Common variant at 16p11.2 conferring risk of psychosis

S. Steinberg; S. De Jong; M. Mattheisen; J. Costas; D. Demontis; S. Jamain; O. P.H. Pietiläinen; K. Lin; S. Papiol; J. Huttenlocher; E. Sigurdsson; E. Vassos; I. Giegling; R. Breuer; G. Fraser; N. Walker; I. Melle; S. Djurovic; I. Agartz; A. Tuulio-Henriksson; J. Suvisaari; J. Lönnqvist; T. Paunio; L. Olsen; T. Hansen; A. Ingason; M. Pirinen; E. Strengman; D. M. Hougaard; T. Orntoft; M. Didriksen; M. V. Hollegaard; M. Nordentoft; L. Abramova; V. Kaleda; M. Arrojo; J. Sanjuán; C. Arango; B. Etain; F. Bellivier; A. Méary; F. Schürhoff; A. Szoke; M. Ribolsi; V. Magni; A. Siracusano; S. Sperling; M. Rossner; C. Christiansen; L. A. Kiemeney; B. Franke; L. H. Van Den Berg; J. Veldink; S. Curran; P. Bolton; M. Poot; W. Staal; K. Rehnstrom; H. Kilpinen; C. M. Freitag; J. Meyer; P. Magnusson; E. Saemundsen; I. Martsenkovsky; I. Bikshaieva; I. Martsenkovska; O. Vashchenko; M. Raleva; K. Paketchieva; B. Stefanovski; N. Durmishi; M. Pejovic Milovancevic; D. Lecic Tosevski; T. Silagadze; N. Naneishvili; N. Mikeladze; S. Surguladze; J. B. Vincent; A. Farmer; P. B. Mitchell; A. Wright; P. R. Schofield; J. M. Fullerton; G. W. Montgomery; N. G. Martin; I. A. Rubino; R. Van Winkel; G. Kenis; M. De Hert; J. M. Réthelyi; I. Bitter; L. Terenius; E. G. Jönsson; S. Bakker; J. Van Os; A. Jablensky; M. Leboyer; E. Bramon; J. Powell; R. Murray; A. Corvin; M. Gill; D. Morris; F. A. O'Neill; K. Kendler; B. Riley; N. Craddock; M. J. Owen; M. C. O'Donovan; U. Thorsteinsdottir; A. Kong; H. Ehrenreich; A. Carracedo; V. Golimbet; O. A. Andreassen; A. D. Børglum; O. Mors; P. B. Mortensen; T. Werge; R. A. Ophoff; M. M. Nöthen; M. Rietschel; S. Cichon; M. Ruggeri; S. Tosato; A. Palotie; D. St Clair; D. Rujescu; D. A. Collier; H. Stefansson; K. Stefansson

doi:10.1038/mp.2012.157

Common variant at 16p11.2 conferring risk of psychosis

S. Steinberg, S. De Jong, M. Mattheisen, J. Costas, D. Demontis, S. Jamain, O. P.H. Pietiläinen, K. Lin, S. Papiol, J. Huttenlocher, E. Sigurdsson, E. Vassos, I. Giegling, R. Breuer, G. Fraser, N. Walker, I. Melle, S. Djurovic, I. Agartz, A. Tuulio-HenrikssonJ. Suvisaari, J. Lönnqvist, T. Paunio, L. Olsen, T. Hansen, A. Ingason, M. Pirinen, E. Strengman, D. M. Hougaard, T. Orntoft, M. Didriksen, M. V. Hollegaard, M. Nordentoft, L. Abramova, V. Kaleda, M. Arrojo, J. Sanjuán, C. Arango, B. Etain, F. Bellivier, A. Méary, F. Schürhoff, A. Szoke, M. Ribolsi, V. Magni, A. Siracusano, S. Sperling, M. Rossner, C. Christiansen, L. A. Kiemeney, B. Franke, L. H. Van Den Berg, J. Veldink, S. Curran, P. Bolton, M. Poot, W. Staal, K. Rehnstrom, H. Kilpinen, C. M. Freitag, J. Meyer, P. Magnusson, E. Saemundsen, I. Martsenkovsky, I. Bikshaieva, I. Martsenkovska, O. Vashchenko, M. Raleva, K. Paketchieva, B. Stefanovski, N. Durmishi, M. Pejovic Milovancevic, D. Lecic Tosevski, T. Silagadze, N. Naneishvili, N. Mikeladze, S. Surguladze, J. B. Vincent, A. Farmer, P. B. Mitchell, A. Wright, P. R. Schofield, J. M. Fullerton, G. W. Montgomery, N. G. Martin, I. A. Rubino, R. Van Winkel, G. Kenis, M. De Hert, J. M. Réthelyi, I. Bitter, L. Terenius, E. G. Jönsson, S. Bakker, J. Van Os, A. Jablensky, M. Leboyer, E. Bramon, J. Powell, R. Murray, A. Corvin, M. Gill, D. Morris, F. A. O'Neill, K. Kendler, B. Riley, N. Craddock, M. J. Owen, M. C. O'Donovan, U. Thorsteinsdottir, A. Kong, H. Ehrenreich, A. Carracedo, V. Golimbet, O. A. Andreassen, A. D. Børglum, O. Mors, P. B. Mortensen, T. Werge, R. A. Ophoff, M. M. Nöthen, M. Rietschel, S. Cichon, M. Ruggeri, S. Tosato, A. Palotie, D. St Clair, D. Rujescu, D. A. Collier, H. Stefansson, K. Stefansson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

Abstract

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255T; odds ratio=1.08; P=6.6 × 10 -11). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255T is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Original language	English
Pages (from-to)	108-114
Number of pages	7
Journal	Molecular Psychiatry
Volume	19
Issue number	1
DOIs	https://doi.org/10.1038/mp.2012.157
Publication status	Published - Jan 2014

Bibliographical note

Funding Information:
We would like to thank the subjects, their families and the recruitment centre staff. We would also like to acknowledge the help of Maria Dolores Moltó (Genetics Department, Valencia University, CIBERSAM), Eduardo Paz and Ramón Ramos-Ríos (Complexo Hospitalario de Santiago), and the contribution of Fundación Botín. This study makes use of seven external, publicly available data sets. First, it makes use of data generated by the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project whose principal investigators were Jeffrey A Lieberman, MD, T Scott Stroup, MD, MPH, and Joseph P McEvoy, MD. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. Second, the GAIN/ BiGs data sets used in this work were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000017.v3.p1. Third, the study uses samples genotyped using the Ilumina 550K platform by the Pritzker Consortium, supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. The Pritzker Consortium includes scientists at the University of Michigan (H Akil and S J Watson, Site Directors, and Michael Boehnke, lead on bipolar genotyping effort); Stanford University (Rick Myers and Alan Schatzberg, Site Directors); the University of California at Davis (Ted Jones, Site Director); the University of California at Irvine (William Bunney, Site Director); and the Weill Medical College of Cornell University (Jack Barchas, Site Director). Fourth, the work uses data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) project, led by Gary Sachs, MD, and coordinated by Massachusetts General Hospital in Boston, MA (NIMH grant number was 2N01MH080001–001). Fifth, this study makes use of data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. Sixth, we gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium* and the participating AGRE families. The AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). Seventh, the Autism Genome Project (AGP) data sets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number, phs000267.v1.p1. Submission of the data to dbGaP was provided by Dr Bernie Devlin on behalf of the AGP. Collection and submission of the data to dbGaP were supported by a grant from the Medical Research Council (G0601030) and the Wellcome Trust (075491/Z/04), Anthony P Monaco, PI, University of Oxford. This work was also supported by the European Union (grant numbers LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene), HEALTH-F2-2009-223423 (Project PsychCNVs), HEALTH-F4-2009-242257 (Project ADAMS) and IMI-JU-New-Meds); the National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) (grant numbers 01GS08144 (MooDS-Net) and 01GS08147 (NGFNplus)); the National Institute of Mental Health (R01 MH078075, and N01 MH900001, MH074027 to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project); the Centre of Excellence for Complex Disease Genetics of the Academy of Finland (grant numbers 213506 and 129680); the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki; the Stanley Medical Research Institute; the Danish Council for Strategic Research (grant number 2101-07-0059); H Lundbeck A/S; the Research Council of Norway (grant number 163070/V50); the Danish Medical Research Council; the South-East Norway Health Authority (grant number 2004-123); the Medical Research Council; Ministerio de Sanidad y Consumo, Spain (grant number PI081522 to JC); Xunta de Galicia (grant number 08CSA005208PR to A Carracedo); the Swedish Research Council; the Wellcome Trust (Wellcome Trust grants 085475/B/08/Z and 085475/Z/08/Z as part of the Wellcome Trust Case Control Consortium 2); the Max Planck Society; Saarland University (grant number T6 03 10 00–45 to CMF); the Netherlands Foundation for Brain Research (Hersenstichting) (grant number 2008(1).34 to M Poot); and Eli Lilly and Company (genotyping for CATIE and part of the TOP sample). For further acknowledgements, see the Supplementary Material.

Other keywords

16p11.2
association
bipolar disorder
cross-disorder
schizophrenia

Access to Document

10.1038/mp.2012.157

Cite this

Steinberg, S., De Jong, S., Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietiläinen, O. P. H., Lin, K., Papiol, S., Huttenlocher, J., Sigurdsson, E., Vassos, E., Giegling, I., Breuer, R., Fraser, G., Walker, N., Melle, I., Djurovic, S., Agartz, I., ... Stefansson, K. (2014). Common variant at 16p11.2 conferring risk of psychosis. Molecular Psychiatry, 19(1), 108-114. https://doi.org/10.1038/mp.2012.157

@article{31c489e73a324e8e9a40c822e2c5d75c,

title = "Common variant at 16p11.2 conferring risk of psychosis",

abstract = "Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255T; odds ratio=1.08; P=6.6 × 10 -11). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255T is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).",

keywords = "16p11.2, association, bipolar disorder, cross-disorder, schizophrenia",

author = "S. Steinberg and {De Jong}, S. and M. Mattheisen and J. Costas and D. Demontis and S. Jamain and Pietil{\"a}inen, {O. P.H.} and K. Lin and S. Papiol and J. Huttenlocher and E. Sigurdsson and E. Vassos and I. Giegling and R. Breuer and G. Fraser and N. Walker and I. Melle and S. Djurovic and I. Agartz and A. Tuulio-Henriksson and J. Suvisaari and J. L{\"o}nnqvist and T. Paunio and L. Olsen and T. Hansen and A. Ingason and M. Pirinen and E. Strengman and Hougaard, {D. M.} and T. Orntoft and M. Didriksen and Hollegaard, {M. V.} and M. Nordentoft and L. Abramova and V. Kaleda and M. Arrojo and J. Sanju{\'a}n and C. Arango and B. Etain and F. Bellivier and A. M{\'e}ary and F. Sch{\"u}rhoff and A. Szoke and M. Ribolsi and V. Magni and A. Siracusano and S. Sperling and M. Rossner and C. Christiansen and Kiemeney, {L. A.} and B. Franke and {Van Den Berg}, {L. H.} and J. Veldink and S. Curran and P. Bolton and M. Poot and W. Staal and K. Rehnstrom and H. Kilpinen and Freitag, {C. M.} and J. Meyer and P. Magnusson and E. Saemundsen and I. Martsenkovsky and I. Bikshaieva and I. Martsenkovska and O. Vashchenko and M. Raleva and K. Paketchieva and B. Stefanovski and N. Durmishi and {Pejovic Milovancevic}, M. and {Lecic Tosevski}, D. and T. Silagadze and N. Naneishvili and N. Mikeladze and S. Surguladze and Vincent, {J. B.} and A. Farmer and Mitchell, {P. B.} and A. Wright and Schofield, {P. R.} and Fullerton, {J. M.} and Montgomery, {G. W.} and Martin, {N. G.} and Rubino, {I. A.} and {Van Winkel}, R. and G. Kenis and {De Hert}, M. and R{\'e}thelyi, {J. M.} and I. Bitter and L. Terenius and J{\"o}nsson, {E. G.} and S. Bakker and {Van Os}, J. and A. Jablensky and M. Leboyer and E. Bramon and J. Powell and R. Murray and A. Corvin and M. Gill and D. Morris and O'Neill, {F. A.} and K. Kendler and B. Riley and N. Craddock and Owen, {M. J.} and O'Donovan, {M. C.} and U. Thorsteinsdottir and A. Kong and H. Ehrenreich and A. Carracedo and V. Golimbet and Andreassen, {O. A.} and B{\o}rglum, {A. D.} and O. Mors and Mortensen, {P. B.} and T. Werge and Ophoff, {R. A.} and N{\"o}then, {M. M.} and M. Rietschel and S. Cichon and M. Ruggeri and S. Tosato and A. Palotie and {St Clair}, D. and D. Rujescu and Collier, {D. A.} and H. Stefansson and K. Stefansson",

note = "Funding Information: We would like to thank the subjects, their families and the recruitment centre staff. We would also like to acknowledge the help of Maria Dolores Molt{\'o} (Genetics Department, Valencia University, CIBERSAM), Eduardo Paz and Ram{\'o}n Ramos-R{\'i}os (Complexo Hospitalario de Santiago), and the contribution of Fundaci{\'o}n Bot{\'i}n. This study makes use of seven external, publicly available data sets. First, it makes use of data generated by the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project whose principal investigators were Jeffrey A Lieberman, MD, T Scott Stroup, MD, MPH, and Joseph P McEvoy, MD. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. Second, the GAIN/ BiGs data sets used in this work were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000017.v3.p1. Third, the study uses samples genotyped using the Ilumina 550K platform by the Pritzker Consortium, supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. The Pritzker Consortium includes scientists at the University of Michigan (H Akil and S J Watson, Site Directors, and Michael Boehnke, lead on bipolar genotyping effort); Stanford University (Rick Myers and Alan Schatzberg, Site Directors); the University of California at Davis (Ted Jones, Site Director); the University of California at Irvine (William Bunney, Site Director); and the Weill Medical College of Cornell University (Jack Barchas, Site Director). Fourth, the work uses data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) project, led by Gary Sachs, MD, and coordinated by Massachusetts General Hospital in Boston, MA (NIMH grant number was 2N01MH080001–001). Fifth, this study makes use of data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. Sixth, we gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium* and the participating AGRE families. The AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). Seventh, the Autism Genome Project (AGP) data sets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number, phs000267.v1.p1. Submission of the data to dbGaP was provided by Dr Bernie Devlin on behalf of the AGP. Collection and submission of the data to dbGaP were supported by a grant from the Medical Research Council (G0601030) and the Wellcome Trust (075491/Z/04), Anthony P Monaco, PI, University of Oxford. This work was also supported by the European Union (grant numbers LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene), HEALTH-F2-2009-223423 (Project PsychCNVs), HEALTH-F4-2009-242257 (Project ADAMS) and IMI-JU-New-Meds); the National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) (grant numbers 01GS08144 (MooDS-Net) and 01GS08147 (NGFNplus)); the National Institute of Mental Health (R01 MH078075, and N01 MH900001, MH074027 to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project); the Centre of Excellence for Complex Disease Genetics of the Academy of Finland (grant numbers 213506 and 129680); the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki; the Stanley Medical Research Institute; the Danish Council for Strategic Research (grant number 2101-07-0059); H Lundbeck A/S; the Research Council of Norway (grant number 163070/V50); the Danish Medical Research Council; the South-East Norway Health Authority (grant number 2004-123); the Medical Research Council; Ministerio de Sanidad y Consumo, Spain (grant number PI081522 to JC); Xunta de Galicia (grant number 08CSA005208PR to A Carracedo); the Swedish Research Council; the Wellcome Trust (Wellcome Trust grants 085475/B/08/Z and 085475/Z/08/Z as part of the Wellcome Trust Case Control Consortium 2); the Max Planck Society; Saarland University (grant number T6 03 10 00–45 to CMF); the Netherlands Foundation for Brain Research (Hersenstichting) (grant number 2008(1).34 to M Poot); and Eli Lilly and Company (genotyping for CATIE and part of the TOP sample). For further acknowledgements, see the Supplementary Material.",

year = "2014",

month = jan,

doi = "10.1038/mp.2012.157",

language = "English",

volume = "19",

pages = "108--114",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "1",

}

Steinberg, S, De Jong, S, Mattheisen, M, Costas, J, Demontis, D, Jamain, S, Pietiläinen, OPH, Lin, K, Papiol, S, Huttenlocher, J, Sigurdsson, E, Vassos, E, Giegling, I, Breuer, R, Fraser, G, Walker, N, Melle, I, Djurovic, S, Agartz, I, Tuulio-Henriksson, A, Suvisaari, J, Lönnqvist, J, Paunio, T, Olsen, L, Hansen, T, Ingason, A, Pirinen, M, Strengman, E, Hougaard, DM, Orntoft, T, Didriksen, M, Hollegaard, MV, Nordentoft, M, Abramova, L, Kaleda, V, Arrojo, M, Sanjuán, J, Arango, C, Etain, B, Bellivier, F, Méary, A, Schürhoff, F, Szoke, A, Ribolsi, M, Magni, V, Siracusano, A, Sperling, S, Rossner, M, Christiansen, C, Kiemeney, LA, Franke, B, Van Den Berg, LH, Veldink, J, Curran, S, Bolton, P, Poot, M, Staal, W, Rehnstrom, K, Kilpinen, H, Freitag, CM, Meyer, J, Magnusson, P, Saemundsen, E, Martsenkovsky, I, Bikshaieva, I, Martsenkovska, I, Vashchenko, O, Raleva, M, Paketchieva, K, Stefanovski, B, Durmishi, N, Pejovic Milovancevic, M, Lecic Tosevski, D, Silagadze, T, Naneishvili, N, Mikeladze, N, Surguladze, S, Vincent, JB, Farmer, A, Mitchell, PB, Wright, A, Schofield, PR, Fullerton, JM, Montgomery, GW, Martin, NG, Rubino, IA, Van Winkel, R, Kenis, G, De Hert, M, Réthelyi, JM, Bitter, I, Terenius, L, Jönsson, EG, Bakker, S, Van Os, J, Jablensky, A, Leboyer, M, Bramon, E, Powell, J, Murray, R, Corvin, A, Gill, M, Morris, D, O'Neill, FA, Kendler, K, Riley, B, Craddock, N, Owen, MJ, O'Donovan, MC, Thorsteinsdottir, U, Kong, A, Ehrenreich, H, Carracedo, A, Golimbet, V, Andreassen, OA, Børglum, AD, Mors, O, Mortensen, PB, Werge, T, Ophoff, RA, Nöthen, MM, Rietschel, M, Cichon, S, Ruggeri, M, Tosato, S, Palotie, A, St Clair, D, Rujescu, D, Collier, DA, Stefansson, H & Stefansson, K 2014, 'Common variant at 16p11.2 conferring risk of psychosis', Molecular Psychiatry, vol. 19, no. 1, pp. 108-114. https://doi.org/10.1038/mp.2012.157

TY - JOUR

T1 - Common variant at 16p11.2 conferring risk of psychosis

AU - Steinberg, S.

AU - De Jong, S.

AU - Mattheisen, M.

AU - Costas, J.

AU - Demontis, D.

AU - Jamain, S.

AU - Pietiläinen, O. P.H.

AU - Lin, K.

AU - Papiol, S.

AU - Huttenlocher, J.

AU - Sigurdsson, E.

AU - Vassos, E.

AU - Giegling, I.

AU - Breuer, R.

AU - Fraser, G.

AU - Walker, N.

AU - Melle, I.

AU - Djurovic, S.

AU - Agartz, I.

AU - Tuulio-Henriksson, A.

AU - Suvisaari, J.

AU - Lönnqvist, J.

AU - Paunio, T.

AU - Olsen, L.

AU - Hansen, T.

AU - Ingason, A.

AU - Pirinen, M.

AU - Strengman, E.

AU - Hougaard, D. M.

AU - Orntoft, T.

AU - Didriksen, M.

AU - Hollegaard, M. V.

AU - Nordentoft, M.

AU - Abramova, L.

AU - Kaleda, V.

AU - Arrojo, M.

AU - Sanjuán, J.

AU - Arango, C.

AU - Etain, B.

AU - Bellivier, F.

AU - Méary, A.

AU - Schürhoff, F.

AU - Szoke, A.

AU - Ribolsi, M.

AU - Magni, V.

AU - Siracusano, A.

AU - Sperling, S.

AU - Rossner, M.

AU - Christiansen, C.

AU - Kiemeney, L. A.

AU - Franke, B.

AU - Van Den Berg, L. H.

AU - Veldink, J.

AU - Curran, S.

AU - Bolton, P.

AU - Poot, M.

AU - Staal, W.

AU - Rehnstrom, K.

AU - Kilpinen, H.

AU - Freitag, C. M.

AU - Meyer, J.

AU - Magnusson, P.

AU - Saemundsen, E.

AU - Martsenkovsky, I.

AU - Bikshaieva, I.

AU - Martsenkovska, I.

AU - Vashchenko, O.

AU - Raleva, M.

AU - Paketchieva, K.

AU - Stefanovski, B.

AU - Durmishi, N.

AU - Pejovic Milovancevic, M.

AU - Lecic Tosevski, D.

AU - Silagadze, T.

AU - Naneishvili, N.

AU - Mikeladze, N.

AU - Surguladze, S.

AU - Vincent, J. B.

AU - Farmer, A.

AU - Mitchell, P. B.

AU - Wright, A.

AU - Schofield, P. R.

AU - Fullerton, J. M.

AU - Montgomery, G. W.

AU - Martin, N. G.

AU - Rubino, I. A.

AU - Van Winkel, R.

AU - Kenis, G.

AU - De Hert, M.

AU - Réthelyi, J. M.

AU - Bitter, I.

AU - Terenius, L.

AU - Jönsson, E. G.

AU - Bakker, S.

AU - Van Os, J.

AU - Jablensky, A.

AU - Leboyer, M.

AU - Bramon, E.

AU - Powell, J.

AU - Murray, R.

AU - Corvin, A.

AU - Gill, M.

AU - Morris, D.

AU - O'Neill, F. A.

AU - Kendler, K.

AU - Riley, B.

AU - Craddock, N.

AU - Owen, M. J.

AU - O'Donovan, M. C.

AU - Thorsteinsdottir, U.

AU - Kong, A.

AU - Ehrenreich, H.

AU - Carracedo, A.

AU - Golimbet, V.

AU - Andreassen, O. A.

AU - Børglum, A. D.

AU - Mors, O.

AU - Mortensen, P. B.

AU - Werge, T.

AU - Ophoff, R. A.

AU - Nöthen, M. M.

AU - Rietschel, M.

AU - Cichon, S.

AU - Ruggeri, M.

AU - Tosato, S.

AU - Palotie, A.

AU - St Clair, D.

AU - Rujescu, D.

AU - Collier, D. A.

AU - Stefansson, H.

AU - Stefansson, K.

N1 - Funding Information: We would like to thank the subjects, their families and the recruitment centre staff. We would also like to acknowledge the help of Maria Dolores Moltó (Genetics Department, Valencia University, CIBERSAM), Eduardo Paz and Ramón Ramos-Ríos (Complexo Hospitalario de Santiago), and the contribution of Fundación Botín. This study makes use of seven external, publicly available data sets. First, it makes use of data generated by the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project whose principal investigators were Jeffrey A Lieberman, MD, T Scott Stroup, MD, MPH, and Joseph P McEvoy, MD. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. Second, the GAIN/ BiGs data sets used in this work were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000017.v3.p1. Third, the study uses samples genotyped using the Ilumina 550K platform by the Pritzker Consortium, supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. The Pritzker Consortium includes scientists at the University of Michigan (H Akil and S J Watson, Site Directors, and Michael Boehnke, lead on bipolar genotyping effort); Stanford University (Rick Myers and Alan Schatzberg, Site Directors); the University of California at Davis (Ted Jones, Site Director); the University of California at Irvine (William Bunney, Site Director); and the Weill Medical College of Cornell University (Jack Barchas, Site Director). Fourth, the work uses data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) project, led by Gary Sachs, MD, and coordinated by Massachusetts General Hospital in Boston, MA (NIMH grant number was 2N01MH080001–001). Fifth, this study makes use of data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. Sixth, we gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium* and the participating AGRE families. The AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). Seventh, the Autism Genome Project (AGP) data sets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number, phs000267.v1.p1. Submission of the data to dbGaP was provided by Dr Bernie Devlin on behalf of the AGP. Collection and submission of the data to dbGaP were supported by a grant from the Medical Research Council (G0601030) and the Wellcome Trust (075491/Z/04), Anthony P Monaco, PI, University of Oxford. This work was also supported by the European Union (grant numbers LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene), HEALTH-F2-2009-223423 (Project PsychCNVs), HEALTH-F4-2009-242257 (Project ADAMS) and IMI-JU-New-Meds); the National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) (grant numbers 01GS08144 (MooDS-Net) and 01GS08147 (NGFNplus)); the National Institute of Mental Health (R01 MH078075, and N01 MH900001, MH074027 to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project); the Centre of Excellence for Complex Disease Genetics of the Academy of Finland (grant numbers 213506 and 129680); the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki; the Stanley Medical Research Institute; the Danish Council for Strategic Research (grant number 2101-07-0059); H Lundbeck A/S; the Research Council of Norway (grant number 163070/V50); the Danish Medical Research Council; the South-East Norway Health Authority (grant number 2004-123); the Medical Research Council; Ministerio de Sanidad y Consumo, Spain (grant number PI081522 to JC); Xunta de Galicia (grant number 08CSA005208PR to A Carracedo); the Swedish Research Council; the Wellcome Trust (Wellcome Trust grants 085475/B/08/Z and 085475/Z/08/Z as part of the Wellcome Trust Case Control Consortium 2); the Max Planck Society; Saarland University (grant number T6 03 10 00–45 to CMF); the Netherlands Foundation for Brain Research (Hersenstichting) (grant number 2008(1).34 to M Poot); and Eli Lilly and Company (genotyping for CATIE and part of the TOP sample). For further acknowledgements, see the Supplementary Material.

PY - 2014/1

Y1 - 2014/1

N2 - Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255T; odds ratio=1.08; P=6.6 × 10 -11). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255T is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

AB - Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255T; odds ratio=1.08; P=6.6 × 10 -11). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255T is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

KW - 16p11.2

KW - association

KW - bipolar disorder

KW - cross-disorder

KW - schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=84896062209&partnerID=8YFLogxK

U2 - 10.1038/mp.2012.157

DO - 10.1038/mp.2012.157

M3 - Article

C2 - 23164818

AN - SCOPUS:84896062209

SN - 1359-4184

VL - 19

SP - 108

EP - 114

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 1

ER -

Common variant at 16p11.2 conferring risk of psychosis

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