., Mather, K.A., Schofield, P.R., Thalamuthu, A., Kwok, J.B., Wright, M.J., Ames, D., Trollor, J., Jiang, J., Brodaty, H., Wen, W., Vernooij, M.W., Hofman, A., Uitterlinden, A.G., Niessen, W.J., Wittfeld, K., Bülow, R., Völker, U., Pausova, Z., Bruce Pike, G., Maingault, S., Crivello, F., Tzourio, C., Amouyel, P., Mazoyer, B., Neale, M.C., Franz, C.E., Lyons, M.J., Panizzon, M.S., Andreassen, O.A., Dale, A.M., Logue, M.A., Grasby, K.L., Jahanshad, N., Painter, J.N., Colodro-Conde, L., Bralten, J., Hibar, D.P., Lind, P.A., Pizzagalli, F., Stein, J.L., Thompson, P.M., Medland, S.E., Sachdev, P.S., Kremen, W.S., Wardlaw, J.M., Villringer, A., van Duijn, C.M., Grabe, H.J., Longstreth, W.T., Fornage, M., Paus, T., Debette, S., Arfan Ikram, M., Schmidt, H., Schmidt, R., Seshadri, S., Hofer, E., Roshchupkin, G.V., Adams, H.H.H., Knol, M.J., Lin, H., Li, S., Zare, H., Ahmad, S., Armstrong, N.J., Satizabal, C.L., Bernard, M., Bis, J.C., Gillespie, N.A., Luciano, M., Mishra, A., Scholz, M., Teumer, A., Xia, R., Jian, X., Mosley, T.H., Saba, Y., Pirpamer, L., Seiler, S., Becker, J.T., Carmichael, O., Rotter, J.I., Psaty, B.M., Lopez, O.L., Amin, N., van der Lee, S.J., Yang, Q., Himali, J.J., Maillard, P., Beiser, A.S., DeCarli, C., Karama, S., Lewis, L., Harris, M., Bastin, M.E., Deary, I.J., Veronica Witte, A., Beyer, F., Loeffler, M., Mather, K.A., Schofield, P.R., Thalamuthu, A., Kwok, J.B., Wright, M.J., Ames, D., Trollor, J., Jiang, J., Brodaty, H., Wen, W., Vernooij, M.W., Hofman, A., Uitterlinden, A.G., Niessen, W.J., Wittfeld, K., Bülow, R., Völker, U., Pausova, Z., Bruce Pike, G., Maingault, S., Crivello, F., Tzourio, C., Amouyel, P., Mazoyer, B., Neale, M.C., Franz, C.E., Lyons, M.J., Panizzon, M.S., Andreassen, O.A., Dale, A.M., Logue, M.A., Grasby, K.L., Jahanshad, N., Painter, J.N., Colodro-Conde, L., Bralten, J., Hibar, D.P., Lind, P.A., Pizzagalli, F., Stein, J.L., Thompson, P.M., Medland, S.E., Sachdev, P.S., Kremen, W.S., Wardlaw, J.M., Villringer, A., van Duijn, C.M., Grabe, H.J., Longstreth, W.T., Fornage, M., Paus, T., Debette, S., Arfan Ikram, M., Schmidt, H., Schmidt, R., and Seshadri, S.

Abstract

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Published
2020

7. Genome-wide meta-analyses of FTND and TTFC phenotypes

Author

Chen, J., Loukola, A., Gillespie, N.A., Peterson, R.E., Jia, P., Riley, B.P., Vink, J.M., Kaprio, J., Chen, X., Chen, J., Loukola, A., Gillespie, N.A., Peterson, R.E., Jia, P., Riley, B.P., Vink, J.M., Kaprio, J., and Chen, X.

Abstract

Item does not contain fulltext, FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported.Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND.Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND.Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

Published
2020

8. Global and regional development of the human cerebral cortex: Molecular architecture and occupational aptitudes

Author

Paus, T., Seshadri, S., Pausova, Z., Sestan, N., Jahanshad, N., Ding, L., Kremen, W.S., Franz, C.E., Gillespie, N.A., Debette, S., Maingault, S., Mishra, A., Tzourio, C., Grabe, H.J., Bülow, R., Wittfeld, K., van der -Palitschka, S., Frenzel, S., Ikram, M.A., Adams, H.H.H.H., Evans, T.E., Terzikhan, N., Sachdev, P.S., Wen, W., Brodaty, H., Wright, M.J., Trollor, J.N., Thalamuthu, A., Schofield, P.R., Kwok, J.B., Jiang, J., Ames, D., Mather, K.A., Armstrong, N.J., Villringer, A., Beyer, F., Witte, A.V., Loeffler, M., Scholz, M., Deary, I.E., Wardlaw, J.M., Harris, M.A., Bastin, M.E., Lewis, L., Karama, S., Luciano, M., Yang, Q., Li, S., Bis, J.C., Mazoyer, B., Crivello, F., Carrion-Castillo, A., Schmidt, H., Schmidt, R., Pirpamer, L., Saba, Y., Fornage, M., Mosley, T.H., Gottesman, R., Jian, X., Sousa, A.M.M., Roshchupkin, G.V., Tilley, S., Vosberg, D.E., Patel, Y., Hofer, E., Ma, S., Shin, J., Paus, T., Seshadri, S., Pausova, Z., Sestan, N., Jahanshad, N., Ding, L., Kremen, W.S., Franz, C.E., Gillespie, N.A., Debette, S., Maingault, S., Mishra, A., Tzourio, C., Grabe, H.J., Bülow, R., Wittfeld, K., van der -Palitschka, S., Frenzel, S., Ikram, M.A., Adams, H.H.H.H., Evans, T.E., Terzikhan, N., Sachdev, P.S., Wen, W., Brodaty, H., Wright, M.J., Trollor, J.N., Thalamuthu, A., Schofield, P.R., Kwok, J.B., Jiang, J., Ames, D., Mather, K.A., Armstrong, N.J., Villringer, A., Beyer, F., Witte, A.V., Loeffler, M., Scholz, M., Deary, I.E., Wardlaw, J.M., Harris, M.A., Bastin, M.E., Lewis, L., Karama, S., Luciano, M., Yang, Q., Li, S., Bis, J.C., Mazoyer, B., Crivello, F., Carrion-Castillo, A., Schmidt, H., Schmidt, R., Pirpamer, L., Saba, Y., Fornage, M., Mosley, T.H., Gottesman, R., Jian, X., Sousa, A.M.M., Roshchupkin, G.V., Tilley, S., Vosberg, D.E., Patel, Y., Hofer, E., Ma, S., and Shin, J.

Abstract

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.

Published
2020

9. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (vol 9, 2098, 2018)

Author

Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., Lee, S.J. van der, Ware, E.B., Windham, B.G., Wright, M.J., Yang, J.Y., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Bohmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kahonen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Hellard, S. le, Lee, T., Lehtimaki, T., Li, S.C., Lill, C.M., Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikainen, L.P., Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumare, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., Jager, P.L. de, Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hagg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Raikkonen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., Duijn, C.M. van, Villringer, A., Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., and Deary, I.J.

Published
2019

10. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (Nature Communications, (2018), 9, 1, (2098), 10.1038/s41467-018-04362-x)

Author

Davies, G. Lam, M. Harris, S.E. Trampush, J.W. Luciano, M. Hill, W.D. Hagenaars, S.P. Ritchie, S.J. Marioni, R.E. Fawns-Ritchie, C. Liewald, D.C.M. Okely, J.A. Ahola-Olli, A.V. Barnes, C.L.K. Bertram, L. Bis, J.C. Burdick, K.E. Christoforou, A. DeRosse, P. Djurovic, S. Espeseth, T. Giakoumaki, S. Giddaluru, S. Gustavson, D.E. Hayward, C. Hofer, E. Ikram, M.A. Karlsson, R. Knowles, E. Lahti, J. Leber, M. Li, S. Mather, K.A. Melle, I. Morris, D. Oldmeadow, C. Palviainen, T. Payton, A. Pazoki, R. Petrovic, K. Reynolds, C.A. Sargurupremraj, M. Scholz, M. Smith, J.A. Smith, A.V. Terzikhan, N. Thalamuthu, A. Trompet, S. van der Lee, S.J. Ware, E.B. Windham, B.G. Wright, M.J. Yang, J. Yu, J. Ames, D. Amin, N. Amouyel, P. Andreassen, O.A. Armstrong, N.J. Assareh, A.A. Attia, J.R. Attix, D. Avramopoulos, D. Bennett, D.A. Böhmer, A.C. Boyle, P.A. Brodaty, H. Campbell, H. Cannon, T.D. Cirulli, E.T. Congdon, E. Conley, E.D. Corley, J. Cox, S.R. Dale, A.M. Dehghan, A. Dick, D. Dickinson, D. Eriksson, J.G. Evangelou, E. Faul, J.D. Ford, I. Freimer, N.A. Gao, H. Giegling, I. Gillespie, N.A. Gordon, S.D. Gottesman, R.F. Griswold, M.E. Gudnason, V. Harris, T.B. Hartmann, A.M. Hatzimanolis, A. Heiss, G. Holliday, E.G. Joshi, P.K. Kähönen, M. Kardia, S.L.R. Karlsson, I. Kleineidam, L. Knopman, D.S. Kochan, N.A. Konte, B. Kwok, J.B. Le Hellard, S. Lee, T. Lehtimäki, T. Li, S.-C. Lill, C.M. Liu, T. Koini, M. London, E. Longstreth, W.T., Jr. Lopez, O.L. Loukola, A. Luck, T. Lundervold, A.J. Lundquist, A. Lyytikäinen, L.-P. Martin, N.G. Montgomery, G.W. Murray, A.D. Need, A.C. Noordam, R. Nyberg, L. Ollier, W. Papenberg, G. Pattie, A. Polasek, O. Poldrack, R.A. Psaty, B.M. Reppermund, S. Riedel-Heller, S.G. Rose, R.J. Rotter, J.I. Roussos, P. Rovio, S.P. Saba, Y. Sabb, F.W. Sachdev, P.S. Satizabal, C.L. Schmid, M. Scott, R.J. Scult, M.A. Simino, J. Slagboom, P.E. Smyrnis, N. Soumaré, A. Stefanis, N.C. Stott, D.J. Straub, R.E. Sundet, K. Taylor, A.M. Taylor, K.D. Tzoulaki, I. Tzourio, C. Uitterlinden, A. Vitart, V. Voineskos, A.N. Kaprio, J. Wagner, M. Wagner, H. Weinhold, L. Wen, K.H. Widen, E. Yang, Q. Zhao, W. Adams, H.H.H. Arking, D.E. Bilder, R.M. Bitsios, P. Boerwinkle, E. Chiba-Falek, O. Corvin, A. De Jager, P.L. Debette, S. Donohoe, G. Elliott, P. Fitzpatrick, A.L. Gill, M. Glahn, D.C. Hägg, S. Hansell, N.K. Hariri, A.R. Ikram, M.K. Jukema, J.W. Vuoksimaa, E. Keller, M.C. Kremen, W.S. Launer, L. Lindenberger, U. Palotie, A. Pedersen, N.L. Pendleton, N. Porteous, D.J. Räikkönen, K. Raitakari, O.T. Ramirez, A. Reinvang, I. Rudan, I. Dan Rujescu Schmidt, R. Schmidt, H. Schofield, P.W. Schofield, P.R. Starr, J.M. Steen, V.M. Trollor, J.N. Turner, S.T. Van Duijn, C.M. Villringer, A. Weinberger, D.R. Weir, D.R. Wilson, J.F. Malhotra, A. McIntosh, A.M. Gale, C.R. Seshadri, S. Mosley, T.H., Jr. Bressler, J. Lencz, T. Deary, I.J.

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article. © 2019, The Author(s).

Published
2019

11. Author correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia liability

Author

Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., Vink, J.M., Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., and Vink, J.M.

Abstract

Item does not contain fulltext, Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability", as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

Published
2019

12. High-potency cannabis and incident psychosis: Correcting the causal assumption

Author

Gillespie, N.A., Pasman, J.A., Treur, J.L., Derkes, E.M., Verweij, K.J.H., Vink, J.M., Gillespie, N.A., Pasman, J.A., Treur, J.L., Derkes, E.M., Verweij, K.J.H., and Vink, J.M.

Abstract

Item does not contain fulltext, A commentary on Di Forti et al., 2019: 'The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study.'

Published
2019

13. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., van der Lee, S.J., Ware, E.B., Windham, B.G., Wright, M.J., Yang, J., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Böhmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kähönen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Le Hellard, S., Lee, T., Lehtimäki, T., Li, S-C., Lill, C.M., Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikäinen, L-P, Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumaré, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., De Jager, P.L., Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hägg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Räikkönen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., van Duijn, C.M., Villringer, A., Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., Deary, I.J., Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., van der Lee, S.J., Ware, E.B., Windham, B.G., Wright, M.J., Yang, J., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Böhmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kähönen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Le Hellard, S., Lee, T., Lehtimäki, T., Li, S-C., Lill, C.M., Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikäinen, L-P, Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumaré, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., De Jager, P.L., Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hägg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Räikkönen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., van Duijn, C.M., Villringer, A., Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., and Deary, I.J.

Abstract

These authors contributed equally: Gail Davies, Max Lam. These authors jointly supervised this work: Todd Lencz, Ian J. Deary.

Published
2019

14. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Author

Vojinovic, D., Adams, H.H., Jian, X.Q., Yang, Q., Smith, A.V., Bis, J.C., Teumer, A., Scholz, M., Armstrong, N.J., Hofer, E., Saba, Y., Luciano, M., Bernard, M., Trompet, S., Yang, J.Y., Gillespie, N.A., Lee, S.J. van der, Neumann, A., Ahmad, S., Andreassen, O.A., Ames, D., Amin, N., Arfanakis, K., Bastin, M.E., Becker, D.M., Beiser, A.S., Beyer, F., Brodaty, H., Bryan, R.N., Bulow, R., Dale, A.M., Jager, P.L. de, Deary, I.J., DeCarli, C., Fleischman, D.A., Gottesman, R.F., Grond, J. van der, Gudnason, V., Harris, T.B., Homuth, G., Knopman, D.S., Kwok, J.B., Lewis, C.E., Li, S., Loeffler, M., Lopez, O.L., Maillard, P., Marroun, H. el, Mather, K.A., Mosley, T.H., Muetzel, R.L., Nauck, M., Nyquist, P.A., Panizzon, M.S., Pausova, Z., Psaty, B.M., Rice, K., Rotter, J.I., Royle, N., Satizabal, C.L., Schmidt, R., Schofield, P.R., Schreiner, P.J., Sidney, S., Stott, D.J., Thalamuthu, A., Uitterlinden, A.G., Hernandez, M.C.V., Vernooij, M.W., Wen, W., White, T., Witte, A.V., Wittfeld, K., Wright, M.J., Yanek, L.R., Tiemeier, H., Kremen, W.S., Bennett, D.A., Jukema, J.W., Paus, T., Wardlaw, J.M., Schmidt, H., Sachdev, P.S., Villringer, A., Grabe, H.J., Longstreth, W.T., Duijn, C.M. van, Launer, L.J., Seshadri, S., Ikram, M.A., and Fornage, M.

Published
2018

16. Genome-Wide Association meta-analysis of age at first cannabis use

Author

Minica, C.C., Verweij, K.J.H., Most, P.J. van der, Mbarek, H., Bernard, M., Eijk, K.R. van, Lind, P.A., Liu, M.Z., Maciejewski, D.F., Palviainen, T., Sánchez-Mora, C., Sherva, R., Taylor, M., Walters, R.K., Abdellaoui, A., Bigdeli, T.B., Branje, S.J.T., Brown, S.A., Casas, M., Corley, R.P., Smith, G.D., Davies, G.E., Ehli, E.A., Farrer, L.A., Fedko, I.O., Garcia-Martinez, I., Gordon, S.D., Hartman, C.A., Heath, A.C., Hickie, I.B., Hickman, M., Hopfer, C.J., Hottenga, J.J., Kahn, R.S., Kaprio, J., Korhonen, T., Kranzler, H.R., Krauter, K., Lier, P.A.C. van, Madden, P.A.F., Medland, S.E., Neale, M.C., Meeus, W.H.J., Montgomery, G.W., Nolte, I.M., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Richarte, V., Rose, R.J., Shin, J., Stallings, M.C., Wall, T.L., Ware, J.J., Wright, M.J., Zhao, H., Koot, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Loukola, A., Boks, M.P.M., Snieder, H., Munafò, M.R., Gelernter, J., Boomsma, D.I., Martin, N.G., Gillespie, N.A., Vink, J.M., Derks, E.M., Minica, C.C., Verweij, K.J.H., Most, P.J. van der, Mbarek, H., Bernard, M., Eijk, K.R. van, Lind, P.A., Liu, M.Z., Maciejewski, D.F., Palviainen, T., Sánchez-Mora, C., Sherva, R., Taylor, M., Walters, R.K., Abdellaoui, A., Bigdeli, T.B., Branje, S.J.T., Brown, S.A., Casas, M., Corley, R.P., Smith, G.D., Davies, G.E., Ehli, E.A., Farrer, L.A., Fedko, I.O., Garcia-Martinez, I., Gordon, S.D., Hartman, C.A., Heath, A.C., Hickie, I.B., Hickman, M., Hopfer, C.J., Hottenga, J.J., Kahn, R.S., Kaprio, J., Korhonen, T., Kranzler, H.R., Krauter, K., Lier, P.A.C. van, Madden, P.A.F., Medland, S.E., Neale, M.C., Meeus, W.H.J., Montgomery, G.W., Nolte, I.M., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Richarte, V., Rose, R.J., Shin, J., Stallings, M.C., Wall, T.L., Ware, J.J., Wright, M.J., Zhao, H., Koot, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Loukola, A., Boks, M.P.M., Snieder, H., Munafò, M.R., Gelernter, J., Boomsma, D.I., Martin, N.G., Gillespie, N.A., Vink, J.M., and Derks, E.M.

Abstract

Contains fulltext : 195854.pdf (publisher's version ) (Closed access), Background and aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identify associations with genetic variants. Methods: A twin-based heritability analysis using 8,055 twins from three cohorts was performed. We then carried-out a genome wide survival meta-analysis of age at first cannabis use in a discovery sample of 24,953 individuals from nine European, North American, and Australian cohorts, and a replication sample of 3,735 individuals. Results: The twin-based heritability for age at first cannabis use was 38% (95% confidence interval [CI] 19-60%). Shared and unique environmental factors explained 39% (95% CI 20-56%) and 22% (95% CI 16-29%). The genome wide survival meta-analysis identified five SNPs on chromosome 16 within the Calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high LD (r2>0.8) with the strongest association at the intronic variant rs1574587 (P=4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P=1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been previously associated with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. Conclusion: Age at cannabis initiation appears to be moderately heritable in Western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

Published
2018

17. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia liability

Author

Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., Vink, J.M., Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.S., Ip, H.F., Zee, M.D. van der, Bartels, M., Day, F.R., Fontanillas, P., Elson, S.L., Wit, H. de, Davis, L.K., MacKillop, J., Derringer, J.L., Branje, S.J.T., Hartman, C.A., Heath, A.C., Lier, P.A.C. van, Madden, P.A.F., Mägi, R., Meeus, W.H.J., Montgomery, G.W., Oldehinkel, A.J., Pausova, Z., Ramos-Quiroga, J.A., Paus, T., Ribases, M., Kaprio, J., Boks, M.P.M., Bell, J.T., Spector, T.D., Gelernter, J., Boomsma, D.I., Martin, N.G., MacGregor, S., Perry, J.R.B., Palmer, A.A., Posthuma, D., Munafò, M.R., Gillespie, N.A., Derks, E.M., and Vink, J.M.

Abstract

Contains fulltext : 195179.pdf (publisher's version ) (Closed access), Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health–related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Published
2018

18. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Davies, G. (Gail), Lam, M. (Max), Harris, S.E. (Sarah), Trampush, J.W. (Joey W.), Luciano, M. (Michelle), Hill, W.D. (W. David), Hagenaars, S. (Saskia), Ritchie, S.J. (Stuart J.), Marioni, R.E. (Riccardo), Fawns-Ritchie, C., Liewald, D.C.M. (David C. M.), Okely, J.A. (Judith A.), Ahola-Olli, A.V. (Ari V.), Barnes, C.L.K. (Catriona L. K.), Bertram, L. (Lars), Bis, J.C. (Joshua), Burdick, K.E. (Katherine E.), Christoforou, A. (Andrea), Derosse, P. (Pamela), Djurovic, S. (Srdjan), Espeseth, T. (Thomas), Giakoumaki, S. (Stella), Giddaluru, S. (Sudheer), Gustavson, D.E. (Daniel E.), Hayward, C. (Caroline), Hofer, E. (Edith), Ikram, M.A. (Arfan), Karlsson, R. (Robert), Knowles, E. (Emma), Lahti, J. (Jari), Leber, I. (Isabelle), Li, S. (Shuo), Mather, R., Melle, I. (Ingrid), Morris, D. (Derek), Oldmeadow, C. (Christopher), Palviainen, T. (Teemu), Payton, A. (Antony), Pazoki, R. (Raha), Petrovic, K. (Katja), Reynolds, C.A. (C.), Sargurupremraj, M. (Muralidharan), Scholz, M. (Markus), Smith, J.A. (Jennifer A), Smith, A.V. (Albert), Terzikhan, N. (Natalie), Thalamuthu, A. (Anbupalam), Trompet, S. (Stella), Lee, S.J. (Sven) van der, Ware, E.B. (Erin B.), Windham, B.G. (Gwen), Wright, M.J. (Margaret J.), Yang, J. (Jingyun), Yu, J. (Jin), Ames, D.J. (David), Amin, N. (Najaf), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Armstrong, N.J. (Nicola J.), Assareh, A.A., Attia, J. (John), Attix, D. (Deborah), Avramopoulos, D. (Dimitrios), Bennett, D.A. (David), Böhmer, M.R. (Marcel), Boyle, P.A. (Patricia A.), Brodaty, H. (Henry), Campbell, H. (Harry), Cannon, T.D. (Tyrone D.), Cirulli, E.T. (Elizabeth T.), Congdon, E. (Eliza), Conley, E.D. (Emily Drabant), Corley, J. (Janie), Cox, S.R. (Simon R.), Dale, A.M. (Anders), Dehghan, A. (Abbas), Dick, D. (Danielle), Dickinson, D. (Dwight), Hagen, K. (Knut), Evangelou, E. (Evangelos), Faul, J.D. (Jessica D.), Ford, I. (Ian), Freimer, N.A. (Nelson A.), Gao, H. (He), Giegling, I. (Ina), Gillespie, N.A. (Nathan A.), Gordon, S.D. (Scott D.), Gottesman, R.F. (Rebecca), Griswold, M.D. (Michael), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Hartmann, A.M. (Annette M), Hatzimanolis, A. (Alex), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Joshi, P.K. (Peter), Kähönen, M. (Mika), Kardia, S.L.R. (Sharon L. R.), Karlsson, I. (Ida), Kleineidam, L. (Luca), Knopman, D.S. (David), Kochan, N.A. (Nicole A.), Konte, B. (Bettina), Kwok, J.B.J. (John), Le Hellard, S. (Stephanie), Lee, T. (Teresa), Lehtimäki, T. (Terho), Li, S.-C. (Shu-Chen), Liu, T. (Tian), Koini, M. (Marisa), London, E. (Edythe), Longstreth Jr, W.T., Lopez, O.L. (Oscar), Loukola, A. (Anu), Luck, T. (Tobias), Lundervold, A.J. (Astri), Lundquist, A. (Anders), Lyytikäinen, L.-P. (Leo-Pekka), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant W.), Murray, A.D. (Alison D.), Need, A.C. (Anna C.), Noordam, R. (Raymond), Nyberg, L. (Lisa), Ollier, W.E.R. (William), Papenberg, G., Pattie, A. (Alison), Polasek, O. (Ozren), Poldrack, R.A. (Russell A.), Psaty, B.M. (Bruce M.), Reppermund, S., Riedel-Heller, S. (Steffi), Rose, R.J. (Richard), Rotter, J.I. (Jerome I.), Roussos, A. (Alexandra), Rovio, S.P. (Suvi P.), Saba, Y. (Yasaman), Sabb, F.W. (Fred W.), Sachdev, P.S. (Perminder), Satizabal, C.L. (Claudia), Schmid, M. (Matthias), Scott, R.J. (Rodney J.), Scult, M.A. (Matthew A.), Simino, J. (Jeannette), Slagboom, P.E. (Eline), Smyrnis, N. (Nikolaos), Soumaré, A. (Aicha), Stefanis, N.C. (Nikos C.), Stott, D.J. (David. J.), Straub, R.E. (Richard), Sundet, K. (Kjetil), Taylor, A.M. (Adele M.), Taylor, K.D. (Kent), Tzoulaki, I., Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vitart, V. (Veronique), Voineskos, A.N. (Aristotle N.), Kaprio, J. (Jaakko), Wagner, M. (Michael), Wagner, H. (Hermann), Weinhold, L. (Leonie), Wen, K.H. (K. Hoyan), Widen, E., Yang, Q. (Qiong Fang), Zhao, W. (Wei), Adams, H.H.H. (Hieab), Arking, D.E. (Dan), Bilder, R.M. (Robert M.), Bitsios, P. (Panos), Boerwinkle, E. (Eric), Chiba-Falek, O. (Ornit), Corvin, A. (Aiden), Jager, P.L. (Philip) de, Debette, S. (Stéphanie), Donohoe, D.J. (Dennis), Elliott, P. (Paul), Fitzpatrick, A.L. (Annette), Gill, M. (Michael), Glahn, D.C. (David), Hägg, S. (Sara), Hansell, N.K. (Narelle), Hariri, A.R. (Ahmad), Ikram, M.K. (Kamran), Jukema, J.W. (Jan Wouter), Vuoksimaa, E. (Eero), Keller, M.C. (Matthew C), Kremen, W.S. (William S.), Launer, L.J. (Lenore), Lindenberger, U. (Ulman), Palotie, A. (Aarno), Pedersen, N.L. (Nancy), Pendleton, N. (Neil), Porteous, D.J. (David J.), Räikkönen, K. (Katri), Raitakari, O.T. (Olli T.), Ramirez, A. (Alfredo), Reinvang, I. (Ivar), Rudan, I. (Igor), Rujescu, D. (Dan), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, P.W. (Peter W.), Schofield, C.J. (Christopher), Starr, J.M. (John), Steen, V.M. (Vidar), Trollor, J., Turner, S.T. (Steven T.), Duijn, C.M. (Cornelia) van, Villringer, A. (Arno), Weinberger, D.R. (Daniel), Weir, D.R. (David R.), Wilson, J.F. (James F.), Malhotra, A.K. (Anil K), McIntosh, A.M. (Andrew), Gale, C.R. (Catharine R.), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), Bressler, J. (Jan), Lencz, T. (Todd), Deary, I.J. (Ian), Davies, G. (Gail), Lam, M. (Max), Harris, S.E. (Sarah), Trampush, J.W. (Joey W.), Luciano, M. (Michelle), Hill, W.D. (W. David), Hagenaars, S. (Saskia), Ritchie, S.J. (Stuart J.), Marioni, R.E. (Riccardo), Fawns-Ritchie, C., Liewald, D.C.M. (David C. M.), Okely, J.A. (Judith A.), Ahola-Olli, A.V. (Ari V.), Barnes, C.L.K. (Catriona L. K.), Bertram, L. (Lars), Bis, J.C. (Joshua), Burdick, K.E. (Katherine E.), Christoforou, A. (Andrea), Derosse, P. (Pamela), Djurovic, S. (Srdjan), Espeseth, T. (Thomas), Giakoumaki, S. (Stella), Giddaluru, S. (Sudheer), Gustavson, D.E. (Daniel E.), Hayward, C. (Caroline), Hofer, E. (Edith), Ikram, M.A. (Arfan), Karlsson, R. (Robert), Knowles, E. (Emma), Lahti, J. (Jari), Leber, I. (Isabelle), Li, S. (Shuo), Mather, R., Melle, I. (Ingrid), Morris, D. (Derek), Oldmeadow, C. (Christopher), Palviainen, T. (Teemu), Payton, A. (Antony), Pazoki, R. (Raha), Petrovic, K. (Katja), Reynolds, C.A. (C.), Sargurupremraj, M. (Muralidharan), Scholz, M. (Markus), Smith, J.A. (Jennifer A), Smith, A.V. (Albert), Terzikhan, N. (Natalie), Thalamuthu, A. (Anbupalam), Trompet, S. (Stella), Lee, S.J. (Sven) van der, Ware, E.B. (Erin B.), Windham, B.G. (Gwen), Wright, M.J. (Margaret J.), Yang, J. (Jingyun), Yu, J. (Jin), Ames, D.J. (David), Amin, N. (Najaf), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Armstrong, N.J. (Nicola J.), Assareh, A.A., Attia, J. (John), Attix, D. (Deborah), Avramopoulos, D. (Dimitrios), Bennett, D.A. (David), Böhmer, M.R. (Marcel), Boyle, P.A. (Patricia A.), Brodaty, H. (Henry), Campbell, H. (Harry), Cannon, T.D. (Tyrone D.), Cirulli, E.T. (Elizabeth T.), Congdon, E. (Eliza), Conley, E.D. (Emily Drabant), Corley, J. (Janie), Cox, S.R. (Simon R.), Dale, A.M. (Anders), Dehghan, A. (Abbas), Dick, D. (Danielle), Dickinson, D. (Dwight), Hagen, K. (Knut), Evangelou, E. (Evangelos), Faul, J.D. (Jessica D.), Ford, I. (Ian), Freimer, N.A. (Nelson A.), Gao, H. (He), Giegling, I. (Ina), Gillespie, N.A. (Nathan A.), Gordon, S.D. (Scott D.), Gottesman, R.F. (Rebecca), Griswold, M.D. (Michael), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Hartmann, A.M. (Annette M), Hatzimanolis, A. (Alex), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Joshi, P.K. (Peter), Kähönen, M. (Mika), Kardia, S.L.R. (Sharon L. R.), Karlsson, I. (Ida), Kleineidam, L. (Luca), Knopman, D.S. (David), Kochan, N.A. (Nicole A.), Konte, B. (Bettina), Kwok, J.B.J. (John), Le Hellard, S. (Stephanie), Lee, T. (Teresa), Lehtimäki, T. (Terho), Li, S.-C. (Shu-Chen), Liu, T. (Tian), Koini, M. (Marisa), London, E. (Edythe), Longstreth Jr, W.T., Lopez, O.L. (Oscar), Loukola, A. (Anu), Luck, T. (Tobias), Lundervold, A.J. (Astri), Lundquist, A. (Anders), Lyytikäinen, L.-P. (Leo-Pekka), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant W.), Murray, A.D. (Alison D.), Need, A.C. (Anna C.), Noordam, R. (Raymond), Nyberg, L. (Lisa), Ollier, W.E.R. (William), Papenberg, G., Pattie, A. (Alison), Polasek, O. (Ozren), Poldrack, R.A. (Russell A.), Psaty, B.M. (Bruce M.), Reppermund, S., Riedel-Heller, S. (Steffi), Rose, R.J. (Richard), Rotter, J.I. (Jerome I.), Roussos, A. (Alexandra), Rovio, S.P. (Suvi P.), Saba, Y. (Yasaman), Sabb, F.W. (Fred W.), Sachdev, P.S. (Perminder), Satizabal, C.L. (Claudia), Schmid, M. (Matthias), Scott, R.J. (Rodney J.), Scult, M.A. (Matthew A.), Simino, J. (Jeannette), Slagboom, P.E. (Eline), Smyrnis, N. (Nikolaos), Soumaré, A. (Aicha), Stefanis, N.C. (Nikos C.), Stott, D.J. (David. J.), Straub, R.E. (Richard), Sundet, K. (Kjetil), Taylor, A.M. (Adele M.), Taylor, K.D. (Kent), Tzoulaki, I., Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vitart, V. (Veronique), Voineskos, A.N. (Aristotle N.), Kaprio, J. (Jaakko), Wagner, M. (Michael), Wagner, H. (Hermann), Weinhold, L. (Leonie), Wen, K.H. (K. Hoyan), Widen, E., Yang, Q. (Qiong Fang), Zhao, W. (Wei), Adams, H.H.H. (Hieab), Arking, D.E. (Dan), Bilder, R.M. (Robert M.), Bitsios, P. (Panos), Boerwinkle, E. (Eric), Chiba-Falek, O. (Ornit), Corvin, A. (Aiden), Jager, P.L. (Philip) de, Debette, S. (Stéphanie), Donohoe, D.J. (Dennis), Elliott, P. (Paul), Fitzpatrick, A.L. (Annette), Gill, M. (Michael), Glahn, D.C. (David), Hägg, S. (Sara), Hansell, N.K. (Narelle), Hariri, A.R. (Ahmad), Ikram, M.K. (Kamran), Jukema, J.W. (Jan Wouter), Vuoksimaa, E. (Eero), Keller, M.C. (Matthew C), Kremen, W.S. (William S.), Launer, L.J. (Lenore), Lindenberger, U. (Ulman), Palotie, A. (Aarno), Pedersen, N.L. (Nancy), Pendleton, N. (Neil), Porteous, D.J. (David J.), Räikkönen, K. (Katri), Raitakari, O.T. (Olli T.), Ramirez, A. (Alfredo), Reinvang, I. (Ivar), Rudan, I. (Igor), Rujescu, D. (Dan), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, P.W. (Peter W.), Schofield, C.J. (Christopher), Starr, J.M. (John), Steen, V.M. (Vidar), Trollor, J., Turner, S.T. (Steven T.), Duijn, C.M. (Cornelia) van, Villringer, A. (Arno), Weinberger, D.R. (Daniel), Weir, D.R. (David R.), Wilson, J.F. (James F.), Malhotra, A.K. (Anil K), McIntosh, A.M. (Andrew), Gale, C.R. (Catharine R.), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), Bressler, J. (Jan), Lencz, T. (Todd), and Deary, I.J. (Ian)

Abstract

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the c

Published
2018
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19. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., van der Lee, S.J., Ware, E.B., Windham, B.G., Wright, M.J., Yang, J., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Böhmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kähönen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Le Hellard, S., Lee, T., Lehtimäki, T., Li, S-C, Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikäinen, L-P, Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumaré, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., De Jager, P.L., Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hägg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Räikkönen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., van Duijn, C.M., Villringer, Arno, Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., Deary, I.J., Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., van der Lee, S.J., Ware, E.B., Windham, B.G., Wright, M.J., Yang, J., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Böhmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kähönen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Le Hellard, S., Lee, T., Lehtimäki, T., Li, S-C, Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikäinen, L-P, Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumaré, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., De Jager, P.L., Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hägg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Räikkönen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., van Duijn, C.M., Villringer, Arno, Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., and Deary, I.J.

Abstract

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Published
2018

20. The International Cannabis Consortium: What did we learn about the genetics of cannabis

Author

Verweij, K.J.H., Minica, C.C., Stringer, S., Most, P.J. van der, Mbarek, H., Nivard, M.G., Abdellaoui, A., Hottenga, J.J., Martin, N.G., Boomsma, D.I., Gillespie, N.A., Derks, E.M., Vink, J.M., Verweij, K.J.H., Minica, C.C., Stringer, S., Most, P.J. van der, Mbarek, H., Nivard, M.G., Abdellaoui, A., Hottenga, J.J., Martin, N.G., Boomsma, D.I., Gillespie, N.A., Derks, E.M., and Vink, J.M.

Abstract

Item does not contain fulltext, Background: Cannabis is the most frequently used and abused illicit drug worldwide and cannabis (ab)use is associated with social, physical, and psychological problems. Twin and family studies have shown that cannabis use and abuse are heritable traits. The International Cannabis Consortium was initiated with the aim of identifying genetic risk variants for cannabis use phenotypes by meta-analysing data from many contributing cohorts. The (partly preliminary) results of the International Cannabis Consortium will be presented: genome-wide association (GWA) meta-analyses on lifetime cannabis use and age at initiation of use. Additionally, findings from several follow-up studies will be presented, including the genetic association of cannabis use with use of other substances, schizophrenia, and conduct disorder. Methods: GWA analyses of lifetime cannabis use were performed by each contributing group independently (13 groups, total N=32,330) and were subsequently meta-analysed. We tested for replication, and the SNP results were used to perform a gene-based test of association. We also estimated the total SNP-based heritability and the genetic correlation between lifetime cannabis use and cigarette use based on LD-score regression analysis. Secondly, we meta-analysed GWA results of age at initiation of cannabis use from 8 groups (N=24,222) using a survival analysis. Again SNP results are followed up by a gene-based test of association and an estimate of SNP-based heritability. In follow-up projects, LD-score regression analyses were used to determine the genetic correlation of cannabis use with nicotine, alcohol, and caffeine use, as well as schizophrenia and conduct disorder. We also created polygenic risk scores for cannabis use in an independent target sample and determined to what extent these polygenic scores predicted conduct symptoms. Results: Although none of the SNPs were significantly associated with lifetime cannabis use, the gene-based analysis identified 4

Published
2017

21. Short communication: Genetic association between schizophrenia and cannabis use

Author

Verweij, K.J.H., Abdellaoui, A., Nivard, M.G., Sainz Cort, A., Ligthart, R.S.L., Draisma, H.H.M., Minica, C.C., Gillespie, N.A., Willemsen, G., Hottenga, J.J., Boomsma, D.I., Vink, J.M., Verweij, K.J.H., Abdellaoui, A., Nivard, M.G., Sainz Cort, A., Ligthart, R.S.L., Draisma, H.H.M., Minica, C.C., Gillespie, N.A., Willemsen, G., Hottenga, J.J., Boomsma, D.I., and Vink, J.M.

Abstract

Item does not contain fulltext, Background and aim: Previous studies have shown a relationship between schizophrenia and cannabis use. As both traits are substantially heritable, a shared genetic liability could explain the association. We use two recently developed genomics methods to investigate the genetic overlap between schizophrenia and cannabis use. Methods: Firstly, polygenic risk scores for schizophrenia were created based on summary statistics from the largest schizophrenia genome-wide association (GWA) meta-analysis to date. We analysed the association between these schizophrenia polygenic scores and multiple cannabis use phenotypes (lifetime use, regular use, age at initiation, and quantity and frequency of use) in a sample of 6,931 individuals. Secondly, we applied LD-score regression to the GWA summary statistics of schizophrenia and lifetime cannabis use to calculate the genome-wide genetic correlation. Results: Polygenic risk scores for schizophrenia were significantly (alpha < 0.05) associated with five of the eight cannabis use phenotypes, including lifetime use, regular use, and quantity of use, with risk scores explaining up to 0.5% of the variance. Associations were not significant for age at initiation of use and two measures of frequency of use analyzed in lifetime users only, potentially because of reduced power due to a smaller sample size. The LD-score regression revealed a significant genetic correlation of rg = 0.22 (SE = 0.07, p = 0.003) between schizophrenia and lifetime cannabis use. Conclusions: Common genetic variants underlying schizophrenia and lifetime cannabis use are partly overlapping. Individuals with a stronger genetic predisposition to schizophrenia are more likely to initiate cannabis use, use cannabis more regularly, and consume more cannabis over their lifetime.

Published
2017

22. Erratum to 'Short communication: Genetic association between schizophrenia and cannabis use' [Drug Alcohol Depend. 171 (2017) 117-121]

Author

Verweij, K.J.H., Abdellaoui, A., Nivard, M.G., Sainz Cort, A., Ligthart, R.S.L., Draisma, H.H.M., Minica, C.C., Gillespie, N.A., Willemsen, G., Hottenga, J.J., Boomsma, D.I., Vink, J.M., Verweij, K.J.H., Abdellaoui, A., Nivard, M.G., Sainz Cort, A., Ligthart, R.S.L., Draisma, H.H.M., Minica, C.C., Gillespie, N.A., Willemsen, G., Hottenga, J.J., Boomsma, D.I., and Vink, J.M.

Abstract

Item does not contain fulltext

Published
2017

23. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

Author

Schmaal, L. (L.), Hibar, D.P. (D. P.), Sämann, P.G. (Philipp), Hall, G.B. (Garry), Baune, B.T., Jahanshad, N. (Neda), Cheung, J.W. (J. W.), Erp, T.G.M. (Theo G.) van, Bos, D. (Daniel), Ikram, M.K. (Kamran), Vernooij, M.W. (Meike), Niessen, W.J. (Wiro), Tiemeier, H.W. (Henning), Hofman, A. (Albert), Wittfeld, K. (Katharina), Grabe, H.J. (Hans Jörgen), Janowitz, D. (Deborah), Bülow, R. (R.), Selonke, M. (M.), Völzke, H. (Henry), Grotegerd, D. (D.), Dannlowski, U. (U.), Arolt, V. (Volker), Opel, N. (N.), Heindel, W. (W.), Kugel, H. (H.), Hoehn, D. (David), Czisch, M. (Michael), Couvy-Duchesne, B. (Baptiste), Rentería, M.E. (Miguel), Strike, L.T. (Lachlan), Wright, M.J. (Margaret), Mills, N.T., Zubicaray, G.I. (Greig) de, Mcmahon, K.L. (Katie), Medland, S.E. (Sarah), Martin, N.G. (Nicholas), Gillespie, N.A. (N. A.), Goya-Maldonado, R., Gruber, O. (Oliver), Krämer, B.K. (Bernhard), Hatton, W., Lagopoulos, J. (Jim), Hickie, I.B. (Ian), Frodl, T. (Thomas), Carballedo, A., Frey, E.M., Van Velzen, L.S., Penninx, B.W.J.H. (Brenda), Tol, M.J.D. (Marie-José) van, Wee, N.J. (Nic) van der, Davey, C.G. (Christopher), Harrison, B.J. (B. J.), Mwangi, B. (Benson), Cao, B. (B.), Soares, J.C. (J. C.), Veer, I.M. (Ilya), Walter, H.J. (Henrik), Schoepf, D., Zurowski, B., Konrad, C. (C.), Schramm, E. (E.), Normann, C., Schnell, K. (Kerry), Sacchet, M.D. (M. D.), Gotlib, I.H. (I. H.), MacQueen, G.M. (Glenda), Godlewska, B. (Beata), Nickson, T., McIntosh, A.M. (Andrew), Papmeyer, M. (Martina), Whalley, H.C. (H. C.), Hall, J. (Jeremy), Sussmann, J. (Jessika), Li, M. (M.), Walter, M. (M.), Aftanas, L. (L.), Brack, I. (I.), Bokhan, N.A. (N. A.), Thompson, P.M. (Paul), Veltman, D.J. (Dick), Schmaal, L. (L.), Hibar, D.P. (D. P.), Sämann, P.G. (Philipp), Hall, G.B. (Garry), Baune, B.T., Jahanshad, N. (Neda), Cheung, J.W. (J. W.), Erp, T.G.M. (Theo G.) van, Bos, D. (Daniel), Ikram, M.K. (Kamran), Vernooij, M.W. (Meike), Niessen, W.J. (Wiro), Tiemeier, H.W. (Henning), Hofman, A. (Albert), Wittfeld, K. (Katharina), Grabe, H.J. (Hans Jörgen), Janowitz, D. (Deborah), Bülow, R. (R.), Selonke, M. (M.), Völzke, H. (Henry), Grotegerd, D. (D.), Dannlowski, U. (U.), Arolt, V. (Volker), Opel, N. (N.), Heindel, W. (W.), Kugel, H. (H.), Hoehn, D. (David), Czisch, M. (Michael), Couvy-Duchesne, B. (Baptiste), Rentería, M.E. (Miguel), Strike, L.T. (Lachlan), Wright, M.J. (Margaret), Mills, N.T., Zubicaray, G.I. (Greig) de, Mcmahon, K.L. (Katie), Medland, S.E. (Sarah), Martin, N.G. (Nicholas), Gillespie, N.A. (N. A.), Goya-Maldonado, R., Gruber, O. (Oliver), Krämer, B.K. (Bernhard), Hatton, W., Lagopoulos, J. (Jim), Hickie, I.B. (Ian), Frodl, T. (Thomas), Carballedo, A., Frey, E.M., Van Velzen, L.S., Penninx, B.W.J.H. (Brenda), Tol, M.J.D. (Marie-José) van, Wee, N.J. (Nic) van der, Davey, C.G. (Christopher), Harrison, B.J. (B. J.), Mwangi, B. (Benson), Cao, B. (B.), Soares, J.C. (J. C.), Veer, I.M. (Ilya), Walter, H.J. (Henrik), Schoepf, D., Zurowski, B., Konrad, C. (C.), Schramm, E. (E.), Normann, C., Schnell, K. (Kerry), Sacchet, M.D. (M. D.), Gotlib, I.H. (I. H.), MacQueen, G.M. (Glenda), Godlewska, B. (Beata), Nickson, T., McIntosh, A.M. (Andrew), Papmeyer, M. (Martina), Whalley, H.C. (H. C.), Hall, J. (Jeremy), Sussmann, J. (Jessika), Li, M. (M.), Walter, M. (M.), Aftanas, L. (L.), Brack, I. (I.), Bokhan, N.A. (N. A.), Thompson, P.M. (Paul), and Veltman, D.J. (Dick)

Abstract

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Published
2017
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24. Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

Author

Rietschel, L. (Liz), Streit, F. (Fabian), Zhu, G. (Gu), McAloney, K. (Kerrie), Frank, J. (Josef), Couvy-Duchesne, B. (Baptiste), Witt, S.H. (Stephanie H), Binz, T.M. (Tina M.), McGrath, J. (John), Hickie, I.B. (Ian), Hansell, N.K. (Narelle), Wright, M.J. (Margaret J.), Gillespie, N.A. (Nathan A.), Forstner, A.J. (Andreas), Schulze, T.G. (Thomas), Wüst, S. (Stefan), Nöthen, M.M. (Markus), Baumgartner, M.R. (Markus R.), Walker, B.R. (Brian), Crawford, A.A. (Andrew A.), Colodro-Conde, L. (Lucía), Medland, S.E. (Sarah), Martin, N.G. (Nicholas G.), Rietschel, M. (Marcella), Rietschel, L. (Liz), Streit, F. (Fabian), Zhu, G. (Gu), McAloney, K. (Kerrie), Frank, J. (Josef), Couvy-Duchesne, B. (Baptiste), Witt, S.H. (Stephanie H), Binz, T.M. (Tina M.), McGrath, J. (John), Hickie, I.B. (Ian), Hansell, N.K. (Narelle), Wright, M.J. (Margaret J.), Gillespie, N.A. (Nathan A.), Forstner, A.J. (Andreas), Schulze, T.G. (Thomas), Wüst, S. (Stefan), Nöthen, M.M. (Markus), Baumgartner, M.R. (Markus R.), Walker, B.R. (Brian), Crawford, A.A. (Andrew A.), Colodro-Conde, L. (Lucía), Medland, S.E. (Sarah), Martin, N.G. (Nicholas G.), and Rietschel, M. (Marcella)

Abstract

Hair cortisol concentration (HCC) is a promising measure of long-Term hypothalamus-pituitary-Adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.

Published
2017
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25. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group

Author

Schmaal, L., Veltman, D.J., Erp, T.G.M. van, Samann, P.G., Frodl, T., Jahanshad, N., Loehrer, E., Tiemeier, H., Hofman, A., Niessen, W.J., Vernooij, M.W., Ikram, M.A., Wittfeld, K., Grabe, H.J., Block, A., Hegenscheid, K., Volzke, H., Hoehn, D., Czisch, M., Lagopoulos, J., Hatton, S.N., Hickie, I.B., Goya-Maldonado, R., Kramer, B., Gruber, O., Couvy-Duchesne, B., Renteria, M.E., Strike, L.T., Mills, N.T., Zubicaray, G.I. de, McMahon, K.L., Medland, S.E., Martin, N.G., Gillespie, N.A., Wright, M.J., Hall, G.B., MacQueen, G.M., Frey, E.M., Carballedo, A., Velzen, L.S. van, Tol, M.J. van, Wee, N.J. van der, Veer, I.M., Walter, H., Schnell, K., Schramm, E., Normann, C., Schoepf, D., Konrad, C., Zurowski, B., Nickson, T., McIntosh, A.M., Papmeyer, M., Whalley, H.C., Sussmann, J.E., Godlewska, B.R., Cowen, P.J., Fischer, F.H., Rose, M., Penninx, B.W.J.H., Thompson, P.M., Hibar, D.P., ENIGMA-Major Depressive Disorder W, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, Epidemiology, Medical Informatics, Radiology & Nuclear Medicine, Neurology, and Erasmus MC other

Subjects
Male, STRESS, hippocampus, SEGMENTATION, Hippocampus, UNIPOLAR DEPRESSION, Medical and Health Sciences, Lateral ventricles, 0302 clinical medicine, pathology [Brain], 2.1 Biological and endogenous factors, Aetiology, Letter to the Editor, First episode, Psychiatry, pathology [Depressive Disorder, Major], ENIGMA consortium, ABNORMALITIES, Depression, Brain, Middle Aged, Biological Sciences, Serious Mental Illness, Magnetic Resonance Imaging, 3. Good health, AMYGDALA VOLUME, Psychiatry and Mental health, structural volumes, Mental Health, VOXEL-BASED MORPHOMETRY, Neurological, Cardiology, Major depressive disorder, Biomedical Imaging, ONSET DEPRESSION, Original Article, Female, Psychology, methods [Neuroimaging], Clinical psychology, Adult, medicine.medical_specialty, Major Depressive Disorder, HIPPOCAMPAL VOLUME, Neuroimaging, behavioral disciplines and activities, 03 medical and health sciences, Cellular and Molecular Neuroscience, Clinical Research, Internal medicine, medicine, Subcortical brain alterations, depressive disorder, ENIGMA, Humans, Bipolar disorder, ddc:610, Molecular Biology, METAANALYSIS, Depressive Disorder, Major, Depressive Disorder, Brain morphometry, Psychology and Cognitive Sciences, Neurosciences, Major, Voxel-based morphometry, medicine.disease, 030227 psychiatry, Brain Disorders, meta-analysis, pathology [Hippocampus], Case-Control Studies, Age of onset, MATTER, 030217 neurology & neurosurgery
Abstract

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.Molecular Psychiatry advance online publication, 30 June 2015; doi:10.1038/mp.2015.69. peerReviewed

Published
2016

26. Structural brain alterations in major depression: findings from the ENIGMA Major Depressive Disorder Working Group

Author

Schmaal, L., Veltman, D.J., Erp, T.G. van, Samann, P.G., Frodl, T., Jahanshad, N., Loehrer, E., Tiemeier, H., Hofman, A., Niessen, W.J., Vernooij, M.W., Ikram, M.A., Wittfeld, K., Grabe, H.J., Block, A., Hegenscheid, K., Volzke, H., Hoehn, D., Czisch, M., Lagopoulos, J., Hatton, S.N., Hickie, I.B., Goya-Maldonado, R., Kramer, B., Gruber, O., Couvy-Duchesne, B., Renteria, M.E., Strike, L.T., Mills, N.T., Zubicaray, G.I. de, McMahon, K.L., Medland, S.E., Martin, N.G., Gillespie, N.A., Wright, M.J., Hall, G.B., MacQueen, G.M., Frey, E.M., Carballedo, A., Velzen, L.S. van, Tol, M.J. van, Wee, N.J. van der, Veer, I.M., Walter, H., Schnell, K., Schramm, E., Normann, C., Schoepf, D., Konrad, C., Zurowski, B., Nickson, T., McIntosh, A.M., Papmeyer, M., Whalley, H.C., Sussmann, J.E., Godlewska, B.R., Cowen, P.J., Fischer, F.H., Rose, M., Penninx, B.W., Thompson, P.M., Hibar, D.P., and ENIGMA-Major Depressive Disorder W

Published
2015

27. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

Author

Stringer, S., Minica, C.C., Verweij, K.J.H., Mbarek, H., Bernard, M., Derringer, J.L., Eijk, K.R. van, Isen, J.D., Loukola, A., Maciejewski, D.F., Mihailov, E., Most, P.J. van der, Sánchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J.J., Abdellaoui, A., Bigdeli, T.B., Branje, S.J.T., Brown, S.A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S.D., Harris, J.M., Hartman, C.A., Henders, A.K., Heath, A.C., Hickie, I.B., Hickman, M., Hopfer, C.J., Hottenga, J.J., Huizink, A.C., Irons, D.E., Kahn, R.S., Korhonen, T., Kranzler, H.R., Krauter, K., Lier, P.A.C. van, Lubke, G.H., Madden, P.A.F., Mägi, R., McGue, M.K., Medland, S.E., Meeus, W.H.J., Miller, M.B., Montgomery, G.W., Nivard, M.G., Nolte, I.M., Oldehinkel, A.J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J.A., Richarte, V., Rose, R.J., Shin, J., Stallings, M.C., Stiby, A.I., Wall, T.L., Wright, M.J., Koot, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Kaprio, J., Boks, M.P.M., Snieder, H., Spector, T., Munafò, M.R., Metspalu, A., Gelernter, J., Boomsma, D.I., Iacono, W.G., Martin, N.G., Gillespie, N.A., Derks, E.M., Vink, J.M., Stringer, S., Minica, C.C., Verweij, K.J.H., Mbarek, H., Bernard, M., Derringer, J.L., Eijk, K.R. van, Isen, J.D., Loukola, A., Maciejewski, D.F., Mihailov, E., Most, P.J. van der, Sánchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J.J., Abdellaoui, A., Bigdeli, T.B., Branje, S.J.T., Brown, S.A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S.D., Harris, J.M., Hartman, C.A., Henders, A.K., Heath, A.C., Hickie, I.B., Hickman, M., Hopfer, C.J., Hottenga, J.J., Huizink, A.C., Irons, D.E., Kahn, R.S., Korhonen, T., Kranzler, H.R., Krauter, K., Lier, P.A.C. van, Lubke, G.H., Madden, P.A.F., Mägi, R., McGue, M.K., Medland, S.E., Meeus, W.H.J., Miller, M.B., Montgomery, G.W., Nivard, M.G., Nolte, I.M., Oldehinkel, A.J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J.A., Richarte, V., Rose, R.J., Shin, J., Stallings, M.C., Stiby, A.I., Wall, T.L., Wright, M.J., Koot, J.M., Paus, T., Hewitt, J.K., Ribasés, M., Kaprio, J., Boks, M.P.M., Snieder, H., Spector, T., Munafò, M.R., Metspalu, A., Gelernter, J., Boomsma, D.I., Iacono, W.G., Martin, N.G., Gillespie, N.A., Derks, E.M., and Vink, J.M.

Abstract

Contains fulltext : 156357.pdf (publisher's version ) (Open Access), Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10-8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Published
2016

28. Response to Dr Fried & Dr Kievit, and Dr Malhi et al.

Author

Schmaal, L. (Lianne), Veltman, D.J. (Dick), Van Erp, T.G.M., Smann, P.G., Frodl, T. (Thomas), Jahanshad, N., Loehrer, E. (Elizabeth), Vernooij, M.W. (Meike), Niessen, W.J. (Wiro), Ikram, M.A. (Arfan), Wittfeld, K., Grabe, H.J. (Hans Jörgen), Block, A. (Andrea), Hegenscheid, K. (Katrin), Hoehn, D. (David), Czisch, M. (Michael), Lagopoulos, J. (Jim), Hatton, W., Hickie, I.B. (Ian), Goya-Maldonado, R., Krmer, B., Gruber, O., Couvy-Duchesne, B. (Baptiste), Rentera, M.E., Strike, L.T. (Lachlan), Wright, M.J., Zubicaray, G.I. (Greig) de, McMahon, K.L., Medland, S.E. (Sarah), Gillespie, N.A., Hall, G.B., Van Velzen, L.S., Tol, M.J.D. (Marie-José) van, Wee, N.J. (Nic) van der, Veer, I.M. (Ilya), Walter, H., Schramm, E., Normann, C., Schoepf, D., Konrad, C., Zurowski, B., McIntosh, A.M., Whalley, H.C., Sussmann, J. (Jessika), Godlewska, B. (Beata), Fischer, F.H., Penninx, B.W.J.H., Thompson, P.M., Hibar, D.P. (Derrek), Schmaal, L. (Lianne), Veltman, D.J. (Dick), Van Erp, T.G.M., Smann, P.G., Frodl, T. (Thomas), Jahanshad, N., Loehrer, E. (Elizabeth), Vernooij, M.W. (Meike), Niessen, W.J. (Wiro), Ikram, M.A. (Arfan), Wittfeld, K., Grabe, H.J. (Hans Jörgen), Block, A. (Andrea), Hegenscheid, K. (Katrin), Hoehn, D. (David), Czisch, M. (Michael), Lagopoulos, J. (Jim), Hatton, W., Hickie, I.B. (Ian), Goya-Maldonado, R., Krmer, B., Gruber, O., Couvy-Duchesne, B. (Baptiste), Rentera, M.E., Strike, L.T. (Lachlan), Wright, M.J., Zubicaray, G.I. (Greig) de, McMahon, K.L., Medland, S.E. (Sarah), Gillespie, N.A., Hall, G.B., Van Velzen, L.S., Tol, M.J.D. (Marie-José) van, Wee, N.J. (Nic) van der, Veer, I.M. (Ilya), Walter, H., Schramm, E., Normann, C., Schoepf, D., Konrad, C., Zurowski, B., McIntosh, A.M., Whalley, H.C., Sussmann, J. (Jessika), Godlewska, B. (Beata), Fischer, F.H., Penninx, B.W.J.H., Thompson, P.M., and Hibar, D.P. (Derrek)

Published
2016
Full Text
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29. Subcortical brain alterations in major depressive disorder: Findings from the ENIGMA Major Depressive Disorder working group

Author

Schmaal, L. (Lianne), Veltman, D.J. (Dick), Van Erp, T.G.M., Smann, P.G., Frodl, T. (Thomas), Jahanshad, N., Loehrer, E. (Elizabeth), Tiemeier, H.W. (Henning), Hofman, A., Niessen, W.J. (Wiro), Vernooij, M.W. (Meike), Ikram, M.A. (Arfan), Wittfeld, K. (Katharina), Grabe, H.J. (Hans Jörgen), Block, A. (Andrea), Hegenscheid, K. (Katrin), Völzke, H. (Henry), Hoehn, D. (David), Czisch, M. (Michael), Lagopoulos, J. (Jim), Hatton, W., Hickie, I.B. (Ian), Goya-Maldonado, R., Krmer, B., Gruber, O., Couvy-Duchesne, B. (Baptiste), Rentera, M.E., Strike, L.T. (Lachlan), Mills, N.T., Zubicaray, G.I. (Greig) de, Mcmahon, K.L. (Katie), Medland, S.E. (Sarah), Martin, N.G. (Nicholas), Gillespie, N.A., Wright, M.J. (Margaret), Hall, G.B., MacQueen, G.M. (Glenda), Frey, E.M., Carballedo, A., Van Velzen, L.S., Tol, M.J.D. (Marie-José) van, Wee, N.J. (Nic) van der, Veer, I.M. (Ilya), Walter, H., Schnell, K., Schramm, E., Normann, C., Schoepf, D., Konrad, C., Zurowski, B., Nickson, T., McIntosh, A.M. (Andrew), Papmeyer, M. (Martina), Whalley, H.C., Sussmann, J. (Jessika), Godlewska, B. (Beata), Cowen, P.J., Fischer, F.H., Rose, M., Penninx, B.W.J.H. (Brenda), Thompson, P.M., Hibar, D.P. (Derrek), Schmaal, L. (Lianne), Veltman, D.J. (Dick), Van Erp, T.G.M., Smann, P.G., Frodl, T. (Thomas), Jahanshad, N., Loehrer, E. (Elizabeth), Tiemeier, H.W. (Henning), Hofman, A., Niessen, W.J. (Wiro), Vernooij, M.W. (Meike), Ikram, M.A. (Arfan), Wittfeld, K. (Katharina), Grabe, H.J. (Hans Jörgen), Block, A. (Andrea), Hegenscheid, K. (Katrin), Völzke, H. (Henry), Hoehn, D. (David), Czisch, M. (Michael), Lagopoulos, J. (Jim), Hatton, W., Hickie, I.B. (Ian), Goya-Maldonado, R., Krmer, B., Gruber, O., Couvy-Duchesne, B. (Baptiste), Rentera, M.E., Strike, L.T. (Lachlan), Mills, N.T., Zubicaray, G.I. (Greig) de, Mcmahon, K.L. (Katie), Medland, S.E. (Sarah), Martin, N.G. (Nicholas), Gillespie, N.A., Wright, M.J. (Margaret), Hall, G.B., MacQueen, G.M. (Glenda), Frey, E.M., Carballedo, A., Van Velzen, L.S., Tol, M.J.D. (Marie-José) van, Wee, N.J. (Nic) van der, Veer, I.M. (Ilya), Walter, H., Schnell, K., Schramm, E., Normann, C., Schoepf, D., Konrad, C., Zurowski, B., Nickson, T., McIntosh, A.M. (Andrew), Papmeyer, M. (Martina), Whalley, H.C., Sussmann, J. (Jessika), Godlewska, B. (Beata), Cowen, P.J., Fischer, F.H., Rose, M., Penninx, B.W.J.H. (Brenda), Thompson, P.M., and Hibar, D.P. (Derrek)

Abstract

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ≤21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Published
2016
Full Text
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31. P.2.b.017 Structural brain alterations in major depression: findings from the ENIGMA Major Depressive Disorder Working Group

Author

Schmaal, L., primary, Veltman, D.J, additional, Van Erp, T.G, additional, Sämann, P.G, additional, Frodl, T., additional, Jahanshad, N., additional, Loehrer, E., additional, Tiemeier, H., additional, Hofman, A., additional, Niessen, W.J, additional, Vernooij, M.W, additional, Ikram, M.A, additional, Wittfeld, K., additional, Grabe, H.J., additional, Block, A., additional, Hegenscheid, K., additional, Völzke, H., additional, Hoehn, D., additional, Czisch, M., additional, Lagopoulos, J., additional, Hatton, S.N, additional, Hickie, I.B., additional, Goya-Maldonado, R., additional, Krämer, B., additional, Gruber, O., additional, Couvy-Duchesne, B., additional, Rentería, M.E, additional, Strike, L.T, additional, Mills, N.T, additional, De Zubicaray, G.I, additional, McMahon, K.L, additional, Medland, S.E., additional, Martin, N.G, additional, Gillespie, N.A, additional, Wright, M.J, additional, Hall, G.B, additional, MacQueen, G.M, additional, Frey, E.M, additional, Carballedo, A., additional, Van Velzen, L.S., additional, Van Tol, M.J, additional, Van der Wee, N.J, additional, Veer, I.M., additional, Walter, H., additional, Schnell, K., additional, Schramm, E., additional, Normann, C., additional, Schoepf, D., additional, Konrad, C., additional, Zurowski, B., additional, Nickson, T., additional, McIntosh, A.M, additional, Papmeyer, M., additional, Whalley, H.C, additional, Sussmann, J.E, additional, Godlewska, B.R, additional, Cowen, P.J, additional, Fischer, F.H, additional, Rose, M., additional, Penninx, B.W, additional, Thompson, P.M, additional, and Hibar, D.P, additional

Published
2015
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33. Familial clustering of major depression and anxiety disorders in Australian and Dutch twins and siblings

Author

Middeldorp, C.M., Birley, A.J., Cath, D.C., Gillespie, N.A., Willemsen, G., Statham, D.J., de Geus, E.J.C., Andrews, J.G., van Dyck, R., Beem, A.L., Sullivan, P.F., Martin, N.G., Boomsma, D.I., and Biological Psychology

Subjects
Netherlands Twin Register (NTR), mental disorders, behavioral disciplines and activities, humanities
Abstract

The aim of this study was to investigate familial influences and their dependence on sex for panic disorder and/or agoraphobia, social phobia, generalized anxiety disorder and major depression. Data from Australian (N = 2287) and Dutch (N = 1185) twins and siblings who were selected for a linkage study and participated in clinical interviews to obtain lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnoses were used. In a liability model, tetrachoric correlations were estimated in sibling pairs and sex differences between sibling correlations were tested. For each diagnosis, the sibling correlations could be constrained to be equal across the Australian and Dutch samples. With the exception of panic disorder and/or agoraphobia, all sibling correlations were the same for brother, sister and opposite-sex sibling pairs and were around .20. For panic disorder and/or agoraphobia, the correlation was .23 in brother and sister pairs, but absent in opposite-sex sibling pairs. From these results it can be concluded that upper heritability estimates, based on twice the correlations in the sibling pairs, vary between 36% (major depression) and 50% (social phobia). Furthermore, different genetic risk factors appear to contribute to the vulnerability for panic disorder and/or agoraphobia in men and women. No other sex differences were found.

Published
2005

34. The genetics of addiction: A translational perspective

Author

Agrawal, A., Verweij, K.J.H., Gillespie, N.A., Heath, A.C., Lessov-Schlaggar, C.N., Martin, N.G., Nelson, E.C., Slutske, W.S., Whitfield, J.B., Lynskey, M.T., Agrawal, A., Verweij, K.J.H., Gillespie, N.A., Heath, A.C., Lessov-Schlaggar, C.N., Martin, N.G., Nelson, E.C., Slutske, W.S., Whitfield, J.B., and Lynskey, M.T.

Abstract

Contains fulltext : 156134.pdf (publisher's version ) (Open Access), Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene-environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.

Published
2012

38. 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.

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