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1. Common variant at 16p11.2 conferring risk of psychosis

Author

Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, 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., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., et al., Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, 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., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., and et al.

Abstract

Item does not contain fulltext, 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 (rs4583255[T]; odds ratio=1.08; P=6.6 x 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), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Published
2014

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

Author

Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, 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., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., et al., Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, 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., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., and et al.

Abstract

Item does not contain fulltext, 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 (rs4583255[T]; odds ratio=1.08; P=6.6 x 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), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Published
2014

3. Common variant at 16p11.2 conferring risk of psychosis

Author

Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, 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., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., et al., Steinberg, S., Jong, S. de, Mattheisen, M., Costas, J., Demontis, D., Jamain, S., Pietilainen, 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., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Olsen, L., Hansen, T., Ingason, A., Pirinen, M., Strengman, E., Hougaard, D.M., Orntoft, T., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Etain, B., Bellivier, F., Meary, A., Schurhoff, F., Szoke, A., Ribolsi, M., Magni, V., Siracusano, A., Sperling, S., Rossner, M., Christiansen, C., Kiemeney, B., Franke, B., Berg, L.H. van den, Veldink, J., Curran, S., Bolton, P., Poot, M., Staal, W., Rehnstrom, K., Kilpinen, H., Freitag, C.M., Meyer, J., Magnusson, P., Saemundsen, E., Martsenkovsky, I., Bikshaieva, I., Martsenkovska, I., Vashchenko, O., Raleva, M., Paketchieva, K., Stefanovski, B., Durmishi, N., Milovancevic, M.P., Tosevski, D.L., Silagadze, T., Naneishvili, N., Mikeladze, N., Surguladze, S., Vincent, J.B., Farmer, A., Mitchell, P.B., Wright, A., Schofield, P.R., Fullerton, J.M., Montgomery, G.W., Martin, N.G., Rubino, I.A., Winkel, R. van, Kenis, G., Hert, M. de, Rethelyi, J.M., Bitter, I., Terenius, L., Jonsson, E.G., Bakker, S., Os, J. van, Jablensky, A., Leboyer, M., Bramon, E., and et al.

Abstract

Item does not contain fulltext, 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 (rs4583255[T]; odds ratio=1.08; P=6.6 x 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), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Published
2014

4. Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Author

Steinberg, S., Jong, S. de, Andreassen, O.A., Werge, T., Borglum, A.D., Mors, O., Mortensen, P.B., Gustafsson, O., Costas, J., Pietilainen, O.P.H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., Jurgens, G., Glenthoj, B., Terenius, L., Hougaard, D.M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Winkel, R. van, Kenis, G., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L.A.L.M., Veldink, J., Berg, L. van den, Ingason, A., Muglia, P., Murray, R., Nothen, Markus, Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I.A., Hert, M. de, Rethelyi, J.M., Bitter, I., Jonsson, E.G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M.J., O'Donovan, M.C., Ruggeri, M., Tosato, S., Peltonen, L., Ophoff, R.A., Collier, D.A., St Clair, D., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., Stefansson, K., Steinberg, S., Jong, S. de, Andreassen, O.A., Werge, T., Borglum, A.D., Mors, O., Mortensen, P.B., Gustafsson, O., Costas, J., Pietilainen, O.P.H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., Jurgens, G., Glenthoj, B., Terenius, L., Hougaard, D.M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Winkel, R. van, Kenis, G., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L.A.L.M., Veldink, J., Berg, L. van den, Ingason, A., Muglia, P., Murray, R., Nothen, Markus, Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I.A., Hert, M. de, Rethelyi, J.M., Bitter, I., Jonsson, E.G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M.J., O'Donovan, M.C., Ruggeri, M., Tosato, S., Peltonen, L., Ophoff, R.A., Collier, D.A., St Clair, D., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., and Stefansson, K.

Abstract

Contains fulltext : 97739.pdf (publisher's version ) (Closed access), Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 x 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 x 10(-9)).

Published
2011

5. Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness

Author

Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A.R., Jakobsen, K.D., Kristinsson, K.T., Roux, L. le, Gustafsson, O., Craddock, N., Moller, H.J., McQuillin, A., Muglia, P., Cichon, S., Rietschel, M., Ophoff, R.A., Djurovic, S., Andreassen, O.A., Pietilainen, O.P.H., Peltonen, L., Dempster, E., Collier, D.A., St Clair, D., Rasmussen, H.B., Glenthoj, B.Y., Kiemeney, L.A.L.M., Franke, B., Tosato, S., Bonetto, C., Saemundsen, E., Hreidarsson, S.J., Nothen, Markus, Gurling, H., O'Donovan, M.C., Owen, M.J., Sigurdsson, E., Petursson, H., Stefansson, H., Rujescu, D., Stefansson, K., Werge, T., Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A.R., Jakobsen, K.D., Kristinsson, K.T., Roux, L. le, Gustafsson, O., Craddock, N., Moller, H.J., McQuillin, A., Muglia, P., Cichon, S., Rietschel, M., Ophoff, R.A., Djurovic, S., Andreassen, O.A., Pietilainen, O.P.H., Peltonen, L., Dempster, E., Collier, D.A., St Clair, D., Rasmussen, H.B., Glenthoj, B.Y., Kiemeney, L.A.L.M., Franke, B., Tosato, S., Bonetto, C., Saemundsen, E., Hreidarsson, S.J., Nothen, Markus, Gurling, H., O'Donovan, M.C., Owen, M.J., Sigurdsson, E., Petursson, H., Stefansson, H., Rujescu, D., Stefansson, K., and Werge, T.

Abstract

Contains fulltext : 97099.pdf (publisher's version ) (Closed access), OBJECTIVE: Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness. METHOD: The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis. RESULTS: Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome. CONCLUSIONS: These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.

Published
2011

6. Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Author

Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O.P.H., Buizer-Voskamp, J.E., Strengman, E., Francks, C., Muglia, P., Gylfason, A, Gustafsson, O., Olason, P.I., Steinberg, S., Hansen, T., Jakobsen, K.D., Rasmussen, H.B., Giegling, I., Moller, H.J., Hartmann, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Bramon, E., Kiemeney, L.A.L.M., Franke, B., Murray, R., Vassos, E., Toulopoulou, T., Muhleisen, T.W., Tosato, S., Ruggeri, M., Djurovic, S., Andreassen, O.A., Zhang, Z., Werge, T., Ophoff, R.A., Rietschel, M., Nothen, Markus, Petursson, H., Stefansson, H., Peltonen, L., Collier, D., Stefansson, K., St Clair, D.M., Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O.P.H., Buizer-Voskamp, J.E., Strengman, E., Francks, C., Muglia, P., Gylfason, A, Gustafsson, O., Olason, P.I., Steinberg, S., Hansen, T., Jakobsen, K.D., Rasmussen, H.B., Giegling, I., Moller, H.J., Hartmann, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Bramon, E., Kiemeney, L.A.L.M., Franke, B., Murray, R., Vassos, E., Toulopoulou, T., Muhleisen, T.W., Tosato, S., Ruggeri, M., Djurovic, S., Andreassen, O.A., Zhang, Z., Werge, T., Ophoff, R.A., Rietschel, M., Nothen, Markus, Petursson, H., Stefansson, H., Peltonen, L., Collier, D., Stefansson, K., and St Clair, D.M.

Abstract

Contains fulltext : 96767.pdf (publisher's version ) (Closed access), Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Published
2011

7. Expanding the range of ZNF804A variants conferring risk of psychosis

Author

Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., Stefansson, K., Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., and Stefansson, K.

Abstract

Contains fulltext : 95884.pdf (publisher's version ) (Closed access), A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 x 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 x 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 x 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Published
2011

8. Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Author

Steinberg, S., Jong, S. de, Andreassen, O.A., Werge, T., Borglum, A.D., Mors, O., Mortensen, P.B., Gustafsson, O., Costas, J., Pietilainen, O.P.H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., Jurgens, G., Glenthoj, B., Terenius, L., Hougaard, D.M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Winkel, R. van, Kenis, G., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L.A.L.M., Veldink, J., Berg, L. van den, Ingason, A., Muglia, P., Murray, R., Nothen, Markus, Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I.A., Hert, M. de, Rethelyi, J.M., Bitter, I., Jonsson, E.G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M.J., O'Donovan, M.C., Ruggeri, M., Tosato, S., Peltonen, L., Ophoff, R.A., Collier, D.A., St Clair, D., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., Stefansson, K., Steinberg, S., Jong, S. de, Andreassen, O.A., Werge, T., Borglum, A.D., Mors, O., Mortensen, P.B., Gustafsson, O., Costas, J., Pietilainen, O.P.H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., Jurgens, G., Glenthoj, B., Terenius, L., Hougaard, D.M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Winkel, R. van, Kenis, G., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L.A.L.M., Veldink, J., Berg, L. van den, Ingason, A., Muglia, P., Murray, R., Nothen, Markus, Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I.A., Hert, M. de, Rethelyi, J.M., Bitter, I., Jonsson, E.G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M.J., O'Donovan, M.C., Ruggeri, M., Tosato, S., Peltonen, L., Ophoff, R.A., Collier, D.A., St Clair, D., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., and Stefansson, K.

Abstract

Contains fulltext : 97739.pdf (publisher's version ) (Closed access), Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 x 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 x 10(-9)).

Published
2011

9. Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness

Author

Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A.R., Jakobsen, K.D., Kristinsson, K.T., Roux, L. le, Gustafsson, O., Craddock, N., Moller, H.J., McQuillin, A., Muglia, P., Cichon, S., Rietschel, M., Ophoff, R.A., Djurovic, S., Andreassen, O.A., Pietilainen, O.P.H., Peltonen, L., Dempster, E., Collier, D.A., St Clair, D., Rasmussen, H.B., Glenthoj, B.Y., Kiemeney, L.A.L.M., Franke, B., Tosato, S., Bonetto, C., Saemundsen, E., Hreidarsson, S.J., Nothen, Markus, Gurling, H., O'Donovan, M.C., Owen, M.J., Sigurdsson, E., Petursson, H., Stefansson, H., Rujescu, D., Stefansson, K., Werge, T., Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A.R., Jakobsen, K.D., Kristinsson, K.T., Roux, L. le, Gustafsson, O., Craddock, N., Moller, H.J., McQuillin, A., Muglia, P., Cichon, S., Rietschel, M., Ophoff, R.A., Djurovic, S., Andreassen, O.A., Pietilainen, O.P.H., Peltonen, L., Dempster, E., Collier, D.A., St Clair, D., Rasmussen, H.B., Glenthoj, B.Y., Kiemeney, L.A.L.M., Franke, B., Tosato, S., Bonetto, C., Saemundsen, E., Hreidarsson, S.J., Nothen, Markus, Gurling, H., O'Donovan, M.C., Owen, M.J., Sigurdsson, E., Petursson, H., Stefansson, H., Rujescu, D., Stefansson, K., and Werge, T.

Abstract

Contains fulltext : 97099.pdf (publisher's version ) (Closed access), OBJECTIVE: Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness. METHOD: The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis. RESULTS: Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome. CONCLUSIONS: These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.

Published
2011

10. Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Author

Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O.P.H., Buizer-Voskamp, J.E., Strengman, E., Francks, C., Muglia, P., Gylfason, A, Gustafsson, O., Olason, P.I., Steinberg, S., Hansen, T., Jakobsen, K.D., Rasmussen, H.B., Giegling, I., Moller, H.J., Hartmann, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Bramon, E., Kiemeney, L.A.L.M., Franke, B., Murray, R., Vassos, E., Toulopoulou, T., Muhleisen, T.W., Tosato, S., Ruggeri, M., Djurovic, S., Andreassen, O.A., Zhang, Z., Werge, T., Ophoff, R.A., Rietschel, M., Nothen, Markus, Petursson, H., Stefansson, H., Peltonen, L., Collier, D., Stefansson, K., St Clair, D.M., Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O.P.H., Buizer-Voskamp, J.E., Strengman, E., Francks, C., Muglia, P., Gylfason, A, Gustafsson, O., Olason, P.I., Steinberg, S., Hansen, T., Jakobsen, K.D., Rasmussen, H.B., Giegling, I., Moller, H.J., Hartmann, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Bramon, E., Kiemeney, L.A.L.M., Franke, B., Murray, R., Vassos, E., Toulopoulou, T., Muhleisen, T.W., Tosato, S., Ruggeri, M., Djurovic, S., Andreassen, O.A., Zhang, Z., Werge, T., Ophoff, R.A., Rietschel, M., Nothen, Markus, Petursson, H., Stefansson, H., Peltonen, L., Collier, D., Stefansson, K., and St Clair, D.M.

Abstract

Contains fulltext : 96767.pdf (publisher's version ) (Closed access), Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Published
2011

11. Expanding the range of ZNF804A variants conferring risk of psychosis

Author

Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., Stefansson, K., Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., and Stefansson, K.

Abstract

Contains fulltext : 95884.pdf (publisher's version ) (Closed access), A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 x 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 x 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 x 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Published
2011

12. Expanding the range of ZNF804A variants conferring risk of psychosis

Author

Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., Stefansson, K., Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., and Stefansson, K.

Abstract

Contains fulltext : 95884.pdf (publisher's version ) (Closed access), A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 x 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 x 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 x 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Published
2011

13. Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Author

Steinberg, S., Jong, S. de, Andreassen, O.A., Werge, T., Borglum, A.D., Mors, O., Mortensen, P.B., Gustafsson, O., Costas, J., Pietilainen, O.P.H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., Jurgens, G., Glenthoj, B., Terenius, L., Hougaard, D.M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Winkel, R. van, Kenis, G., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L.A.L.M., Veldink, J., Berg, L. van den, Ingason, A., Muglia, P., Murray, R., Nothen, Markus, Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I.A., Hert, M. de, Rethelyi, J.M., Bitter, I., Jonsson, E.G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M.J., O'Donovan, M.C., Ruggeri, M., Tosato, S., Peltonen, L., Ophoff, R.A., Collier, D.A., St Clair, D., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., Stefansson, K., Steinberg, S., Jong, S. de, Andreassen, O.A., Werge, T., Borglum, A.D., Mors, O., Mortensen, P.B., Gustafsson, O., Costas, J., Pietilainen, O.P.H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio-Henriksson, A., Suvisaari, J., Lonnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., Jurgens, G., Glenthoj, B., Terenius, L., Hougaard, D.M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M.V., Nordentoft, M., Winkel, R. van, Kenis, G., Abramova, L.I., Kaleda, V., Arrojo, M., Sanjuan, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L.A.L.M., Veldink, J., Berg, L. van den, Ingason, A., Muglia, P., Murray, R., Nothen, Markus, Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I.A., Hert, M. de, Rethelyi, J.M., Bitter, I., Jonsson, E.G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M.J., O'Donovan, M.C., Ruggeri, M., Tosato, S., Peltonen, L., Ophoff, R.A., Collier, D.A., St Clair, D., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., and Stefansson, K.

Abstract

Contains fulltext : 97739.pdf (publisher's version ) (Closed access), Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 x 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 x 10(-9)).

Published
2011

14. Common variants conferring risk of schizophrenia.

Author

Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O.P.H., Mors, O., Mortensen, P.B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A.D., Hartmann, A., Fink-Jensen, A., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Bottcher, Y., Olesen, J., Breuer, R., Moller, H.J., Giegling, I., Rasmussen, H.B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J.M., Magnusdottir, B.B., Sigmundsson, T., Olason, P., Masson, G., Gulcher, J.R., Haraldsson, M., Fossdal, R., Thorgeirsson, T.E., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Sanjuan, J., Frutos, R. de, Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A.C., Ge, D., Yoon, J.L., Shianna, K.V., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Matthews, P.M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D.B, Stefansson, K., Collier, D.A., Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O.P.H., Mors, O., Mortensen, P.B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A.D., Hartmann, A., Fink-Jensen, A., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Bottcher, Y., Olesen, J., Breuer, R., Moller, H.J., Giegling, I., Rasmussen, H.B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J.M., Magnusdottir, B.B., Sigmundsson, T., Olason, P., Masson, G., Gulcher, J.R., Haraldsson, M., Fossdal, R., Thorgeirsson, T.E., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Sanjuan, J., Frutos, R. de, Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A.C., Ge, D., Yoon, J.L., Shianna, K.V., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Matthews, P.M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D.B, Stefansson, K., and Collier, D.A.

Abstract

Contains fulltext : 81575.pdf (publisher's version ) (Closed access), Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Published
2009

15. Disruption of the neurexin 1 gene is associated with schizophrenia.

Author

Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., Collier, D.A., Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., and Collier, D.A.

Abstract

Contains fulltext : 80670.pdf (publisher's version ) (Closed access), Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Published
2009

16. Common variants conferring risk of schizophrenia.

Author

Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O.P.H., Mors, O., Mortensen, P.B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A.D., Hartmann, A., Fink-Jensen, A., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Bottcher, Y., Olesen, J., Breuer, R., Moller, H.J., Giegling, I., Rasmussen, H.B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J.M., Magnusdottir, B.B., Sigmundsson, T., Olason, P., Masson, G., Gulcher, J.R., Haraldsson, M., Fossdal, R., Thorgeirsson, T.E., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Sanjuan, J., Frutos, R. de, Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A.C., Ge, D., Yoon, J.L., Shianna, K.V., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Matthews, P.M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D.B, Stefansson, K., Collier, D.A., Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O.P.H., Mors, O., Mortensen, P.B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A.D., Hartmann, A., Fink-Jensen, A., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Bottcher, Y., Olesen, J., Breuer, R., Moller, H.J., Giegling, I., Rasmussen, H.B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J.M., Magnusdottir, B.B., Sigmundsson, T., Olason, P., Masson, G., Gulcher, J.R., Haraldsson, M., Fossdal, R., Thorgeirsson, T.E., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Sanjuan, J., Frutos, R. de, Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A.C., Ge, D., Yoon, J.L., Shianna, K.V., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Matthews, P.M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D.B, Stefansson, K., and Collier, D.A.

Abstract

Contains fulltext : 81575.pdf (publisher's version ) (Closed access), Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Published
2009

17. Disruption of the neurexin 1 gene is associated with schizophrenia.

Author

Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., Collier, D.A., Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., and Collier, D.A.

Abstract

Contains fulltext : 80670.pdf (publisher's version ) (Closed access), Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Published
2009

18. Common variants conferring risk of schizophrenia.

Author

Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O.P.H., Mors, O., Mortensen, P.B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A.D., Hartmann, A., Fink-Jensen, A., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Bottcher, Y., Olesen, J., Breuer, R., Moller, H.J., Giegling, I., Rasmussen, H.B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J.M., Magnusdottir, B.B., Sigmundsson, T., Olason, P., Masson, G., Gulcher, J.R., Haraldsson, M., Fossdal, R., Thorgeirsson, T.E., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Sanjuan, J., Frutos, R. de, Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A.C., Ge, D., Yoon, J.L., Shianna, K.V., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Matthews, P.M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D.B, Stefansson, K., Collier, D.A., Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O.P.H., Mors, O., Mortensen, P.B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A.D., Hartmann, A., Fink-Jensen, A., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Bottcher, Y., Olesen, J., Breuer, R., Moller, H.J., Giegling, I., Rasmussen, H.B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J.M., Magnusdottir, B.B., Sigmundsson, T., Olason, P., Masson, G., Gulcher, J.R., Haraldsson, M., Fossdal, R., Thorgeirsson, T.E., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Sanjuan, J., Frutos, R. de, Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A.C., Ge, D., Yoon, J.L., Shianna, K.V., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Matthews, P.M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D.B, Stefansson, K., and Collier, D.A.

Abstract

Contains fulltext : 81575.pdf (publisher's version ) (Closed access), Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Published
2009

19. Large recurrent microdeletions associated with schizophrenia.

Author

Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P.H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A, Halldorsson, B.V., Gudbjartsson, D.F., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, B., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B, Nothen, Markus, Peltonen, L., Collier, D.A., St Clair, D., Stefansson, K., Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P.H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A, Halldorsson, B.V., Gudbjartsson, D.F., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, B., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B, Nothen, Markus, Peltonen, L., Collier, D.A., St Clair, D., and Stefansson, K.

Abstract

Contains fulltext : 69527.pdf (publisher's version ) (Closed access)

Published
2008

20. Large recurrent microdeletions associated with schizophrenia.

Author

Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P.H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A, Halldorsson, B.V., Gudbjartsson, D.F., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, B., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B, Nothen, Markus, Peltonen, L., Collier, D.A., St Clair, D., Stefansson, K., Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P.H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A, Halldorsson, B.V., Gudbjartsson, D.F., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, B., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B, Nothen, Markus, Peltonen, L., Collier, D.A., St Clair, D., and Stefansson, K.

Abstract

Contains fulltext : 69527.pdf (publisher's version ) (Closed access)

Published
2008

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