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3. Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Author

Rees, E, Kirov, G, Walters, JT, Richards, AL, Howrigan, D, Kavanagh, DH, Pocklington, AJ, Fromer, M, Ruderfer, DM, Georgieva, L, Carrera, N, Gormley, P, Palta, P, Williams, H, Dwyer, S, Johnson, JS, Roussos, P, Barker, DD, Banks, E, Milanova, V, Rose, SA, Chambert, K, Mahajan, M, Scolnick, EM, Moran, JL, Tsuang, MT, Glatt, SJ, Chen, WJ, Hwu, H-G, Taiwanese Trios Exome Sequencing Consortium, Neale, BM, Palotie, A, Sklar, P, Purcell, SM, McCarroll, SA, Holmans, P, Owen, MJ, and O'Donovan, MC

Subjects
Taiwanese Trios Exome Sequencing Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Family, Schizophrenia, Gene Frequency, Genotype, Heterozygote, Homozygote, Genes, Recessive, Female, Male, Exome, Voltage-Gated Sodium Channels, Genes, Recessive, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.

Published
2015

7. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Blokland, GAM, Grove, J, Chen, CY, Cotsapas, C, Tobet, S, Handa, R, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Blokland, GAM, Grove, J, Chen, CY, Cotsapas, C, Tobet, S, Handa, R, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, and Hirschhorn, JN

Abstract

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functio

Published
2021

8. Phenotypic variability in familial prion diseases due to the D178N mutation

Author

Zarranz, J.J., Digon, A., Atares, B., Rodriguez-Martinez, A.B., Arce, A., Carrera, N., Fernandez-Manchola, I., Fernandez-Martinez, M., Fernandez-Maiztegui, C., Forcadas, I., Galdos, L., Gomez-Esteban, J.C., Ibanez, A., Lezcano, E., Lopez de Munain, A., Marti-Masso, J.F., Mendibe, M.M., Urtasun, M., Uterga, J.M., Saracibar, N., Velasco, F., and de Pancorbo, M.M.

Subjects
Epidemiology -- Genetic aspects, Epidemiology -- Research, Gene mutations -- Analysis, Phenotype -- Analysis, Prion diseases -- Genetic aspects, Prion diseases -- Diagnosis, Health, Psychology and mental health
Published
2005

10. La interdisciplina como herramienta para la conservación del patrimonio biocultural

Author

Carrera, N. I. and Lizana, C.

Abstract

Durante las últimas décadas, los investigadores dedicados a la producción de conocimientos han manifestado abiertamente sus limitaciones para articular fenómenos que escapan o se resisten a los métodos clásicos de la investigación positivista. La complejidad propia de las dinámicas territoriales en contextos de modernidad -donde los símbolos culturales parecen colisionar con los intereses del mercado- delimitan la posibilidad aprehender/producir conocimientos adecuada y multidimensionalmente, entramándose en los intersticios de una epistemología en crisis y que afecta al conjunto de ciencias (formales, fácticas, naturales y sociales). No obstante, derivado del ...

Published
2019

11. Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Author

Rees, E, Carrera, N, Morgan, J, Hambridge, K, Escott-Price, V, Pocklington, AJ, Richards, AL, Pardinas, AF, McDonald, C, Donohoe, G, Morris, DW, Kenny, E, Kelleher, E, Gill, M, Corvin, A, Kirov, G, Walters, JTR, Holmans, P, Owen, MJ, O'Donovan, MC, Alizadeh, BZ, van Amelsvoort, T, Bartels-Velthuis, AA, Beveren, JM, Bruggeman, R, Cahn, W, de Haan, L, Delespaul, P, Meijer, CJ, Myin-Germeys, I, Kahn, RS, Schirmbeck, F, Simons, CJP, van Haren, NE, van Os, J, van Winkel, R, Luykx, JJ, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), Neurosciences, and Psychiatry

Subjects
Psychiatry, RISK, Science & Technology, DISORDERS, Neurosciences, OF-FUNCTION VARIANTS, SUSCEPTIBILITY, FRAMEWORK, ARC, NMDAR, INDIVIDUALS, DE-NOVO MUTATIONS, mental disorders, SETD1A, Genetics, Schizophrenia, Sequencing, Neurosciences & Neurology, GENOME-WIDE ASSOCIATION, Voltage-gated sodium channels, BURDEN, Life Sciences & Biomedicine, Biological Psychiatry
Abstract

BACKGROUND: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. METHODS: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. RESULTS: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10-4) and NMDAR (p = 1.7 × 10-5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10-4). CONCLUSIONS: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes. ispartof: BIOLOGICAL PSYCHIATRY vol:85 issue:7 pages:554-562 ispartof: location:United States status: published

Published
2019

12. Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Author

Rees, E., Carrera, N, Morgan, J. (John), Hambridge, K., Escott-Price, V, Pocklington, AJ, Richards, AL, Pardinas, A.F., McDonald, C. (Colm), Donohoe, G, Morris, D.W. (Derek W), Kenny, A., Kelleher, E., Gill, M. (Michael), Corvin, A. (Aiden), Kirov, G, Walters, JTR, Holmans, P.A. (Peter), Owen, M.J., O'Donovan, M. (Michael), Alizadeh, BZ, van Amelsvoort, T, Bartels-Velthuis, A.A., van Beveren, NJ, Bruggeman, R. (Richard), Cahn, W. (Wiepke), Willigenburg, T. (Theo) van, Delespaul, P., Meijer, C.J., Myin-Germeys, I. (Inez), Kahn, R.S. (René), Schirmbeck, F., Simons, CJP, van Haren, N.E., Os, J. (Jim) van, Winkel, R. (Ruud) van, Luykx, J.J., Rees, E., Carrera, N, Morgan, J. (John), Hambridge, K., Escott-Price, V, Pocklington, AJ, Richards, AL, Pardinas, A.F., McDonald, C. (Colm), Donohoe, G, Morris, D.W. (Derek W), Kenny, A., Kelleher, E., Gill, M. (Michael), Corvin, A. (Aiden), Kirov, G, Walters, JTR, Holmans, P.A. (Peter), Owen, M.J., O'Donovan, M. (Michael), Alizadeh, BZ, van Amelsvoort, T, Bartels-Velthuis, A.A., van Beveren, NJ, Bruggeman, R. (Richard), Cahn, W. (Wiepke), Willigenburg, T. (Theo) van, Delespaul, P., Meijer, C.J., Myin-Germeys, I. (Inez), Kahn, R.S. (René), Schirmbeck, F., Simons, CJP, van Haren, N.E., Os, J. (Jim) van, Winkel, R. (Ruud) van, and Luykx, J.J.

Abstract

Background Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. Methods We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage

Published
2019
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13. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author

Harold, D, Connolly, S, Riley, BP, Kendler, KS, McCarthy, SE, McCombie, WR, Richards, A, Owen, MJ, O'Donovan, MC, Walters, J, Donnelly, P, Bates, L, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Hopkins, L, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Ripke, S, Neale, BM, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M-L, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chan, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Lee, J, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Muller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Buxbaum, JD, Borglum, AD, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, Harold, D, Connolly, S, Riley, BP, Kendler, KS, McCarthy, SE, McCombie, WR, Richards, A, Owen, MJ, O'Donovan, MC, Walters, J, Donnelly, P, Bates, L, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Hopkins, L, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Ripke, S, Neale, BM, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M-L, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chan, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Lee, J, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Muller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Buxbaum, JD, Borglum, AD, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, and Sullivan, PF

Abstract

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Published
2019

14. Deciphering the sardic (Ordovician) and variscan deformations in the eastern pyrenees, sw europe

Author

Álvaro, J.J., Puddu, Claudia, Carrera, N., Casas, Josep Maria, Álvaro, J.J., Puddu, Claudia, Carrera, N., and Casas, Josep Maria

Abstract

Detailed geological mapping of the La Cerdanya area (Canigó unit, Eastern Pyrenees) provides new data characterizing the different structural styles exhibited by Cambrian–Lower Ordovician (Jujols Group) and Upper Ordovician successions. Their unconformable contact, related to the Sardic Phase, ranges from 0° (paraconformity) to 90° (angular discordance). The Jujols Group rocks topped by the unconformity are affected by Sardic foliation-free open folds. The pre-Sardic succession, the Sardic Unconformity and the lower part of the post-Sardic succession (Rabassa Conglomerate and Cava formations) are cut and offset by several Late Ordovician NNE–SSW-trending synsedimentary extensional faults associated with hydrothermal activity, which dramatically affected the thickness of the lower part of the Upper Ordovician succession. We relate (1) the Mid-Ordovician Sardic uplift and erosion, and (2) a Mid-to Late-Ordovician upward propagating extensional fault system bounding the outline of half-grabens, subsequently infilled by alluvial deposits, to a thermal doming event (about 475– 450 Ma) that led to the uplift and stretching of the Ordovician lithosphere. Thermal doming may be caused by mafic magma underplating and responsible for the coeval calc-alkaline magmatic activity broadly developed in the Eastern Pyrenees. We discuss the similarities between the Mid-Ordovician Sardic Unconformity and other Early Paleozoic unconformities described in neighbouring areas. Finally, we suggest a geodynamic scenario in which a regional-scale thermal event was related to the opening of the Rheic Ocean that led to the drift of Avalonia from the SW European margin of Gondwana.

Published
2019

15. Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

Author

Bigdeli, T. B, Ripke, S, Bacanu, Sa, Lee, S. H, Wray, Nr, Gejman, P. V, Rietschel, M, Cichon, S, St Clair, D, Corvin, A, Kirov, G, Mcquillin, A, Gurling, H, Rujescu, D, Andreassen, O. A, Werge, T, Blackwood, D. H. R, Pato, C. N, Pato, M. T, Malhotra, A. K, O'Donovan, M. C, Kendler, K. S, Fanous, A. H, Neale, Bm, Walters, Jt, Farh, Kh, Holmans, Pa, Lee, P, Bulik Sullivan, B, Collier, Da, Huang, H, Pers, Th, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Begemann, M, Belliveau, Ra, Bene, J, Bergen, Se, Bevilacqua, E, Bigdeli, Tb, Black, Dw, Børglum, Ad, Bruggeman, R, Buccola, Ng, Buckner, Rl, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, Rm, Carr, Vj, Carrera, N, Catts, Sv, Chambert, Kd, Chan, Rc, Chen, Ry, Chen, Ey, Cheng, W, Cheung, Ef, Chong, Sa, Cloninger, C, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, Jj, Curtis, D, Davidson, M, Davis, Kl, Degenhardt, F, Del, Favero, J, Delisi, Le, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott Price, V, Essioux, L, Fanous, Ah, Farrell, Ms, Frank, J, Franke, L, Freedman, R, Freimer, Nb, Friedl, M, Friedman, Ji, Fromer, M, Genovese, G, Georgieva, L, Gershon, Es, Giegling, I, Giusti Rodríguez, P, Godard, S, Goldstein, Ji, Golimbet, V, Gopal, S, Gratten, J, Grove, J, Haan, De, L, Hammer, C, Hamshere, Ml, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, Am, Henskens, Fa, Herms, S, Hirschhorn, Jn, Hoffmann, P, Hofman, A, Hollegaard, Mv, Hougaard, Dm, Ikeda, M, Joa, I, Julìa, A, Kahn, Rs, Kalaydjieva, L, Karachanak Yankova, S, Karjalainen, J, Kavanagh, D, Keller, Mc, Kelly, Bj, Kennedy, Jl, Khrunin, A, Kim, Y, Klovins, J, Knowles, Ja, Konte, B, Kucinskas, V, Kucinskiene, Za, Kuzelova Ptackova, H, Kähler, Ak, Laurent, C, Keong, Jl, Lee, S, Legge, Se, Lerer, B, Li, M, Li, T, Liang, Ky, Lieberman, J, Limborska, S, Loughland, Cm, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, Pk, Maher, Bs, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, Mccarley, Rw, Mcdonald, C, Mcintosh, Am, Meier, S, Meijer, Cj, Melegh, B, Melle, I, Mesholam Gately, Ri, Metspalu, A, Michie, Pt, Milani, L, Milanova, V, Mokrab, Y, Morris, Dw, Mors, O, Mortensen, Pb, Murphy, Kc, Murray, Rm, Myin Germeys, I, Müller Myhsok, B, Nelis, M, Nenadic, I, Nertney, Da, Nestadt, G, Nicodemus, Kk, Nikitina Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, F, Sy, Oh, Olincy, A, Olsen, L, Jv, Os, Pantelis, C, Papadimitriou, Gn, Papiol, S, Parkhomenko, E, Pato, Mt, Paunio, T, Pejovic Milovancevic, M, Perkins, Do, Pietiläinen, O, Pimm, J, Pocklington, Aj, Powell, J, Price, A, Pulver, Ae, Purcell, Sm, Quested, D, Rasmussen, Hb, Reichenberg, A, Reimers, Ma, Richards, Al, Roffman, Jl, Roussos, P, Ruderfer, Dm, Salomaa, V, Sanders, Ar, Schall, U, Schubert, Cr, Schulze, Tg, Schwab, Sg, Scolnick, Em, Scott, Rj, Seidman, Lj, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, Jm, Sim, K, Slominsky, P, Smoller, Jw, Hc, So, Spencer, Cc, Stahl, Ea, Stefansson, H, Steinberg, S, Stogmann, E, Straub, Re, Strengman, E, Strohmaier, J, Stroup, T, Subramaniam, M, Suvisaari, J, Svrakic, Dm, Szatkiewicz, Jp, Söderman, E, Thirumalai, S, Toncheva, D, Tooney, Pa, Tosato, Sarah, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, Bt, Weiser, M, Wildenauer, Db, Williams, Nm, Williams, S, Witt, Sh, Wolen, Ar, Wong, Eh, Wormley, Bk, Jq, Wu, Hs, Xi, Zai, Cc, Zheng, X, Zimprich, F, Stefansson, K, Visscher, Pm, Adolfsson, R, Andreassen, Oa, Blackwood, Dh, Bramon, E, Buxbaum, Jd, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, Pv, Gill, M, Hultman, Cm, Iwata, N, Jablensky, Av, Jönsson, Eg, Kendler, Ks, Knight, J, Lencz, T, Levinson, Df, Qs, Li, Liu, J, Malhotra, Ak, Mccarroll, Sa, Moran, Jl, Mowry, Bj, Nöthen, Mm, Ophoff, Ra, Owen, Mj, Palotie, A, Pato, Cn, Petryshen, Tl, Posthuma, D, Riley, Bp, Sham, Pc, Sklar, P, Clair, Ds, Weinberger, Dr, Wendland, Jr, Daly, Mj, Sullivan, Pf, O'Donovan, Mc, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Bigdeli, Tim B, Ripke, Stephan, Bacanu, Silviu-Alin, Lee, Sang Hong, Fanous, Ayman H, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotype International Consortium, Wellcome Trust Case-Control Consortium 2, Other departments, Adult Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), and Del-Favero, Jurgen

Subjects
0301 basic medicine, Multifactorial Inheritance, Bipolar Disorder, Inheritance Patterns, Genome-wide association study, Single-nucleotide polymorphism, polygenic, heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, SNP, GWAS, Family, Genetic Predisposition to Disease, Family history, Allele, Genetics (clinical), Genetic association, Genetics & Heredity, Psychiatry, Genetics, Depressive Disorder, Major, family history, Models, Genetic, Case-control study, medicine.disease, 3. Good health, schizophrenia, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Case-Control Studies, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N=978), cases reporting no such family history (N=4,503), and unscreened controls (N=8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R-2=0.0021; P=0.00331; P-value threshold

Published
2016

17. Global Asylum Governance and the European Union's Role

Author

Carrera Nunez, Sergio, Karageorgiou, Eleni, Ovacik, Gamze, and Tan, Nikolas Feith

Subjects
United Nations Global Compact for Refugees, Asylum Governance, Refugee Protection, Resettlement of People, Vulnerability and Migration, Responsibility Attribution, Contained Mobility of Refugees, Human Rights, thema EDItEUR::J Society and Social Sciences::JP Politics and government::JPP Public administration, thema EDItEUR::J Society and Social Sciences::JP Politics and government::JPV Political control and freedoms::JPVH Human rights, civil rights, thema EDItEUR::J Society and Social Sciences::JB Society and culture: general::JBF Social and ethical issues::JBFH Migration, immigration and emigration, thema EDItEUR::R Earth Sciences, Geography, Environment, Planning::RG Geography::RGC Human geography::RGCG Population and migration geography
Abstract

This open access book provides a state-of-the-field of the interactions between emerging national asylum governance systems and the 2018 United Nations Global Compact for Refugees (UN GCR). It provides a detailed examination of the relationship and compatibility between asylum governance and refugee protection and human rights, and the responsibilities for states and other implementing actors in cases of human rights violations. This book analyses the characteristics and impacts of existing and emerging asylum governance instruments and their practical implementation in selected countries hosting large communities of refugees around the world. Particular focus is given to the cases of Bangladesh, Brazil, Canada, Jordan, Niger, Serbia, South Africa and Turkey. Attention is put into regional and country-specific asylum instruments and actors from the perspective of their effectiveness, fairness and consistency with refugee protection and human rights standards as well as the UN GCR commitments. By doing so, the book identifies key lessons learned and offers a critical view on policies framed as `promising practices' so as to inform future steps in the UN GCR implementation and asylum governance more generally. As such, the book provides a better understanding of the concept of “mobility” in asylum governance, and the ways in which it is articulated into legal and policy instruments framed as "protection" and - in the language of the UN GCR - “third country solutions” for refugee mobility, including resettlement, private/community sponsorships, humanitarian corridors, in the European Union and around the world.

Published
2025
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18. A correction for sample overlap in genome-wide association studies in a polygenic pleiotropy-informed framework

Author

LeBlanc, M, Zuber, V, Thompson, WK, Andreassen, OA, Frigessi, A, Andreassen, BK, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crespo-Facorro, B, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Favero, JD, DeLisi, LE, Demontis, D, Dikeos, D, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Gershon, ES, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, LeBlanc, M, Zuber, V, Thompson, WK, Andreassen, OA, Frigessi, A, Andreassen, BK, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crespo-Facorro, B, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Favero, JD, DeLisi, LE, Demontis, D, Dikeos, D, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Gershon, ES, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, and Hirschhorn, JN

Abstract

Background: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). Results: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. Conclusions: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS.

Published
2018

19. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Author

Ruderfer, DM, Ripke, S, McQuillin, A, Boocock, J, Stahl, EA, Pavlides, JMW, Mullins, N, Charney, AW, Ori, APS, Loohuis, LMO, Domenici, E, Di Florio, A, Papiol, S, Kalman, JL, Trubetskoy, V, Adolfsson, R, Agartz, I, Agerbo, E, Akil, H, Albani, D, Albus, M, Alda, M, Alexander, M, Alliey-Rodriguez, N, Als, TD, Amin, F, Anjorin, A, Arranz, MJ, Awasthi, S, Bacanu, SA, Badner, JA, Baekvad-Hansen, M, Bakker, S, Band, G, Barchas, JD, Barroso, I, Bass, N, Bauer, M, Baune, BT, Begemann, M, Bellenguez, C, Belliveau, RA, Bellivier, F, Bender, S, Bene, J, Bergen, SE, Berrettini, WH, Bevilacqua, E, Biernacka, JM, Bigdeli, TB, Black, DW, Blackburn, H, Blackwell, JM, Blackwood, DHR, Pedersen, CB, Boehnke, M, Boks, M, Borglum, AD, Bramon, E, Breen, G, Brown, MA, Bruggeman, R, Buccola, NG, Buckner, RL, Budde, M, Bulik-Sullivan, B, Bumpstead, SJ, Bunney, W, Burmeister, M, Buxbaum, JD, Bybjerg-Grauholm, J, Byerley, W, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Casas, JP, Casas, M, Catts, SV, Cervantes, P, Chambert, KD, Chan, RCK, Chen, EYH, Chen, RYL, Cheng, W, Cheung, EFC, Chong, SA, Clarke, TK, Cloninger, CR, Cohen, D, Cohen, N, Coleman, JRI, Collier, DA, Cormican, P, Coryell, W, Craddock, N, Craig, DW, Ruderfer, DM, Ripke, S, McQuillin, A, Boocock, J, Stahl, EA, Pavlides, JMW, Mullins, N, Charney, AW, Ori, APS, Loohuis, LMO, Domenici, E, Di Florio, A, Papiol, S, Kalman, JL, Trubetskoy, V, Adolfsson, R, Agartz, I, Agerbo, E, Akil, H, Albani, D, Albus, M, Alda, M, Alexander, M, Alliey-Rodriguez, N, Als, TD, Amin, F, Anjorin, A, Arranz, MJ, Awasthi, S, Bacanu, SA, Badner, JA, Baekvad-Hansen, M, Bakker, S, Band, G, Barchas, JD, Barroso, I, Bass, N, Bauer, M, Baune, BT, Begemann, M, Bellenguez, C, Belliveau, RA, Bellivier, F, Bender, S, Bene, J, Bergen, SE, Berrettini, WH, Bevilacqua, E, Biernacka, JM, Bigdeli, TB, Black, DW, Blackburn, H, Blackwell, JM, Blackwood, DHR, Pedersen, CB, Boehnke, M, Boks, M, Borglum, AD, Bramon, E, Breen, G, Brown, MA, Bruggeman, R, Buccola, NG, Buckner, RL, Budde, M, Bulik-Sullivan, B, Bumpstead, SJ, Bunney, W, Burmeister, M, Buxbaum, JD, Bybjerg-Grauholm, J, Byerley, W, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Casas, JP, Casas, M, Catts, SV, Cervantes, P, Chambert, KD, Chan, RCK, Chen, EYH, Chen, RYL, Cheng, W, Cheung, EFC, Chong, SA, Clarke, TK, Cloninger, CR, Cohen, D, Cohen, N, Coleman, JRI, Collier, DA, Cormican, P, Coryell, W, Craddock, N, and Craig, DW

Abstract

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment. Genetic analysis of multiple bipolar disorder and schizophrenia cohorts reveals loci and polygenic risk scores that differentiate the clinical symptoms of these two highly correlated disorders.

Published
2018

20. Age at first birth in women is genetically associated with increased risk of schizophrenia

Author

Ni, G. (Guiyan), Gratten, J. (Jacob), Wray, N.R. (Naomi R.), Lee, S.H. (Sang Hong), Ripke, S. (Stephan), Neale, B.M. (Benjamin), Corvin, A. (Aiden), Walters, J.T. (James), Farh, K.-H. (Kai-How), Holmans, P.A. (Peter A.), Lee, P.H. (Phil H.), Bulik-Sullivan, B.K. (Brendan), Collier, D.A. (David), Huang, H. (Hailiang), Pers, T.H. (Tune), Agartz, I. (Ingrid), Agerbo, E. (Esben), Albus, M. (Margot), Alexander, M. (Madeline), Amin, F. (Farooq), Bacanu, S.A. (Silviu), Begemann, M. (Martin), Belliveau, R.A. (Richard A.), Bene, J. (Judit), Bergen, S.E. (Sarah), Bevilacqua, E. (Elizabeth), Bigdeli, T.B. (Tim B.), Black, D.W. (Donald), Bruggeman, R. (Richard), Buccola, N.G. (Nancy G), Buckner, M., Byerley, W.F. (William F), Cahn, W. (Wiepke), Cai, G. (Guiqing), Campion, D. (Dominique), Cantor, R.M., Carr, V.J. (Vaughan J.), Carrera, N. (Noa), Catts, S.V. (Stanley), Chambert, K. (Kimberly), Chan, R.C.K. (Raymond C. K.), Chen, R.Y.L. (Ronald Y.), Chen, E.Y.H. (Eric Y. H.), Cheng, W. (Wei), Cheung, E.F.C. (Eric F. C.), Chong, S.A. (Siow Ann), Cloninger, C.R. (C Robert), Cohen, D.J. (David J.), Cohen, N. (Nadine), Cormican, P. (Paul), Craddock, N.J. (Nick), Crowley, J.J. (James), Curtis, D. (David), Davidson, M.W. (Michael ), Davis, K.L. (Kenneth), Degenhardt, F., Del-Favero, J. (Jurgen), Demontis, D. (Ditte), Dikeos, D. (Dimitris), Dinan, T. (Timothy), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drapeau, E. (Elodie), Duan, J. (Jubao), Dudbridge, F. (Frank), Durmishi, N. (Naser), Eichhammer, P. (Peter), Hagen, K. (Knut), Escott-Price, V. (Valentina), Essioux, L. (Laurent), Fanous, A.H. (Ayman H.), Farrell, M.S. (Martilias), Frank, J. (Josef), Franke, L. (Lude), Freedman, R. (Robert), Freimer, N.B. (Nelson), Friedl, M., Friedman, J.I. (Joseph), Fromer, M. (Menachem), Genovese, G. (Giulio), Georgieva, I. (Irina), Giegling, I. (Ina), Giusti-Rodríguez, P. (Paola), Godard, S. (Stephanie), Goldstein, J.I. (Jacqueline), Golimbet, V. (Vera), Gopal, R. (Robin), Haan, L. (Lieuwe) de, Hammer, C. (Christian), Hamshere, M.L. (Marian), Hansen, M. (Mark), Hansen, T. (Thomas), Haroutunian, V. (Vahram), Hartmann, A.M. (Annette M.), Henskens, F.A. (Frans), Herms, S. (Stefan), Hirschhorn, J.N. (Joel), Hoffmann, P. (Per), Hofman, A. (Andrea), Hollegaard, M.V. (Mads V), Hougaard, D.M. (David), Ikeda, M. (Masashi), Joa, I. (Inge), Juliá, A. (Antonio), Kahn, R. (René), Kalaydjieva, L. (Luba), Karachanak-Yankova, S. (Sena), Karjalainen, J. (Juha), Kavanagh, D. (David), Keller, M.C. (Matthew C), Kennedy, J.L., Khrunin, A. (Andrey), Kim, Y. (Yunjung), Klovins, J. (Janis), Knowles, J.A. (James A), Konte, B. (Bettina), Kučinskas, V. (Vaidutis), Kucinskiene, Z.A. (Zita Ausrele), Kuzelova-Ptackova, H. (Hana), Kähler, J. (Jan), Laurent, C. (Camille), Keong, J.L.C. (Jimmy Lee Chee), Legge, S.E. (Sophie), Lerer, B. (Bernard), Li, M. (Miaoxin), Li, T. (Tao), Liang, K.-Y. (Kung-Yee), Lieberman, A.P. (Andrew), Limborska, S. (Svetlana), Loughland, C.M. (Carmel), Lubinski, J. (Jan), Lönnqvist, J. (Jouko), Macek, M. (Milan MI), Magnusson, P.K. (Patrik), Maher, B.S. (Brion), Maier, W. (Wolfgang), Mallet, V. (Vincent), Marsal, S. (Sara), Mattheisen, M. (Manuel), Mattingsdal, M. (Morten), McCarley, R.W. (Robert), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Meier, S., Meijer, C. (Carin), Melegh, B. (Bela), Melle, I. (Ingrid), Mesholam-Gately, R.I. (Raquelle), Metspalu, A. (Andres), Michie, P.T. (Patricia), Milani, L. (Lili), Milanova, V. (Vihra), Mokrab, Y. (Younes), Morris, D.W. (Derek W.), Mors, O., Murphy, K.C. (Kieran), Murray, R. (Robin), Myin-Germeys, I. (Inez), Müller-Myhsok, B. (B.), Nelis, M. (Mari), Nenadic, I. (Igor), Nertney, D.A. (Deborah), Nestadt, G. (Gerald), Nicodemus, K.K. (Kristin), Nikitina-Zake, L. (Liene), Nisenbaum, L. (Laura), Nordin, A. (Annelie), O'Callaghan, E. (Eadbhard), O'Dushlaine, C. (Colm), O'neill, F.A. (F. Anthony), Oh, S.-Y. (Sang-Yun), Olincy, A. (Ann), Olsen, L. (Line), Os, J.V. (Jim Van), Pantelis, C. (Christos), Papadimitriou, G.N. (George), Papiol, S. (Sergi), Parkhomenko, E. (Elena), Pato, C. (Carlos), Paunio, T. (Tiina), Pejovic-Milovancevic, M. (Milica), Perkins, D.O. (Diana O.), Pietiläinen, O.P.H. (Olli), Pimm, J. (Jonathan), Pocklington, A.J. (Andrew), Powell, J. (John), Price, A. (Alkes), Pulver, A.E. (Ann), Purcell, S.M. (Shaun M.), Quested, D.J. (Digby J), Rasmussen, H.B. (Henrik B), Reichenberg, A. (Abraham), Reimers, B. (Bernhard), Richards, A. (Alex), Roffman, J.L. (Joshua), Roussos, A. (Alexandra), Ruderfer, D. (Douglas), Salomaa, V. (Veikko), Sanders, A.R. (Alan), Schall, J.D. (Jeffrey), Schubert, C.R. (Christian R.), Schulze, T.G. (Thomas), Schwab, S.G. (Sibylle G.), Scolnick, E. (Edward), Scott, R.J. (Rodney J.), Seidman, L.J. (Larry), Shi, J. (Jianxin), Sigurdsson, E. (Engilbert), Silagadze, T. (Teimuraz), Silverman, J.M. (Jeremy M.), Sim, K. (Kang), Slominsky, P. (Petr), Smoller, J.W., So, H.-C. (Hon-Cheong), Spencer, C.C.A. (Chris C.), Stahl, E.A. (Eli A.), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Stogmann, E. (Elisabeth), Straub, R.E. (Richard), Strengman, E. (Eric), Strohmaier, J. (Jana), Stroup, T.S. (T. Scott), Subramaniam, V. (Venkat), Suvisaari, J. (Jaana), Svrakic, D.M. (Dragan), Szatkiewicz, J.P. (Jin P.), Söderman, E. (Erik), Thirumalai, S. (Srinivasa), Toncheva, D. (Draga), Tosato, S. (Sarah), Veijola, J. (Juha), Waddington, J. (John), Walsh, D. (Dermot), Wang, D. (Dai), Wang, Q. (Qiang), Webb, B.T. (Bradley T.), Weiser, M. (Mark), Wildenauer, D.B. (Dieter), Williams, N.M. (Nigel M.), Williams, S. (Stephanie), Witt, S.H. (Stephanie H), Wolen, A.R. (Aaron), Wong, E.H.M. (Emily H.M.), Wormley, B.K. (Brandon K.), Xi, H.S. (Hualin Simon), Zai, C.C. (Clement C.), Zheng, X. (Xuebin), Zimprich, F. (Fritz), Zwart, J-A. (John-Anker), Visscher, P.M. (Peter), Adolfsson, R., Andreassen, O.A. (Ole), Blackwood, D.H.R. (Douglas), Bramon, E. (Elvira), Buxbaum, J.D. (Joseph D.), Borglum, A.D. (Anders), Cichon, S. (Sven), Darvasi, A. (Ariel), Domenici, E. (Enrico), Ehrenreich, H. (Hannelore), Esko, T. (Tõnu), Gejman, P.V. (Pablo), Gill, M. (Michael), Gurling, H. (Hugh), Hultman, C.M. (Christina), Iwata, N. (Nakao), Jablensky, A. (Assen), Jönsson, E.G. (Erik), Kendler, K. (K.), Kirov, G. (George), Knight, J. (Jo), Lencz, T. (Todd), Levinson, D.F. (Douglas F.), Li, Q.S. (Qingqin S.), Liu, J. (Jianjun), Malhotra, A.K. (Anil K), McCarroll, S.A. (Steve), McQuillin, A. (Andrew), Moran, J.L. (Jennifer L.), Mortensen, P.B., Mowry, B.J. (Bryan J), Nöthen, M.M. (Markus), Ophoff, R.A. (Roel), Owen, M.J. (Michael), Palotie, A. (Aarno), Petryshen, T.L. (Tracey L.), Posthuma, D. (Danielle), Rietschel, M. (Marcella), Riley, B.P. (Brien P.), Rujescu, D. (Dan), Sham, P.C. (Pak C.), Sklar, P. (Pamela), Clair, D.S., Weinberger, D.R. (Daniel), Wendland, A. (Annika), Werge, T.M. (Thomas), Daly, M.J. (Mark J.), Sullivan, P.F. (Patrick), O'donovan, M.C. (Michael), Ni, G. (Guiyan), Gratten, J. (Jacob), Wray, N.R. (Naomi R.), Lee, S.H. (Sang Hong), Ripke, S. (Stephan), Neale, B.M. (Benjamin), Corvin, A. (Aiden), Walters, J.T. (James), Farh, K.-H. (Kai-How), Holmans, P.A. (Peter A.), Lee, P.H. (Phil H.), Bulik-Sullivan, B.K. (Brendan), Collier, D.A. (David), Huang, H. (Hailiang), Pers, T.H. (Tune), Agartz, I. (Ingrid), Agerbo, E. (Esben), Albus, M. (Margot), Alexander, M. (Madeline), Amin, F. (Farooq), Bacanu, S.A. (Silviu), Begemann, M. (Martin), Belliveau, R.A. (Richard A.), Bene, J. (Judit), Bergen, S.E. (Sarah), Bevilacqua, E. (Elizabeth), Bigdeli, T.B. (Tim B.), Black, D.W. (Donald), Bruggeman, R. (Richard), Buccola, N.G. (Nancy G), Buckner, M., Byerley, W.F. (William F), Cahn, W. (Wiepke), Cai, G. (Guiqing), Campion, D. (Dominique), Cantor, R.M., Carr, V.J. (Vaughan J.), Carrera, N. (Noa), Catts, S.V. (Stanley), Chambert, K. (Kimberly), Chan, R.C.K. (Raymond C. K.), Chen, R.Y.L. (Ronald Y.), Chen, E.Y.H. (Eric Y. H.), Cheng, W. (Wei), Cheung, E.F.C. (Eric F. C.), Chong, S.A. (Siow Ann), Cloninger, C.R. (C Robert), Cohen, D.J. (David J.), Cohen, N. (Nadine), Cormican, P. (Paul), Craddock, N.J. (Nick), Crowley, J.J. (James), Curtis, D. (David), Davidson, M.W. (Michael ), Davis, K.L. (Kenneth), Degenhardt, F., Del-Favero, J. (Jurgen), Demontis, D. (Ditte), Dikeos, D. (Dimitris), Dinan, T. (Timothy), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drapeau, E. (Elodie), Duan, J. (Jubao), Dudbridge, F. (Frank), Durmishi, N. (Naser), Eichhammer, P. (Peter), Hagen, K. (Knut), Escott-Price, V. (Valentina), Essioux, L. (Laurent), Fanous, A.H. (Ayman H.), Farrell, M.S. (Martilias), Frank, J. (Josef), Franke, L. (Lude), Freedman, R. (Robert), Freimer, N.B. (Nelson), Friedl, M., Friedman, J.I. (Joseph), Fromer, M. (Menachem), Genovese, G. (Giulio), Georgieva, I. (Irina), Giegling, I. (Ina), Giusti-Rodríguez, P. (Paola), Godard, S. (Stephanie), Goldstein, J.I. (Jacqueline), Golimbet, V. (Vera), Gopal, R. (Robin), Haan, L. (Lieuwe) de, Hammer, C. (Christian), Hamshere, M.L. (Marian), Hansen, M. (Mark), Hansen, T. (Thomas), Haroutunian, V. (Vahram), Hartmann, A.M. (Annette M.), Henskens, F.A. (Frans), Herms, S. (Stefan), Hirschhorn, J.N. (Joel), Hoffmann, P. (Per), Hofman, A. (Andrea), Hollegaard, M.V. (Mads V), Hougaard, D.M. (David), Ikeda, M. (Masashi), Joa, I. (Inge), Juliá, A. (Antonio), Kahn, R. (René), Kalaydjieva, L. (Luba), Karachanak-Yankova, S. (Sena), Karjalainen, J. (Juha), Kavanagh, D. (David), Keller, M.C. (Matthew C), Kennedy, J.L., Khrunin, A. (Andrey), Kim, Y. (Yunjung), Klovins, J. (Janis), Knowles, J.A. (James A), Konte, B. (Bettina), Kučinskas, V. (Vaidutis), Kucinskiene, Z.A. (Zita Ausrele), Kuzelova-Ptackova, H. (Hana), Kähler, J. (Jan), Laurent, C. (Camille), Keong, J.L.C. (Jimmy Lee Chee), Legge, S.E. (Sophie), Lerer, B. (Bernard), Li, M. (Miaoxin), Li, T. (Tao), Liang, K.-Y. (Kung-Yee), Lieberman, A.P. (Andrew), Limborska, S. (Svetlana), Loughland, C.M. (Carmel), Lubinski, J. (Jan), Lönnqvist, J. (Jouko), Macek, M. (Milan MI), Magnusson, P.K. (Patrik), Maher, B.S. (Brion), Maier, W. (Wolfgang), Mallet, V. (Vincent), Marsal, S. (Sara), Mattheisen, M. (Manuel), Mattingsdal, M. (Morten), McCarley, R.W. (Robert), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Meier, S., Meijer, C. (Carin), Melegh, B. (Bela), Melle, I. (Ingrid), Mesholam-Gately, R.I. (Raquelle), Metspalu, A. (Andres), Michie, P.T. (Patricia), Milani, L. (Lili), Milanova, V. (Vihra), Mokrab, Y. (Younes), Morris, D.W. (Derek W.), Mors, O., Murphy, K.C. (Kieran), Murray, R. (Robin), Myin-Germeys, I. (Inez), Müller-Myhsok, B. (B.), Nelis, M. (Mari), Nenadic, I. (Igor), Nertney, D.A. (Deborah), Nestadt, G. (Gerald), Nicodemus, K.K. (Kristin), Nikitina-Zake, L. (Liene), Nisenbaum, L. (Laura), Nordin, A. (Annelie), O'Callaghan, E. (Eadbhard), O'Dushlaine, C. (Colm), O'neill, F.A. (F. Anthony), Oh, S.-Y. (Sang-Yun), Olincy, A. (Ann), Olsen, L. (Line), Os, J.V. (Jim Van), Pantelis, C. (Christos), Papadimitriou, G.N. (George), Papiol, S. (Sergi), Parkhomenko, E. (Elena), Pato, C. (Carlos), Paunio, T. (Tiina), Pejovic-Milovancevic, M. (Milica), Perkins, D.O. (Diana O.), Pietiläinen, O.P.H. (Olli), Pimm, J. (Jonathan), Pocklington, A.J. (Andrew), Powell, J. (John), Price, A. (Alkes), Pulver, A.E. (Ann), Purcell, S.M. (Shaun M.), Quested, D.J. (Digby J), Rasmussen, H.B. (Henrik B), Reichenberg, A. (Abraham), Reimers, B. (Bernhard), Richards, A. (Alex), Roffman, J.L. (Joshua), Roussos, A. (Alexandra), Ruderfer, D. (Douglas), Salomaa, V. (Veikko), Sanders, A.R. (Alan), Schall, J.D. (Jeffrey), Schubert, C.R. (Christian R.), Schulze, T.G. (Thomas), Schwab, S.G. (Sibylle G.), Scolnick, E. (Edward), Scott, R.J. (Rodney J.), Seidman, L.J. (Larry), Shi, J. (Jianxin), Sigurdsson, E. (Engilbert), Silagadze, T. (Teimuraz), Silverman, J.M. (Jeremy M.), Sim, K. (Kang), Slominsky, P. (Petr), Smoller, J.W., So, H.-C. (Hon-Cheong), Spencer, C.C.A. (Chris C.), Stahl, E.A. (Eli A.), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Stogmann, E. (Elisabeth), Straub, R.E. (Richard), Strengman, E. (Eric), Strohmaier, J. (Jana), Stroup, T.S. (T. Scott), Subramaniam, V. (Venkat), Suvisaari, J. (Jaana), Svrakic, D.M. (Dragan), Szatkiewicz, J.P. (Jin P.), Söderman, E. (Erik), Thirumalai, S. (Srinivasa), Toncheva, D. (Draga), Tosato, S. (Sarah), Veijola, J. (Juha), Waddington, J. (John), Walsh, D. (Dermot), Wang, D. (Dai), Wang, Q. (Qiang), Webb, B.T. (Bradley T.), Weiser, M. (Mark), Wildenauer, D.B. (Dieter), Williams, N.M. (Nigel M.), Williams, S. (Stephanie), Witt, S.H. (Stephanie H), Wolen, A.R. (Aaron), Wong, E.H.M. (Emily H.M.), Wormley, B.K. (Brandon K.), Xi, H.S. (Hualin Simon), Zai, C.C. (Clement C.), Zheng, X. (Xuebin), Zimprich, F. (Fritz), Zwart, J-A. (John-Anker), Visscher, P.M. (Peter), Adolfsson, R., Andreassen, O.A. (Ole), Blackwood, D.H.R. (Douglas), Bramon, E. (Elvira), Buxbaum, J.D. (Joseph D.), Borglum, A.D. (Anders), Cichon, S. (Sven), Darvasi, A. (Ariel), Domenici, E. (Enrico), Ehrenreich, H. (Hannelore), Esko, T. (Tõnu), Gejman, P.V. (Pablo), Gill, M. (Michael), Gurling, H. (Hugh), Hultman, C.M. (Christina), Iwata, N. (Nakao), Jablensky, A. (Assen), Jönsson, E.G. (Erik), Kendler, K. (K.), Kirov, G. (George), Knight, J. (Jo), Lencz, T. (Todd), Levinson, D.F. (Douglas F.), Li, Q.S. (Qingqin S.), Liu, J. (Jianjun), Malhotra, A.K. (Anil K), McCarroll, S.A. (Steve), McQuillin, A. (Andrew), Moran, J.L. (Jennifer L.), Mortensen, P.B., Mowry, B.J. (Bryan J), Nöthen, M.M. (Markus), Ophoff, R.A. (Roel), Owen, M.J. (Michael), Palotie, A. (Aarno), Petryshen, T.L. (Tracey L.), Posthuma, D. (Danielle), Rietschel, M. (Marcella), Riley, B.P. (Brien P.), Rujescu, D. (Dan), Sham, P.C. (Pak C.), Sklar, P. (Pamela), Clair, D.S., Weinberger, D.R. (Daniel), Wendland, A. (Annika), Werge, T.M. (Thomas), Daly, M.J. (Mark J.), Sullivan, P.F. (Patrick), and O'donovan, M.C. (Michael)

Abstract

Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia

Published
2018
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21. Age at first birth in women is genetically associated with increased risk of schizophrenia

Author

Ni, G, Gratten, J, Wray, NR, Lee, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Haan, L de, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Juliá, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kähler, AK, Laurent, C, Keong, JLC, Legge, SE, Lerer, B, Li, M, Li, T, Liang, KY, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, SY, Olincy, A, Olsen, L, van Os, JV, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietiläinen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, HC, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, Xuebin, Zimprich, F, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Børglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jönsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Nöthen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, Daniëlle, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Clair, DS, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, O'Donovan, MC, Ni, G, Gratten, J, Wray, NR, Lee, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Haan, L de, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Juliá, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kähler, AK, Laurent, C, Keong, JLC, Legge, SE, Lerer, B, Li, M, Li, T, Liang, KY, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, SY, Olincy, A, Olsen, L, van Os, JV, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietiläinen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, HC, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, Xuebin, Zimprich, F, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Børglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jönsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Nöthen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, Daniëlle, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Clair, DS, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, and O'Donovan, MC

Published
2018

22. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases

Author

Gusev, A, Lee, Sh, SWE SCZ, Consortium, O'Dushlaine, Cgusev, Trynka, G, Finucane, H, Vilhjálmsson, Bj, Xu, H, Zang, C, Ripke, S, Bulik Sullivan, B, Stahl, E, Schizophrenia, Working, Neale, Bm, Corvin, A, Walters, Jt, Farh, Kh, Holmans, Pa, Lee, P, Collier, Da, Huang, H, Pers, Th, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, Sa, Begemann, M, Belliveau, Ra, Bene, J, Bergen, Se, Bevilacqua, E, Bigdeli, Tb, Black, Dw, Børglum, Ad, Bruggeman, R, Buccola, Ng, Buckner, Rl, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, Rm, Carr, Vj, Carrera, N, Catts, Sv, Chambert, Kd, Chan, Rc, Chen, Ry, Chen, Ey, Cheng, W, Cheung, Ef, Chong, Sa, Cloninger, Cr, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, Jj, Curtis, D, Davidson, M, Davis, Kl, Degenhardt, F, Del, Favero, Delisi, Le, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott Price, V, Essioux, L, Fanous, Ah, Farrell, Ms, Frank, J, Franke, L, Freedman, R, Freimer, Nb, Friedl, M, Friedman, Ji, Fromer, M, Genovese, G, Georgieva, L, Gershon, Es, Giegling, I, Giusti Rodrguez, P, Godard, S, Goldstein, Ji, Golimbet, V, Gopal, S, Gratten, J, Grove, J, Haan, De, Hammer, C, Hamshere, Ml, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, Am, Henskens, Fa, Herms, S, Hirschhorn, Jn, Hoffmann, P, Hofman, A, Hollegaard, Mv, Hougaard, Dm, Ikeda, M, Joa, I, Julià, A, Kahn, Rs, Kalaydjieva, L, Karachanak Yankova, S, Karjalainen, J, Kavanagh, D, Keller, Mc, Kelly, Bj, Kennedy, Jl, Khrunin, A, Kim, Y, Klovins, J, Knowles, Ja, Konte, B, Kucinskas, V, Kucinskiene, Za, Kuzelova Ptackova, H, Kähler, Ak, Laurent, C, Keong, Jl, Legge, Se, Lerer, B, Li, M, Li, T, Liang, Ky, Lieberman, J, Limborska, S, Loughland, Cm, Lubinski, J, Lnnqvist, J, Macek, M, Magnusson, Pk, Maher, Bs, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, Mccarley, Rw, Mcdonald, C, Mcintosh, Am, Meier, S, Meijer, Cj, Melegh, B, Melle, I, Mesholam Gately, Ri, Metspalu, A, Michie, Pt, Milani, L, Milanova, V, Mokrab, Y, Morris, Dw, Mors, O, Mortensen, Pb, Murphy, Kc, Murray, Rm, Myin Germeys, I, Mller Myhsok, B, Nelis, M, Nenadic, I, Nertney, Da, Nestadt, G, Nicodemus, Kk, Nikitina Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, Fa, Sy, Oh, Olincy, A, Olsen, L, Van, Os, Pantelis, C, Papadimitriou, Gn, Papiol, S, Parkhomenko, E, Pato, Mt, Paunio, T, Pejovic Milovancevic, M, Perkins, Do, Pietilinen, O, Pimm, J, Pocklington, Aj, Powell, J, Price, A, Pulver, Ae, Purcell, Sm, Quested, D, Rasmussen, Hb, Reichenberg, A, Reimers, Ma, Richards, Al, Roffman, Jl, Roussos, P, Ruderfer, Dm, Salomaa, V, Sanders, Ar, Schall, U, Schubert, Cr, Schulze, Tg, Schwab, Sg, Scolnick, Em, Scott, Rj, Seidman, Lj, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, Jm, Sim, K, Slominsky, P, Smoller, Jw, Hc, So, Spencer, Cc, Stahl, Ea, Stefansson, H, Steinberg, S, Stogmann, E, Straub, Re, Strengman, E, Strohmaier, J, Stroup, Ts, Subramaniam, M, Suvisaari, J, Svrakic, Dm, Szatkiewicz, Jp, Sderman, E, Thirumalai, S, Toncheva, D, Tooney, Pa, Tosato, Sarah, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, Bt, Weiser, M, Wildenauer, Db, Williams, Nm, Williams, S, Witt, Sh, Wolen, Ar, Wong, Eh, Wormley, Bk, Jq, Wu, Hs, Xi, Zai, Cc, Zheng, X, Zimprich, F, Wray, Nr, Stefansson, K, Visscher, Pm, Adolfsson, R, Andreassen, Oa, Blackwood, Dh, Bramon, E, Buxbaum, Jd, Brglum, Ad, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, Pv, Gill, M, Gurling, H, Hultman, Cm, Iwata, N, Jablensky, Av, Jönsson, Eg, Kendler, Ks, Kirov, G, Knight, J, Lencz, T, Levinson, Df, Qs, Li, Liu, J, Malhotra, Ak, Mccarroll, Sa, Mcquillin, A, Moran, Jl, Mowry, Bj, Nthen, Mm, Ophoff, Ra, Owen, Mj, Palotie, A, Pato, Cn, Petryshen, Tl, Posthuma, D, Rietschel, M, Riley, Bp, Rujescu, D, Sham, Pc, Sklar, P, Clair, St, Weinberger, Dr, Wendland, Jr, Werge, T, Daly, Mj, Sullivan, Pf, O'Donovan, Mc, Chambert, K, Akterin, S, Bergen, S, Ruderfer, D, Scolnick, E, Purcell, S, Mccarroll, S, Daly, M, Pasaniuc, B, Raychaudhuri, S, Price, Al, Gusev, Alexander, Lee, S Hong, Trynka, Gosia, Finucane, Hilary K, Price, Alkes L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Complex Trait Genetics, Functional Genomics, and Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease

Subjects
Linkage disequilibrium, GWAS, schizophrenia, SNP, trait heritability, disease architecture, Inheritance Patterns, Single-nucleotide polymorphism, Genome-wide association study, Biology, Article, Open Reading Frames, SDG 3 - Good Health and Well-being, Genetic, Models, Genotype, Genetics, Humans, Genetics(clinical), Computer Simulation, Regulatory Elements, Transcriptional, Exome, Genetics (clinical), genotype imputation, Genetic association, Genetics & Heredity, genome-wide association study, Models, Genetic, Genetic Diseases, Inborn, Genetic Variation, Heritability, exome chips, Regulatory Elements, Inborn, Genetic Diseases, Transcriptional, coding variants, Genome-Wide Association Study
Abstract

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (h(g)(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of h(g)(2) from imputed SNPs (5.1 x enrichment; p = 3.7 x 10(-17)) and 38% (SE = 4%) of h(g)(2) from genotyped SNPs (1.6 x enrichment, p = 1.0 x 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained

Published
2014

23. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author

Marshall, C.R. (Christian), Howrigan, D.P. (Daniel P.), Merico, D. (Daniele), Thiruvahindrapuram, B. (Bhooma), Wu, W. (Wenting), Greer, D.S. (Douglas S.), Antaki, D. (Danny), Shetty, A. (Aniket), Holmans, P.A. (Peter A.), Pinto, D. (Duane), Gujral, M. (Madhusudan), Brandler, W.M. (William M.), Malhotra, D. (Dheeraj), Wang, Z. (Zhouzhi), Fuentes Fajarado, K.V. (Karin V.), Maile, M.S. (Michelle S.), Ripke, S. (Stephan), Agartz, I. (Ingrid), Albus, M. (Margot), Alexander, M. (Madeline), Amin, F. (Farooq), Atkins, J. (Joshua), Bacanu, S.A. (Silviu), Belliveau, R.A. (Richard A.), Bergen, S.E. (Sarah), Bertalan, M. (Marcelo), Bevilacqua, E. (Elizabeth), Bigdeli, T.B. (Tim B.), Black, D.W. (Donald), Bruggeman, R. (Richard), Buccola, N.G. (Nancy G), Buckner, M., Bulik-Sullivan, B.K. (Brendan), Byerley, W.F. (William F), Cahn, W. (Wiepke), Cai, G. (Guiqing), Cairns, M.J. (Murray J.), Campion, D. (Dominique), Cantor, R.M., Carr, V.J. (Vaughan), Carrera, N. (Noa), Catts, S.V. (Stanley), Chambert, K. (Kimberly), Cheng, W. (Wei), Cloninger, C.R. (C Robert), Cohen, D.J. (David J.), Cormican, P. (Paul), Craddock, N.J. (Nick), Crespo-Facorro, B. (Benedicto), Crowley, J.J. (James), Curtis, D. (David), Davidson, M.W. (Michael ), Davis, K.L. (Kenneth), Degenhardt, F., Del-Favero, J. (Jurgen), Delisi, L.E. (Lynn), Dikeos, D. (Dimitris), Dinan, T. (Timothy), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drapeau, E. (Elodie), Duan, J. (Jubao), Dudbridge, F. (Frank), Eichhammer, P. (Peter), Hagen, K. (Knut), Escott-Price, V. (Valentina), Essioux, L. (Laurent), Fanous, A.H. (Ayman H.), Farh, K.-H. (Kai-How), Farrell, M.S. (Martilias), Frank, J. (Josef), Franke, L. (Lude), Freedman, R. (Robert), Freimer, N.B. (Nelson), Friedman, J.I. (Joseph), Forstner, A.J. (Andreas), Fromer, M. (Menachem), Genovese, G. (Giulio), Georgieva, I. (Irina), Gershon, E.S. (Elliot S.), Giegling, I. (Ina), Giusti-Rodríguez, P. (Paola), Godard, S. (Stephanie), Goldstein, J.I. (Jacqueline), Gratten, J. (Jacob), Haan, L. (Lieuwe) de, Hamshere, M.L. (Marian), Hansen, M. (Mark), Hansen, T. (Thomas), Haroutunian, V. (Vahram), Hartmann, A.M. (Annette M), Henskens, F.A. (Frans), Herms, S. (Stefan), Hirschhorn, J.N. (Joel), Hoffmann, P. (Per), Hofman, A. (Andrea), Huang, H. (Hailiang), Ikeda, M. (Masashi), Joa, I. (Inge), Kähler, J. (Jan), Kahn, R. (René), Kalaydjieva, L. (Luba), Karjalainen, J. (Juha), Kavanagh, D. (David), Keller, M.C. (Matthew C), Kelly, B.J. (Brian J.), Kennedy, J.L., Kim, Y. (Yunjung), Knowles, J.A. (James A), Konte, B. (Bettina), Laurent, C. (Camille), Lee, P.H. (Phil), Lee, S.U. (Seung), Legge, S.E. (Sophie), Lerer, B. (Bernard), Levy, D.L. (Deborah L.), Liang, K.-Y. (Kung-Yee), Lieberman, A.P. (Andrew), Lönnqvist, J. (Jouko), Loughland, C.M. (Carmel), Magnusson, P.K. (Patrik), Maher, B.S. (Brion), Maier, W. (Wolfgang), Mallet, V. (Vincent), Mattheisen, M. (Manuel), Mattingsdal, M. (Morten), McCarley, R.W. (Robert), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Meier, S., Meijer, C. (Carin), Melle, I. (Ingrid), Mesholam-Gately, R.I. (Raquelle), Metspalu, A. (Andres), Michie, P.T. (Patricia), Milani, L. (Lili), Milanova, V. (Vihra), Mokrab, Y. (Younes), Morris, D.W. (Derek W), Müller-Myhsok, B. (B.), Murphy, K.C. (Kieran), Murray, R. (Robin), Myin-Germeys, I. (Inez), Nenadic, I. (Igor), Nertney, D.A. (Deborah), Nestadt, G. (Gerald), Nicodemus, K.K. (Kristin), Nisenbaum, L. (Laura), Nordin, A. (Annelie), O'Callaghan, E. (Eadbhard), O'Dushlaine, C. (Colm), Oh, S.-Y. (Sang-Yun), Olincy, A. (Ann), Olsen, L. (Line), O'Neill, F.A. (Francis), Os, J. (Jim) van, Pantelis, C. (Christos), Papadimitriou, G.N. (George), Parkhomenko, E. (Elena), Pato, C. (Carlos), Paunio, T. (Tiina), Perkins, D.O. (Diana O.), Pers, T.H. (Tune), Pietiläinen, O.P.H. (Olli), Pimm, J. (Jonathan), Pocklington, A.J. (Andrew), Powell, J. (John), Price, A. (Alkes), Pulver, A.E. (Ann), Purcell, S.M. (Shaun M.), Quested, D.J. (Digby J), Rasmussen, H.B. (Henrik B), Reichenberg, A. (Abraham), Reimers, B. (Bernhard), Richards, A. (Alex), Roffman, J.L. (Joshua), Roussos, A. (Alexandra), Ruderfer, D. (Douglas), Salomaa, V. (Veikko), Sanders, A.R. (Alan), Savitz, A. (Adam), Schall, J.D. (Jeffrey), Schulze, T.G. (Thomas), Schwab, S.G. (Sibylle G.), Scolnick, E. (Edward), Scott, R.J. (Rodney), Seidman, L.J. (Larry), Shi, J. (Jianxin), Silverman, J.M. (Jeremy M.), Smoller, J.W., Söderman, E. (Erik), Spencer, C.C.A. (Chris C.), Stahl, E.A. (Eli A.), Strengman, E. (Eric), Strohmaier, J., Stroup, T.S. (T. Scott), Suvisaari, J. (Jaana), Svrakic, D.M. (Dragan), Szatkiewicz, J.P. (Jin P.), Thirumalai, S. (Srinivasa), Tooney, P.A. (Paul A.), Veijola, J. (Juha), Visscher, P.M. (Peter), Waddington, J. (Joanne), Walsh, D. (Dermot), Webb, B.T. (Bradley T.), Weiser, M. (Mark), Wildenauer, D.B. (Dieter), Williams, N.M. (Nigel M.), Williams, S. (Stephanie), Witt, S.H. (Stephanie H), Wolen, A.R. (Aaron), Wormley, B.K. (Brandon K.), Wray, N.R. (Naomi), Wu, J.Q. (Jing Qin), Zai, C.C. (Clement), Adolfsson, R., Andreassen, O.A. (Ole A.), Blackwood, D.H.R. (Douglas), Bramon, E. (Elvira), Buxbaum, J.D. (Joseph D), Cichon, S. (Sven), Collier, D.A. (David), Corvin, A. (Aiden), Daly, M.J. (Mark J.), Darvasi, A. (Ariel), Domenici, E. (Enrico), Esko, T. (Tõnu), Gejman, P.V. (Pablo), Gill, M. (Michael), Gurling, H. (Hugh), Hultman, C.M. (Christina), Iwata, N. (Nakao), Jablensky, A. (Assen), Jönsson, E.G. (Erik), Kendler, K. (K.), Kirov, G. (George), Knight, J. (Jo), Levinson, D.F. (Douglas F.), Li, Q.S. (Qingqin S.), McCarroll, S.A. (Steve), McQuillin, A. (Andrew), Moran, J.L. (Jennifer L), Mowry, B.J. (Bryan J), Nöthen, M.M. (Markus), Ophoff, R.A. (Roel A.), Owen, M.J. (Michael), Palotie, A. (Aarno), Petryshen, T.L. (Tracey), Posthuma, D. (Danielle), Rietschel, M. (Marcella), Riley, B.P. (Brien P.), Rujescu, D. (Dan), Sklar, P. (Pamela), St Clair, D. (David), Walters, J.T. (James), Werge, T.M. (Thomas), Sullivan, P.F. (Patrick), O'donovan, M.C. (Michael), Scherer, S.W. (Stephen), Neale, B.M. (Benjamin), Sebat, J. (Jonathan), Marshall, C.R. (Christian), Howrigan, D.P. (Daniel P.), Merico, D. (Daniele), Thiruvahindrapuram, B. (Bhooma), Wu, W. (Wenting), Greer, D.S. (Douglas S.), Antaki, D. (Danny), Shetty, A. (Aniket), Holmans, P.A. (Peter A.), Pinto, D. (Duane), Gujral, M. (Madhusudan), Brandler, W.M. (William M.), Malhotra, D. (Dheeraj), Wang, Z. (Zhouzhi), Fuentes Fajarado, K.V. (Karin V.), Maile, M.S. (Michelle S.), Ripke, S. (Stephan), Agartz, I. (Ingrid), Albus, M. (Margot), Alexander, M. (Madeline), Amin, F. (Farooq), Atkins, J. (Joshua), Bacanu, S.A. (Silviu), Belliveau, R.A. (Richard A.), Bergen, S.E. (Sarah), Bertalan, M. (Marcelo), Bevilacqua, E. (Elizabeth), Bigdeli, T.B. (Tim B.), Black, D.W. (Donald), Bruggeman, R. (Richard), Buccola, N.G. (Nancy G), Buckner, M., Bulik-Sullivan, B.K. (Brendan), Byerley, W.F. (William F), Cahn, W. (Wiepke), Cai, G. (Guiqing), Cairns, M.J. (Murray J.), Campion, D. (Dominique), Cantor, R.M., Carr, V.J. (Vaughan), Carrera, N. (Noa), Catts, S.V. (Stanley), Chambert, K. (Kimberly), Cheng, W. (Wei), Cloninger, C.R. (C Robert), Cohen, D.J. (David J.), Cormican, P. (Paul), Craddock, N.J. (Nick), Crespo-Facorro, B. (Benedicto), Crowley, J.J. (James), Curtis, D. (David), Davidson, M.W. (Michael ), Davis, K.L. (Kenneth), Degenhardt, F., Del-Favero, J. (Jurgen), Delisi, L.E. (Lynn), Dikeos, D. (Dimitris), Dinan, T. (Timothy), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drapeau, E. (Elodie), Duan, J. (Jubao), Dudbridge, F. (Frank), Eichhammer, P. (Peter), Hagen, K. (Knut), Escott-Price, V. (Valentina), Essioux, L. (Laurent), Fanous, A.H. (Ayman H.), Farh, K.-H. (Kai-How), Farrell, M.S. (Martilias), Frank, J. (Josef), Franke, L. (Lude), Freedman, R. (Robert), Freimer, N.B. (Nelson), Friedman, J.I. (Joseph), Forstner, A.J. (Andreas), Fromer, M. (Menachem), Genovese, G. (Giulio), Georgieva, I. (Irina), Gershon, E.S. (Elliot S.), Giegling, I. (Ina), Giusti-Rodríguez, P. (Paola), Godard, S. (Stephanie), Goldstein, J.I. (Jacqueline), Gratten, J. (Jacob), Haan, L. (Lieuwe) de, Hamshere, M.L. (Marian), Hansen, M. (Mark), Hansen, T. (Thomas), Haroutunian, V. (Vahram), Hartmann, A.M. (Annette M), Henskens, F.A. (Frans), Herms, S. (Stefan), Hirschhorn, J.N. (Joel), Hoffmann, P. (Per), Hofman, A. (Andrea), Huang, H. (Hailiang), Ikeda, M. (Masashi), Joa, I. (Inge), Kähler, J. (Jan), Kahn, R. (René), Kalaydjieva, L. (Luba), Karjalainen, J. (Juha), Kavanagh, D. (David), Keller, M.C. (Matthew C), Kelly, B.J. (Brian J.), Kennedy, J.L., Kim, Y. (Yunjung), Knowles, J.A. (James A), Konte, B. (Bettina), Laurent, C. (Camille), Lee, P.H. (Phil), Lee, S.U. (Seung), Legge, S.E. (Sophie), Lerer, B. (Bernard), Levy, D.L. (Deborah L.), Liang, K.-Y. (Kung-Yee), Lieberman, A.P. (Andrew), Lönnqvist, J. (Jouko), Loughland, C.M. (Carmel), Magnusson, P.K. (Patrik), Maher, B.S. (Brion), Maier, W. (Wolfgang), Mallet, V. (Vincent), Mattheisen, M. (Manuel), Mattingsdal, M. (Morten), McCarley, R.W. (Robert), McDonald, C. (Colm), McIntosh, A.M. (Andrew), Meier, S., Meijer, C. (Carin), Melle, I. (Ingrid), Mesholam-Gately, R.I. (Raquelle), Metspalu, A. (Andres), Michie, P.T. (Patricia), Milani, L. (Lili), Milanova, V. (Vihra), Mokrab, Y. (Younes), Morris, D.W. (Derek W), Müller-Myhsok, B. (B.), Murphy, K.C. (Kieran), Murray, R. (Robin), Myin-Germeys, I. (Inez), Nenadic, I. (Igor), Nertney, D.A. (Deborah), Nestadt, G. (Gerald), Nicodemus, K.K. (Kristin), Nisenbaum, L. (Laura), Nordin, A. (Annelie), O'Callaghan, E. (Eadbhard), O'Dushlaine, C. (Colm), Oh, S.-Y. (Sang-Yun), Olincy, A. (Ann), Olsen, L. (Line), O'Neill, F.A. (Francis), Os, J. (Jim) van, Pantelis, C. (Christos), Papadimitriou, G.N. (George), Parkhomenko, E. (Elena), Pato, C. (Carlos), Paunio, T. (Tiina), Perkins, D.O. (Diana O.), Pers, T.H. (Tune), Pietiläinen, O.P.H. (Olli), Pimm, J. (Jonathan), Pocklington, A.J. (Andrew), Powell, J. (John), Price, A. (Alkes), Pulver, A.E. (Ann), Purcell, S.M. (Shaun M.), Quested, D.J. (Digby J), Rasmussen, H.B. (Henrik B), Reichenberg, A. (Abraham), Reimers, B. (Bernhard), Richards, A. (Alex), Roffman, J.L. (Joshua), Roussos, A. (Alexandra), Ruderfer, D. (Douglas), Salomaa, V. (Veikko), Sanders, A.R. (Alan), Savitz, A. (Adam), Schall, J.D. (Jeffrey), Schulze, T.G. (Thomas), Schwab, S.G. (Sibylle G.), Scolnick, E. (Edward), Scott, R.J. (Rodney), Seidman, L.J. (Larry), Shi, J. (Jianxin), Silverman, J.M. (Jeremy M.), Smoller, J.W., Söderman, E. (Erik), Spencer, C.C.A. (Chris C.), Stahl, E.A. (Eli A.), Strengman, E. (Eric), Strohmaier, J., Stroup, T.S. (T. Scott), Suvisaari, J. (Jaana), Svrakic, D.M. (Dragan), Szatkiewicz, J.P. (Jin P.), Thirumalai, S. (Srinivasa), Tooney, P.A. (Paul A.), Veijola, J. (Juha), Visscher, P.M. (Peter), Waddington, J. (Joanne), Walsh, D. (Dermot), Webb, B.T. (Bradley T.), Weiser, M. (Mark), Wildenauer, D.B. (Dieter), Williams, N.M. (Nigel M.), Williams, S. (Stephanie), Witt, S.H. (Stephanie H), Wolen, A.R. (Aaron), Wormley, B.K. (Brandon K.), Wray, N.R. (Naomi), Wu, J.Q. (Jing Qin), Zai, C.C. (Clement), Adolfsson, R., Andreassen, O.A. (Ole A.), Blackwood, D.H.R. (Douglas), Bramon, E. (Elvira), Buxbaum, J.D. (Joseph D), Cichon, S. (Sven), Collier, D.A. (David), Corvin, A. (Aiden), Daly, M.J. (Mark J.), Darvasi, A. (Ariel), Domenici, E. (Enrico), Esko, T. (Tõnu), Gejman, P.V. (Pablo), Gill, M. (Michael), Gurling, H. (Hugh), Hultman, C.M. (Christina), Iwata, N. (Nakao), Jablensky, A. (Assen), Jönsson, E.G. (Erik), Kendler, K. (K.), Kirov, G. (George), Knight, J. (Jo), Levinson, D.F. (Douglas F.), Li, Q.S. (Qingqin S.), McCarroll, S.A. (Steve), McQuillin, A. (Andrew), Moran, J.L. (Jennifer L), Mowry, B.J. (Bryan J), Nöthen, M.M. (Markus), Ophoff, R.A. (Roel A.), Owen, M.J. (Michael), Palotie, A. (Aarno), Petryshen, T.L. (Tracey), Posthuma, D. (Danielle), Rietschel, M. (Marcella), Riley, B.P. (Brien P.), Rujescu, D. (Dan), Sklar, P. (Pamela), St Clair, D. (David), Walters, J.T. (James), Werge, T.M. (Thomas), Sullivan, P.F. (Patrick), O'donovan, M.C. (Michael), Scherer, S.W. (Stephen), Neale, B.M. (Benjamin), and Sebat, J. (Jonathan)

Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Published
2017
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25. Biological insights from 108 schizophrenia-associated genetic loci

Author

Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, and Escott-Price, V

Abstract

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. © 2014 Macmillan Publishers Limited. All rights reserved.

Published
2014

26. Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia

Author

Costas, J, primary, Carrera, N, additional, Alonso, P, additional, Gurriarán, X, additional, Segalàs, C, additional, Real, E, additional, López-Solà, C, additional, Mas, S, additional, Gassó, P, additional, Domènech, L, additional, Morell, M, additional, Quintela, I, additional, Lázaro, L, additional, Menchón, J M, additional, Estivill, X, additional, and Carracedo, Á, additional

Published
2016
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28. Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Rees, E., Kirov, G., Walters, J. T., Richards, A. L., Howrigan, D., Kavanagh, D. H., Pocklington, A. J., Fromer, M., Ruderfer, D. M., Georgieva, L., Carrera, N., Gormley, P., Palta, P., Williams, H., Dwyer, S., Johnson, J. S., Roussos, P., Barker, D. D., Banks, E., Milanova, V., Rose, S. A., Chambert, K., Mahajan, M., Scolnick, E. M., Moran, J. L., Tsuang, M. T., Glatt, S. J., Chen, W. J., Hwu, H-G, Neale, B. M., Palotie, A., Sklar, P., Purcell, S. M., McCarroll, S. A., Holmans, P., Owen, M. J., O'Donovan, M. C., Taiwanese Trios Exome Sequencing C, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Rees, E., Kirov, G., Walters, J. T., Richards, A. L., Howrigan, D., Kavanagh, D. H., Pocklington, A. J., Fromer, M., Ruderfer, D. M., Georgieva, L., Carrera, N., Gormley, P., Palta, P., Williams, H., Dwyer, S., Johnson, J. S., Roussos, P., Barker, D. D., Banks, E., Milanova, V., Rose, S. A., Chambert, K., Mahajan, M., Scolnick, E. M., Moran, J. L., Tsuang, M. T., Glatt, S. J., Chen, W. J., Hwu, H-G, Neale, B. M., Palotie, A., Sklar, P., Purcell, S. M., McCarroll, S. A., Holmans, P., Owen, M. J., O'Donovan, M. C., and Taiwanese Trios Exome Sequencing C

Abstract

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF

Published
2015

29. [Hypertrophic pyloric stenosis: comparison between transversal and supraumbilical incision]

Author

Carrera N, Ja, Cerdá, Cañizo A, Parente A, Laín A, Fanjul M, Corona C, Molina E, de Tomás E, and Vázquez J

Subjects
Male, Infant, Newborn, Humans, Infant, Female, Pyloric Stenosis, Hypertrophic, Digestive System Surgical Procedures, Retrospective Studies
Abstract

The treatment of hypertrophic pyloric stenosis is the Fredet-Ramstedt pyloromyotomy. It is controversial what surgical approach to choose. We evaluate our outcome with the right upper quadrant (RUQ) and the supraumbilical (SU) approach.Between 2003 and 2007, we performed 38 pyloromyotomies through a RUQ incision and 18 through a SU approach. We analyze patient demographics and pre and postoperative data. We group the complications in major (duodenal perforation, inadequate pyloromyotomy, and wound dehiscence) and minor (seroma, hematoma, wound infection and incisional hernia). A nonrandomized comparison was performed between the two groups.We find significant differences in morbidity: 22.2% of major complications ocurred in the SU group versus 2.6% in the RUQ group, and 44.4% of minor complications were encountered in the SU group versus 2.6% in the RUQ group (P0.005).In our study we found a significantly higher overall complication rate in the SU group (p0.005), possibly because of a more difficult delivery of the pylorus through the SU incision and because of a probably increased rate of wound infection associated with the supraumbilical approach in the pediatric population.

Published
2011

31. [Long-term results of patients with congenital diaphragmatic hernia]

Author

Menéndez C, Fariñas M, Parente A, Laín A, Fanjul M, Chimenti P, Carrera N, Huerga A, Corona C, Marsinyach I, Cañizo A, Villar S, Sánchez-Luna M, and Vázquez J

Subjects
Hernia, Diaphragmatic, Cross-Sectional Studies, Time Factors, Infant, Newborn, Humans, Hernias, Diaphragmatic, Congenital
Abstract

Introduction of advanced therapeutic modalities for diaphragmatic congenital hernia (CDH) has allowed to reach considerable improvements in survival rate. Nevertheless, there are few studies which analyze the clinical evolution of the long-term survivors. The aim of this work is to analyze the outcomes of the patients with CDH in our hospital.Fifty-five neonates with CDH were treated in our center between 1998 and 2005. We included in the study those patients that were alive at the moment of first hospital discharge (72%; n=40 patients). ECMO therapy was needed in 6 of them during neonatal treatment. A descriptive transverse review of the clinical record as well as a telephonic interview to the parents was performed for the respiratory, cardiological, digestive and neurological conditions, following standard diagnostic studies in every case. The mean age of the children in the moment of the study was 4.2 years (1-9).The 8.3% of the children needed domiciliary oxygen therapy during a maximum of 3 months in all the cases. 22% of the cases suffered from respiratory problems, being bronchiolitis and pneumonia the most frequent diagnoses. Only a patient developed asthma. The gastroesophageal reflux is the most frequent long-term condition (47%), but only 8.3% needs surgical treatment. Regarding to cardiological problems, 14% developed pulmonary hypertension, being slight - moderate in all the cases but in one case who was the only deceased of the series. Regarding to neurological problems only 1 patient developed serious alterations (brain paralysis), having suffered a hemorrhage parenquimatosa during the treatment with ECMO. No other patient presents motor, visual nor auditory alterations in the development, last mild alteration in language (4 patients). Differences do not exist with the group of patients that did not need ECMO during the treatment in cardiological and digestive complications, being higher percentage with respiratory problems.In our sample only 2 patients present serious sequels (5%). Of this preliminary study we can conclude that the comorbility in the CDH is very low having these patient a good development and good quality of life.

Published
2010

32. [Is it correct to use neonatal intensive care units as operating rooms?]

Author

Parente A, Cañizo A, Huerga A, Laín A, Fanjul M, Carrera N, Corona C, Fariñas M, Menéndez C, Cerdá J, Molina E, and Vázquez J

Subjects
Male, Intensive Care Units, Operating Rooms, Infant, Newborn, Humans, Female
Abstract

The neonatal intensive care unit (NICU) is used in many centres as operating room in order to avoid the co-morbidities that there produces the movement of critical patients. The motive of this work is to analyze the advantages and disadvantages of this type of surgical interventions.Between January, 2004 and December, 2007 405 newborns were operated in the NICU. The most frequent surgical realized interventions were: deferred closing breastbone (172), placement of ECMO (42), ligation of patent ductus arteriosus (45), laparotomies for necrotising enterocolitis (27), repair of congenital diaphragmatic hernia (20), plicate of diaphragms (5) and closing of gastroschisis (4). We realize a retrospective study of a group of 40 patients operated by diaphragmatic hernia and necrotising enterocolitis in the UCIN (group A) and compare them with a group of patients operated in the operating room with the same pathology (group B). We study 22 variables preoperatory, intraoperatory and postoperatory. For the statistical analysis T-student and Chi-square was in use, being considered to be statistically significant p0.05.The average ages of the patients to the intervention were 11.1 +/- 8 days being the predominant sex the masculine one (60 %). The age gestational and the average weight for the group A was 31.9 +/- 5.7 weeks and 1,735 +/- 123 grams being for the group B of 34 +/- 3.5 weeks and 2,037 +/- 728 grams respectively (p = N.S.). 89.3% of the patients of the group A was with intubation orotracheal before the surgery, being 57.2% for the group B. The needs of high frequency ventilation and vasoactives drugs were higher for the group A (p0.01) and the operative time was similar in both groups (81 +/- 34 vs. 98 +/- 33 minutes). We find a difference of corporal temperature pre-post surgery of 0.60 +/- 0.48 degrees C for the group A and 2.18 +/- 0.93 degrees C in the B (p0.01). We don't estimate differences as for episodes of infection of wound, intraabdominal infection or need of reintervention. The survival of the patients was discreetly higher for the group operated in the operating room (82.3%) with regard to the group operated in the NICU (60%) without statistically significant differences existed.In our experience the NICU is a suitable place to realize surgical interventions in critical patients. The higher mortality for the group controlled in the UCIN explains for a major instability preoperatory. The maintenance of the corporal temperature avoiding the hypothermia it's one of the decisive factors to diminish the morbi-mortality.

Published
2009

33. [Characteristics of the anorectal atresia without fistula. Based on 12 cases]

Author

Fanjul M, Molina E, Cerdá J, Parente A, Laín A, Cañizo A, and Carrera N

Subjects
Anus, Imperforate, Male, Humans, Infant
Abstract

Imperforate anus without fistula is an uncommon anorectal malformation, in association to Down syndrome in 50% of cases. This anomaly is described as a lack of annus, with a blind rectal pouch, located about 2 cm above perineal skin, and sharing a common wall with the urethra or vagina. The aim of this work is to present our experience in this condition and to determine the differences between the diagnosis, treatment and long-term outcome of these patients in relation to other forms of anorectal malformation.We reviewed the medical records of 12 patients treated in our department from 1998 to 2008. Eight were boys and 4 girls. Eleven of these patients had significant associated congenital diseases: Down syndrome (6), cardiovascular anomalies (6), urinary tract malformations (5), esophageal atresia (1). In all cases neonatal colostomy was performed, being 7 months (range between 1 and 19 months) the average age of the definitive surgery through posterior sagital approach. In one case a laparotomy was performed. The distance from the rectal pouch to the skin ranged from 1 to 5 cm, founding a very dilatated rectum in 4 patients.The postoperative outcome was favorable. Four patients required removal of a small anal prolapse. All patients older than 2 years (7) have urinary continence, while 5 of them have a significant constipation, resistant to treatment with diet and laxatives, requiring medical management with enemas.Our study confirms the high incidence of Down syndrome in patients with imperforate anus without fistula, and shows a higher incidence of other congenital comobidities. A colostrogram prior to definitive repair seems to be mandatory taking into account the intraopetative findings (height and diameter of rectal pouch). The incidence of anal prolapse is very high and may be related to the hypotonia present in patients with Down syndrome. Since the constipation is very severe in these patients, it should be controlled early in the follow up.

Published
2009

34. [Is immediate prophylactic thyroidectomy indispensable in familiar medullary thyroid carcinoma?]

Author

Cañizo A, Fanjul M, Cerdá J, Menárguez J, Parente A, Laín A, Carrera N, Md, Rodríguez-Arnao, Rodríguez-Sánchez A, Jr, Polo, and Vázquez J

Subjects
Adult, Adolescent, Carcinoma, Medullary, Thyroidectomy, Humans, Thyroid Neoplasms, Child, Retrospective Studies
Abstract

To emphasize the importance of genetic studies in family members and early prophylactic thyroidectomy in oncogene mutation carriers in the management of familiar medullary thyroid carcinoma.A retrospective review of families with familiar medullary thyroid carcinoma treated at our center in the last 7 years was performed. We identified a total of 7 families who has isolated prevalences with thyroid malignancies. Forty members of the 7 families were screened for gene RET mutations. Prophylactic total thyroidectomy was performed in every RET mutation gene carriers.In all families the index case were patients with medullary thyroid carcinoma presenting at a mean age of 37.25 years (range 23-42). The RET oncogen mutation was in codon 634 in exon 11 (multiple endocrine neoplasia type 2A) in all these patients. Fourteen gene carriers were identified with a mean age of 20 years (range 7-37), eleven of whom had medullary thyroid carcinoma at the time of surgery. Five of the gene carriers were children, with a mean age of 11 years (range 7-16), four of whom had microcarcinoma and one had metastatic carcinoma at the time of surgery. After surgery no hypoparathyroidism or recurrent nerve paralysis were documented. No pediatric patient has presented with phaeochromocytoma or hypoparathyroidism to date Four of the five children have normal calcitonin levels (2 pg/ml) and they are free of disease. The one who presented metastatic carcinoma has recurrent disease and is awaiting surgical treatment.Genetic studies of family members related to patients with familiar medullary thyroid carcinoma and RET mutations is indispensable. The RET mutation in codon 634 exon 11 was found to be the most frequent association. Prophylactic thyroidectomy is the only curative treatment and has minimal complications when performed by expert surgeons. Early thyroidectomy is recommended since distant metastatic spread can occur at early age.

Published
2008

37. Geoposition: a tool used to analyze and diagnose contaminated sites in the province of Jujuy, Argentina

Author

Ruggeri, M. A., Zubia, G. F., Romero, A. E., Avila Carrera, N. M. E., Tschambler, J. A., Bovi Mitre, M. G., Ruggeri, M. A., Zubia, G. F., Romero, A. E., Avila Carrera, N. M. E., Tschambler, J. A., and Bovi Mitre, M. G.

Abstract

Georeferenced analysis has been imposed in recent years in scientific research as an essential element of the Integrated Risk evaluations, mainly due to the availability of software for data processing and Geographic Information Systems (GIS). Two works the investigations in two different locations in the province of Jujuy, Argentina were georeferenced which allowed classification as contaminated sites.The first element chemistry geoposition analysis was the arsenic. This will quantify their presence in natural waters from different watersheds in the province of Jujuy. The result of this early research was the identification of high levels of total As in surface water and groundwater in certain areas of the province. The second element was the geo-lead, within the framework of a comprehensive assessment in the town of Abra Pampa, Jujuy, instead of settling for a lead smelter. This study quantified the presence of Pb in blood of children inhabitants of the place.As step integral of two investigations was geoposition of the toxic in both matrices. Are georeferenced in the first investigation a total of 225 sampling points for water 3 watersheds that traverse the province, and in the second investigation, 233 of lead levels among children living in the vicinity of the smelter.As end results of this processing of data yielded two thematic maps have allowed a global-spatial perception on the various situations addressed. In each was viewed, among others, the change of the content of toxic respect to the distance from the area pollutants.Geologically determined the area contaminated by As in Jujuy corresponding mainly to the west of the province. Using this map, the analysis was repeated 20 years after confirming with better technology, water contaminated with this highly toxic; confirmed the change of water to populations that were exposed; were confirmed contaminated drinking water in populations that maintain the same source of supply despite the warning in 1987.In geo, El análisis georreferencial se ha impuesto en los últimos años en la investigación científica como un elemento esencial de las Evaluaciones Integrales sobre el Riesgo, sobre todo debido a la disponibilidad de software de procesamiento de datos y Sistemas de Información Geográfica (GIS). Dos trabajos de investigación realizados en dos localidades distintas de la provincia de Jujuy, Argentina fueron georreferenciados lo que permitió su reconocimiento y tipificación como sitios contaminados.El primer elemento químico analizado georreferencialmente fue el arsénico (As). Para ello se cuantificó su presencia natural en aguas de distintas cuencas acuíferas de la provincia de Jujuy. El resultado de esta primera investigación fue la identificación de elevados niveles de arsénico total en aguas superficiales y subterráneas de determinadas cuencas de la provincia.El segundo elemento georreferenciado fue el plomo, en el marco de una Evaluación Integral en la localidad de Abra Pampa, Jujuy, lugar de asentamiento de una fundición de plomo. En esta investigación se cuantificó la presencia de Pb en sangre de niños pobladores del lugar.Como etapa integral de ambas investigaciones se realizó el georreferenciamiento de cada uno de los tóxicos en ambas matrices. Se georreferenció, en la primera investigación un total de 225 puntos de muestreo de agua de 3 cuencas hídricas que recorren el territorio provincial y, en la segunda investigación, 233 plumbemias de una población infantil que habita en las cercanías de la fundición.Como resultado final de este procesamiento de datos se obtuvieron dos mapas temáticos que permitieron tener una percepción globalespacial sobre las distintas situaciones abordadas. En cada uno se pudo visualizar, entre otros, la variación del contenido del tóxico respecto a la distancia de las zonas contaminantes.Se determinó la zona geológicamente contaminada por As en Jujuy correspondiendo principalmente al Oeste de la provincia. Utilizando este mapa se repitieron

Published
2009

41. [Corticobasal ganglionic degeneration: a report of 7 clinically diagnosed cases]

Author

Jf, Martí Massó, López de Munain A, Jj, Poza, Urtasun M, and Carrera N

Subjects
Antiparkinson Agents, Male, Radiography, Basal Ganglia Diseases, Nerve Degeneration, Humans, Female, Middle Aged, Magnetic Resonance Imaging, Basal Ganglia, Functional Laterality, Aged
Abstract

We report the clinical characteristics of 7 patients (5 women) from 61 through 84 years of age who were diagnosed within the last 3 years as having corticobasal ganglionic degeneration. The disease begin clinically in all patients with on asymmetric motor syndrome. Four experienced tremulousness and myoclonus in one hand, with apraxia and cortical sensory symptoms, astereognosia and sensory extinction. In 3 others, the progressive motor symptoms was mainly a pyramidal syndrome. Hand apraxia caused severe disability in the affected member and was disproportionate to the degree of motor symptoms suffered by the patient. In 3 patients with right side involvement, language-related difficulties were present; in 2 patients with aphasia, difficulties of articulation were partly caused by bucorespiratory apraxia. We believe that this disease, which is more common than believed, has a highly characteristic clinical profile that often allows its clinical diagnosis.

Published
1994

44. Vapor pressures of ruthenium and osmium

Author

Carrera, N. J, Plante, E. R, and Walker, R. F

Subjects
Communications
Abstract

Measurement of vapor pressure and heat of sublimation of ruthenium and osmium using microbalance technique

Published
1964

49. Letters to the editor

Author

Martí Massó, J. F., primary, Carrera, N., additional, Urtasun, M., additional, and Martínez-Martín, P., additional

Published
1993
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50. Structure and thrusting evolution of the southern Cordillera Oriental (N Argentine Andes).

Author

Carrera, N. and Muñoz, J. A.

Subjects
*STRUCTURAL geology, *GEOMETRIC analysis, *INVERSIONS (Geometry), *CARTOGRAPHY, *DEFORMATION of surfaces
Abstract

Detailed mapping of several areas of the southern Cordillera Oriental revealed an important role of the inversion tectonics for the structural evolution of this part of the Andes. The inversion is only moderate but the compressional Andean structures are strongly controlled by the geometry and the location of previous cretaceous extensional structures. The study of growth strata and unconformities in the Cenozoic synorogenic sediments provides evidence for the eastward migration of the Andean deformation from the Puna to the Santa Bárbara System independently of the vergence of the structures. [ABSTRACT FROM AUTHOR]

Published
2009

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