Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway

Kristin K. Nicodemus, April Hargreaves, Derek Morris, Richard Anney, Michael Gill, Aiden Corvin, Gary Donohoe, S. Ripke, A. R. Sanders, K. S. Kendler, D. F. Levinson, P. Sklar, P. A. Holmans, D. Y. Lin, J. Duan, R. A. Ophoff, O. A. Andreassen, E. Scolnick, S. Cichon, D. St ClairH. Gurling, T. Werge, D. Rujescu, D. H. Blackwood, C. N. Pato, A. K. Malhotra, S. Purcell, F. Dudbridge, B. M. Neale, L. Rossin, P. M. Visscher, D. Posthuma, D. M. Ruderfer, A. Fanous, H. Stefansson, S. Steinberg, B. J. Mowry, V. Golimbet, M. De Hert, E. G. Jönsson, I. Bitter, O. P. Pietiläinen, D. A. Collier, S. Tosato, I. Agartz, M. Albus, M. Alexander, R. L. Amdur, F. Amin, N. Bass, S. E. Bergen, D. W. Black, A. D. Børglum, M. A. Brown, R. Bruggeman, N. G. Buccola, W. F. Byerley, W. Cahn, R. M. Cantor, V. J. Carr, S. V. Catts, K. Choudhury, C. Cloninger, P. Cormican, N. Craddock, P. A. Danoy, S. Datta, L. de Haan, D. Demontis, D. Dikeos, S. Djurovic, P. Donnelly, L. Duong, S. Dwyer, A. Fink-Jensen, R. Freedman, N. B. Freimer, M. Friedl, L. Georgieva, I. Giegling, B. Glenthøj, S. Godard, M. Hamshere, M. Hansen, T. Hansen, A. M. Hartmann, F. A. Henskens, D. M. Hougaard, C. M. Hultman, A. Ingason, A. V. Jablensky, K. D. Jakobsen, M. Jay, G. Jürgens, R. S. Kahn, M. C. Keller, G. Kenis, E. Kenny, Y. Kim, G. K. Kirov, H. Konnerth, B. Konte, L. Krabbendam, R. Krasucki, V. K. Lasseter, C. Laurent, J. Lawrence, T. Lencz, F. Lerer, K. Y. Liang, P. Lichtenstein, J. A. Lieberman, D. H. Linszen, J. Lönnqvist, C. M. Loughland, A. W. Maclean, Brion Maher, W. Maier, J. Mallet, P. Malloy, M. Mattheisen, M. Mattingsdal, K. A. McGhee, J. J. McGrath, A. McIntosh, D. E. McLean, A. McQuillin, I. Melle, P. T. Michie, V. Milanova, O. Mors, P. B. Mortensen, V. Moskvina, P. Muglia, I. Myin-Germeys, D. A. Nertney, Gerald Nestadt, J. Nielsen, I. Nikolov, M. Nordentoft, N. Norton, M. M. Nöthen, C. T. O'Dushlaine, A. Olincy, L. Olsen, F. O'Neill, T. F. Ørntoft, M. J. Owen, C. Pantelis, G. Papadimitriou, M. T. Pato, L. Peltonen, H. Petursson, B. Pickard, J. Pimm, Ann E Pulver, V. Puri, D. Quested, E. M. Quinn, H. B. Rasmussen, J. M. Réthelyi, R. Ribble, M. Rietschel, B. P. Riley, M. Ruggeri, U. Schall, T. G. Schulze, S. G. Schwab, R. J. Scott, J. Shi, E. Sigurdsson, J. M. Silverman, C. C. Spencer, K. Stefansson, A. Strange, E. Strengman, T. Stroup, J. Suvisaari, L. Terenius, S. Thirumalai, J. H. Thygesen, S. Timm, D. Toncheva, E. van den Oord, J. van Os, R. van Winkel, J. Veldink, D. Walsh, A. G. Wang, D. Wiersma, D. B. Wildenauer, H. J. Williams, N. M. Williams, B. Wormley, S. Zammit, P. F. Sullivan, M. C. O'Donovan, M. J. Daly, P. Gejman, I. Barroso, J. M. Blackwell, E. Bramon, J. P. Casas, P. Deloukas, A. Duncanson, J. Jankowski, H. S. Markus, C. G. Mathew, C. N. Palmer, R. Plomin, A. Rautanen, S. J. Sawcer, R. C. Trembath, A. C. Viswanathan, N. W. Wood, G. Band, C. Bellenguez, C. Freeman, G. Hellenthal, E. Giannoulatou, M. Pirinen, R. Pearson, Z. Su, D. Vukcevic, C. Langford, S. E. Hunt, S. Edkins, R. Gwilliam, H. Blackburn, S. J. Bumpstead, S. Dronov, M. Gillman, E. Gray, N. Hammond, A. Jayakumar, O. T. McCann, J. Liddle, S. C. Potter, R. Ravindrarajah, M. Ricketts, M. Waller, P. Weston, S. Widaa, P. Whittaker

Research output: Contribution to journalArticle

Abstract

IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.

Original languageEnglish (US)
Pages (from-to)778-785
Number of pages8
JournalJAMA Psychiatry
Volume71
Issue number7
DOIs
StatePublished - Jul 1 2014
Externally publishedYes

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Psychotic Disorders
Cognition
Schizophrenia
Single Nucleotide Polymorphism
Genome-Wide Association Study
Short-Term Memory
Linear Models
Aptitude
Episodic Memory
Major Depressive Disorder
Bipolar Disorder
Psychiatry
Alleles
Phenotype

ASJC Scopus subject areas

  • Psychiatry and Mental health

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Nicodemus, K. K., Hargreaves, A., Morris, D., Anney, R., Gill, M., Corvin, A., ... Whittaker, P. (2014). Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway. JAMA Psychiatry, 71(7), 778-785. https://doi.org/10.1001/jamapsychiatry.2014.528

Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway. / Nicodemus, Kristin K.; Hargreaves, April; Morris, Derek; Anney, Richard; Gill, Michael; Corvin, Aiden; Donohoe, Gary; Ripke, S.; Sanders, A. R.; Kendler, K. S.; Levinson, D. F.; Sklar, P.; Holmans, P. A.; Lin, D. Y.; Duan, J.; Ophoff, R. A.; Andreassen, O. A.; Scolnick, E.; Cichon, S.; St Clair, D.; Gurling, H.; Werge, T.; Rujescu, D.; Blackwood, D. H.; Pato, C. N.; Malhotra, A. K.; Purcell, S.; Dudbridge, F.; Neale, B. M.; Rossin, L.; Visscher, P. M.; Posthuma, D.; Ruderfer, D. M.; Fanous, A.; Stefansson, H.; Steinberg, S.; Mowry, B. J.; Golimbet, V.; De Hert, M.; Jönsson, E. G.; Bitter, I.; Pietiläinen, O. P.; Collier, D. A.; Tosato, S.; Agartz, I.; Albus, M.; Alexander, M.; Amdur, R. L.; Amin, F.; Bass, N.; Bergen, S. E.; Black, D. W.; Børglum, A. D.; Brown, M. A.; Bruggeman, R.; Buccola, N. G.; Byerley, W. F.; Cahn, W.; Cantor, R. M.; Carr, V. J.; Catts, S. V.; Choudhury, K.; Cloninger, C.; Cormican, P.; Craddock, N.; Danoy, P. A.; Datta, S.; de Haan, L.; Demontis, D.; Dikeos, D.; Djurovic, S.; Donnelly, P.; Duong, L.; Dwyer, S.; Fink-Jensen, A.; Freedman, R.; Freimer, N. B.; Friedl, M.; Georgieva, L.; Giegling, I.; Glenthøj, B.; Godard, S.; Hamshere, M.; Hansen, M.; Hansen, T.; Hartmann, A. M.; Henskens, F. A.; Hougaard, D. M.; Hultman, C. M.; Ingason, A.; Jablensky, A. V.; Jakobsen, K. D.; Jay, M.; Jürgens, G.; Kahn, R. S.; Keller, M. C.; Kenis, G.; Kenny, E.; Kim, Y.; Kirov, G. K.; Konnerth, H.; Konte, B.; Krabbendam, L.; Krasucki, R.; Lasseter, V. K.; Laurent, C.; Lawrence, J.; Lencz, T.; Lerer, F.; Liang, K. Y.; Lichtenstein, P.; Lieberman, J. A.; Linszen, D. H.; Lönnqvist, J.; Loughland, C. M.; Maclean, A. W.; Maher, Brion; Maier, W.; Mallet, J.; Malloy, P.; Mattheisen, M.; Mattingsdal, M.; McGhee, K. A.; McGrath, J. J.; McIntosh, A.; McLean, D. E.; McQuillin, A.; Melle, I.; Michie, P. T.; Milanova, V.; Mors, O.; Mortensen, P. B.; Moskvina, V.; Muglia, P.; Myin-Germeys, I.; Nertney, D. A.; Nestadt, Gerald; Nielsen, J.; Nikolov, I.; Nordentoft, M.; Norton, N.; Nöthen, M. M.; O'Dushlaine, C. T.; Olincy, A.; Olsen, L.; O'Neill, F.; Ørntoft, T. F.; Owen, M. J.; Pantelis, C.; Papadimitriou, G.; Pato, M. T.; Peltonen, L.; Petursson, H.; Pickard, B.; Pimm, J.; Pulver, Ann E; Puri, V.; Quested, D.; Quinn, E. M.; Rasmussen, H. B.; Réthelyi, J. M.; Ribble, R.; Rietschel, M.; Riley, B. P.; Ruggeri, M.; Schall, U.; Schulze, T. G.; Schwab, S. G.; Scott, R. J.; Shi, J.; Sigurdsson, E.; Silverman, J. M.; Spencer, C. C.; Stefansson, K.; Strange, A.; Strengman, E.; Stroup, T.; Suvisaari, J.; Terenius, L.; Thirumalai, S.; Thygesen, J. H.; Timm, S.; Toncheva, D.; van den Oord, E.; van Os, J.; van Winkel, R.; Veldink, J.; Walsh, D.; Wang, A. G.; Wiersma, D.; Wildenauer, D. B.; Williams, H. J.; Williams, N. M.; Wormley, B.; Zammit, S.; Sullivan, P. F.; O'Donovan, M. C.; Daly, M. J.; Gejman, P.; Barroso, I.; Blackwell, J. M.; Bramon, E.; Casas, J. P.; Deloukas, P.; Duncanson, A.; Jankowski, J.; Markus, H. S.; Mathew, C. G.; Palmer, C. N.; Plomin, R.; Rautanen, A.; Sawcer, S. J.; Trembath, R. C.; Viswanathan, A. C.; Wood, N. W.; Band, G.; Bellenguez, C.; Freeman, C.; Hellenthal, G.; Giannoulatou, E.; Pirinen, M.; Pearson, R.; Su, Z.; Vukcevic, D.; Langford, C.; Hunt, S. E.; Edkins, S.; Gwilliam, R.; Blackburn, H.; Bumpstead, S. J.; Dronov, S.; Gillman, M.; Gray, E.; Hammond, N.; Jayakumar, A.; McCann, O. T.; Liddle, J.; Potter, S. C.; Ravindrarajah, R.; Ricketts, M.; Waller, M.; Weston, P.; Widaa, S.; Whittaker, P.

In: JAMA Psychiatry, Vol. 71, No. 7, 01.07.2014, p. 778-785.

Research output: Contribution to journalArticle

Nicodemus, KK, Hargreaves, A, Morris, D, Anney, R, Gill, M, Corvin, A, Donohoe, G, Ripke, S, Sanders, AR, Kendler, KS, Levinson, DF, Sklar, P, Holmans, PA, Lin, DY, Duan, J, Ophoff, RA, Andreassen, OA, Scolnick, E, Cichon, S, St Clair, D, Gurling, H, Werge, T, Rujescu, D, Blackwood, DH, Pato, CN, Malhotra, AK, Purcell, S, Dudbridge, F, Neale, BM, Rossin, L, Visscher, PM, Posthuma, D, Ruderfer, DM, Fanous, A, Stefansson, H, Steinberg, S, Mowry, BJ, Golimbet, V, De Hert, M, Jönsson, EG, Bitter, I, Pietiläinen, OP, Collier, DA, Tosato, S, Agartz, I, Albus, M, Alexander, M, Amdur, RL, Amin, F, Bass, N, Bergen, SE, Black, DW, Børglum, AD, Brown, MA, Bruggeman, R, Buccola, NG, Byerley, WF, Cahn, W, Cantor, RM, Carr, VJ, Catts, SV, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, PA, Datta, S, de Haan, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Duong, L, Dwyer, S, Fink-Jensen, A, Freedman, R, Freimer, NB, Friedl, M, Georgieva, L, Giegling, I, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, AM, Henskens, FA, Hougaard, DM, Hultman, CM, Ingason, A, Jablensky, AV, Jakobsen, KD, Jay, M, Jürgens, G, Kahn, RS, Keller, MC, Kenis, G, Kenny, E, Kim, Y, Kirov, GK, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, VK, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, KY, Lichtenstein, P, Lieberman, JA, Linszen, DH, Lönnqvist, J, Loughland, CM, Maclean, AW, Maher, B, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, McGhee, KA, McGrath, JJ, McIntosh, A, McLean, DE, McQuillin, A, Melle, I, Michie, PT, Milanova, V, Mors, O, Mortensen, PB, Moskvina, V, Muglia, P, Myin-Germeys, I, Nertney, DA, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nöthen, MM, O'Dushlaine, CT, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, TF, Owen, MJ, Pantelis, C, Papadimitriou, G, Pato, MT, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, AE, Puri, V, Quested, D, Quinn, EM, Rasmussen, HB, Réthelyi, JM, Ribble, R, Rietschel, M, Riley, BP, Ruggeri, M, Schall, U, Schulze, TG, Schwab, SG, Scott, RJ, Shi, J, Sigurdsson, E, Silverman, JM, Spencer, CC, Stefansson, K, Strange, A, Strengman, E, Stroup, T, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, JH, Timm, S, Toncheva, D, van den Oord, E, van Os, J, van Winkel, R, Veldink, J, Walsh, D, Wang, AG, Wiersma, D, Wildenauer, DB, Williams, HJ, Williams, NM, Wormley, B, Zammit, S, Sullivan, PF, O'Donovan, MC, Daly, MJ, Gejman, P, Barroso, I, Blackwell, JM, Bramon, E, Casas, JP, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CN, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, 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 2014, 'Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway', JAMA Psychiatry, vol. 71, no. 7, pp. 778-785. https://doi.org/10.1001/jamapsychiatry.2014.528
Nicodemus, Kristin K. ; Hargreaves, April ; Morris, Derek ; Anney, Richard ; Gill, Michael ; Corvin, Aiden ; Donohoe, Gary ; Ripke, S. ; Sanders, A. R. ; Kendler, K. S. ; Levinson, D. F. ; Sklar, P. ; Holmans, P. A. ; Lin, D. Y. ; Duan, J. ; Ophoff, R. A. ; Andreassen, O. A. ; Scolnick, E. ; Cichon, S. ; St Clair, D. ; Gurling, H. ; Werge, T. ; Rujescu, D. ; Blackwood, D. H. ; Pato, C. N. ; Malhotra, A. K. ; Purcell, S. ; Dudbridge, F. ; Neale, B. M. ; Rossin, L. ; Visscher, P. M. ; Posthuma, D. ; Ruderfer, D. M. ; Fanous, A. ; Stefansson, H. ; Steinberg, S. ; Mowry, B. J. ; Golimbet, V. ; De Hert, M. ; Jönsson, E. G. ; Bitter, I. ; Pietiläinen, O. P. ; Collier, D. A. ; Tosato, S. ; Agartz, I. ; Albus, M. ; Alexander, M. ; Amdur, R. L. ; Amin, F. ; Bass, N. ; Bergen, S. E. ; Black, D. W. ; Børglum, A. D. ; Brown, M. A. ; Bruggeman, R. ; Buccola, N. G. ; Byerley, W. F. ; Cahn, W. ; Cantor, R. M. ; Carr, V. J. ; Catts, S. V. ; Choudhury, K. ; Cloninger, C. ; Cormican, P. ; Craddock, N. ; Danoy, P. A. ; Datta, S. ; de Haan, L. ; Demontis, D. ; Dikeos, D. ; Djurovic, S. ; Donnelly, P. ; Duong, L. ; Dwyer, S. ; Fink-Jensen, A. ; Freedman, R. ; Freimer, N. B. ; Friedl, M. ; Georgieva, L. ; Giegling, I. ; Glenthøj, B. ; Godard, S. ; Hamshere, M. ; Hansen, M. ; Hansen, T. ; Hartmann, A. M. ; Henskens, F. A. ; Hougaard, D. M. ; Hultman, C. M. ; Ingason, A. ; Jablensky, A. V. ; Jakobsen, K. D. ; Jay, M. ; Jürgens, G. ; Kahn, R. S. ; Keller, M. C. ; Kenis, G. ; Kenny, E. ; Kim, Y. ; Kirov, G. K. ; Konnerth, H. ; Konte, B. ; Krabbendam, L. ; Krasucki, R. ; Lasseter, V. K. ; Laurent, C. ; Lawrence, J. ; Lencz, T. ; Lerer, F. ; Liang, K. Y. ; Lichtenstein, P. ; Lieberman, J. A. ; Linszen, D. H. ; Lönnqvist, J. ; Loughland, C. M. ; Maclean, A. W. ; Maher, Brion ; Maier, W. ; Mallet, J. ; Malloy, P. ; Mattheisen, M. ; Mattingsdal, M. ; McGhee, K. A. ; McGrath, J. J. ; McIntosh, A. ; McLean, D. E. ; McQuillin, A. ; Melle, I. ; Michie, P. T. ; Milanova, V. ; Mors, O. ; Mortensen, P. B. ; Moskvina, V. ; Muglia, P. ; Myin-Germeys, I. ; Nertney, D. A. ; Nestadt, Gerald ; Nielsen, J. ; Nikolov, I. ; Nordentoft, M. ; Norton, N. ; Nöthen, M. M. ; O'Dushlaine, C. T. ; Olincy, A. ; Olsen, L. ; O'Neill, F. ; Ørntoft, T. F. ; Owen, M. J. ; Pantelis, C. ; Papadimitriou, G. ; Pato, M. T. ; Peltonen, L. ; Petursson, H. ; Pickard, B. ; Pimm, J. ; Pulver, Ann E ; Puri, V. ; Quested, D. ; Quinn, E. M. ; Rasmussen, H. B. ; Réthelyi, J. M. ; Ribble, R. ; Rietschel, M. ; Riley, B. P. ; Ruggeri, M. ; Schall, U. ; Schulze, T. G. ; Schwab, S. G. ; Scott, R. J. ; Shi, J. ; Sigurdsson, E. ; Silverman, J. M. ; Spencer, C. C. ; Stefansson, K. ; Strange, A. ; Strengman, E. ; Stroup, T. ; Suvisaari, J. ; Terenius, L. ; Thirumalai, S. ; Thygesen, J. H. ; Timm, S. ; Toncheva, D. ; van den Oord, E. ; van Os, J. ; van Winkel, R. ; Veldink, J. ; Walsh, D. ; Wang, A. G. ; Wiersma, D. ; Wildenauer, D. B. ; Williams, H. J. ; Williams, N. M. ; Wormley, B. ; Zammit, S. ; Sullivan, P. F. ; O'Donovan, M. C. ; Daly, M. J. ; Gejman, P. ; Barroso, I. ; Blackwell, J. M. ; Bramon, E. ; Casas, J. P. ; Deloukas, P. ; Duncanson, A. ; Jankowski, J. ; Markus, H. S. ; Mathew, C. G. ; Palmer, C. N. ; Plomin, R. ; Rautanen, A. ; Sawcer, S. J. ; Trembath, R. C. ; Viswanathan, A. C. ; Wood, N. W. ; Band, G. ; Bellenguez, C. ; Freeman, C. ; Hellenthal, G. ; Giannoulatou, E. ; Pirinen, M. ; Pearson, R. ; Su, Z. ; Vukcevic, D. ; Langford, C. ; Hunt, S. E. ; Edkins, S. ; Gwilliam, R. ; Blackburn, H. ; Bumpstead, S. J. ; Dronov, S. ; Gillman, M. ; Gray, E. ; Hammond, N. ; Jayakumar, A. ; McCann, O. T. ; Liddle, J. ; Potter, S. C. ; Ravindrarajah, R. ; Ricketts, M. ; Waller, M. ; Weston, P. ; Widaa, S. ; Whittaker, P. / Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway. In: JAMA Psychiatry. 2014 ; Vol. 71, No. 7. pp. 778-785.
@article{caf1ff71c8fe4c2f96942e6232277068,
title = "Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway",
abstract = "IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1{\%}to 3{\%}of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2{\%}using the polygenic score only to 4.8{\%}(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.",
author = "Nicodemus, {Kristin K.} and April Hargreaves and Derek Morris and Richard Anney and Michael Gill and Aiden Corvin and Gary Donohoe and S. Ripke and Sanders, {A. R.} and Kendler, {K. S.} and Levinson, {D. F.} and P. Sklar and Holmans, {P. A.} and Lin, {D. Y.} and J. Duan and Ophoff, {R. A.} and Andreassen, {O. A.} and E. Scolnick and S. Cichon and {St Clair}, D. and H. Gurling and T. Werge and D. Rujescu and Blackwood, {D. H.} and Pato, {C. N.} and Malhotra, {A. K.} and S. Purcell and F. Dudbridge and Neale, {B. M.} and L. Rossin and Visscher, {P. M.} and D. Posthuma and Ruderfer, {D. M.} and A. Fanous and H. Stefansson and S. Steinberg and Mowry, {B. J.} and V. Golimbet and {De Hert}, M. and J{\"o}nsson, {E. G.} and I. Bitter and Pietil{\"a}inen, {O. P.} and Collier, {D. A.} and S. Tosato and I. Agartz and M. Albus and M. Alexander and Amdur, {R. L.} and F. Amin and N. Bass and Bergen, {S. E.} and Black, {D. W.} and B{\o}rglum, {A. D.} and Brown, {M. A.} and R. Bruggeman and Buccola, {N. G.} and Byerley, {W. F.} and W. Cahn and Cantor, {R. M.} and Carr, {V. J.} and Catts, {S. V.} and K. Choudhury and C. Cloninger and P. Cormican and N. Craddock and Danoy, {P. A.} and S. Datta and {de Haan}, L. and D. Demontis and D. Dikeos and S. Djurovic and P. Donnelly and L. Duong and S. Dwyer and A. Fink-Jensen and R. Freedman and Freimer, {N. B.} and M. Friedl and L. Georgieva and I. Giegling and B. Glenth{\o}j and S. Godard and M. Hamshere and M. Hansen and T. Hansen and Hartmann, {A. M.} and Henskens, {F. A.} and Hougaard, {D. M.} and Hultman, {C. M.} and A. Ingason and Jablensky, {A. V.} and Jakobsen, {K. D.} and M. Jay and G. J{\"u}rgens and Kahn, {R. S.} and Keller, {M. C.} and G. Kenis and E. Kenny and Y. Kim and Kirov, {G. K.} and H. Konnerth and B. Konte and L. Krabbendam and R. Krasucki and Lasseter, {V. K.} and C. Laurent and J. Lawrence and T. Lencz and F. Lerer and Liang, {K. Y.} and P. Lichtenstein and Lieberman, {J. A.} and Linszen, {D. H.} and J. L{\"o}nnqvist and Loughland, {C. M.} and Maclean, {A. W.} and Brion Maher and W. Maier and J. Mallet and P. Malloy and M. Mattheisen and M. Mattingsdal and McGhee, {K. A.} and McGrath, {J. J.} and A. McIntosh and McLean, {D. E.} and A. McQuillin and I. Melle and Michie, {P. T.} and V. Milanova and O. Mors and Mortensen, {P. B.} and V. Moskvina and P. Muglia and I. Myin-Germeys and Nertney, {D. A.} and Gerald Nestadt and J. Nielsen and I. Nikolov and M. Nordentoft and N. Norton and N{\"o}then, {M. M.} and O'Dushlaine, {C. T.} and A. Olincy and L. Olsen and F. O'Neill and {\O}rntoft, {T. F.} and Owen, {M. J.} and C. Pantelis and G. Papadimitriou and Pato, {M. T.} and L. Peltonen and H. Petursson and B. Pickard and J. Pimm and Pulver, {Ann E} and V. Puri and D. Quested and Quinn, {E. M.} and Rasmussen, {H. B.} and R{\'e}thelyi, {J. M.} and R. Ribble and M. Rietschel and Riley, {B. P.} and M. Ruggeri and U. Schall and Schulze, {T. G.} and Schwab, {S. G.} and Scott, {R. J.} and J. Shi and E. Sigurdsson and Silverman, {J. M.} and Spencer, {C. C.} and K. Stefansson and A. Strange and E. Strengman and T. Stroup and J. Suvisaari and L. Terenius and S. Thirumalai and Thygesen, {J. H.} and S. Timm and D. Toncheva and {van den Oord}, E. and {van Os}, J. and {van Winkel}, R. and J. Veldink and D. Walsh and Wang, {A. G.} and D. Wiersma and Wildenauer, {D. B.} and Williams, {H. J.} and Williams, {N. M.} and B. Wormley and S. Zammit and Sullivan, {P. F.} and O'Donovan, {M. C.} and Daly, {M. J.} and P. Gejman and I. Barroso and Blackwell, {J. M.} and E. Bramon and Casas, {J. P.} and P. Deloukas and A. Duncanson and J. Jankowski and Markus, {H. S.} and Mathew, {C. G.} and Palmer, {C. N.} and R. Plomin and A. Rautanen and Sawcer, {S. J.} and Trembath, {R. C.} and Viswanathan, {A. C.} and Wood, {N. W.} and G. Band and C. Bellenguez and C. Freeman and G. Hellenthal and E. Giannoulatou and M. Pirinen and R. Pearson and Z. Su and D. Vukcevic and C. Langford and Hunt, {S. E.} and S. Edkins and R. Gwilliam and H. Blackburn and Bumpstead, {S. J.} and S. Dronov and M. Gillman and E. Gray and N. Hammond and A. Jayakumar and McCann, {O. T.} and J. Liddle and Potter, {S. C.} and R. Ravindrarajah and M. Ricketts and M. Waller and P. Weston and S. Widaa and P. Whittaker",
year = "2014",
month = "7",
day = "1",
doi = "10.1001/jamapsychiatry.2014.528",
language = "English (US)",
volume = "71",
pages = "778--785",
journal = "JAMA Psychiatry",
issn = "2168-622X",
publisher = "American Medical Association",
number = "7",

}

TY - JOUR

T1 - Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway

AU - Nicodemus, Kristin K.

AU - Hargreaves, April

AU - Morris, Derek

AU - Anney, Richard

AU - Gill, Michael

AU - Corvin, Aiden

AU - Donohoe, Gary

AU - Ripke, S.

AU - Sanders, A. R.

AU - Kendler, K. S.

AU - Levinson, D. F.

AU - Sklar, P.

AU - Holmans, P. A.

AU - Lin, D. Y.

AU - Duan, J.

AU - Ophoff, R. A.

AU - Andreassen, O. A.

AU - Scolnick, E.

AU - Cichon, S.

AU - St Clair, D.

AU - Gurling, H.

AU - Werge, T.

AU - Rujescu, D.

AU - Blackwood, D. H.

AU - Pato, C. N.

AU - Malhotra, A. K.

AU - Purcell, S.

AU - Dudbridge, F.

AU - Neale, B. M.

AU - Rossin, L.

AU - Visscher, P. M.

AU - Posthuma, D.

AU - Ruderfer, D. M.

AU - Fanous, A.

AU - Stefansson, H.

AU - Steinberg, S.

AU - Mowry, B. J.

AU - Golimbet, V.

AU - De Hert, M.

AU - Jönsson, E. G.

AU - Bitter, I.

AU - Pietiläinen, O. P.

AU - Collier, D. A.

AU - Tosato, S.

AU - Agartz, I.

AU - Albus, M.

AU - Alexander, M.

AU - Amdur, R. L.

AU - Amin, F.

AU - Bass, N.

AU - Bergen, S. E.

AU - Black, D. W.

AU - Børglum, A. D.

AU - Brown, M. A.

AU - Bruggeman, R.

AU - Buccola, N. G.

AU - Byerley, W. F.

AU - Cahn, W.

AU - Cantor, R. M.

AU - Carr, V. J.

AU - Catts, S. V.

AU - Choudhury, K.

AU - Cloninger, C.

AU - Cormican, P.

AU - Craddock, N.

AU - Danoy, P. A.

AU - Datta, S.

AU - de Haan, L.

AU - Demontis, D.

AU - Dikeos, D.

AU - Djurovic, S.

AU - Donnelly, P.

AU - Duong, L.

AU - Dwyer, S.

AU - Fink-Jensen, A.

AU - Freedman, R.

AU - Freimer, N. B.

AU - Friedl, M.

AU - Georgieva, L.

AU - Giegling, I.

AU - Glenthøj, B.

AU - Godard, S.

AU - Hamshere, M.

AU - Hansen, M.

AU - Hansen, T.

AU - Hartmann, A. M.

AU - Henskens, F. A.

AU - Hougaard, D. M.

AU - Hultman, C. M.

AU - Ingason, A.

AU - Jablensky, A. V.

AU - Jakobsen, K. D.

AU - Jay, M.

AU - Jürgens, G.

AU - Kahn, R. S.

AU - Keller, M. C.

AU - Kenis, G.

AU - Kenny, E.

AU - Kim, Y.

AU - Kirov, G. K.

AU - Konnerth, H.

AU - Konte, B.

AU - Krabbendam, L.

AU - Krasucki, R.

AU - Lasseter, V. K.

AU - Laurent, C.

AU - Lawrence, J.

AU - Lencz, T.

AU - Lerer, F.

AU - Liang, K. Y.

AU - Lichtenstein, P.

AU - Lieberman, J. A.

AU - Linszen, D. H.

AU - Lönnqvist, J.

AU - Loughland, C. M.

AU - Maclean, A. W.

AU - Maher, Brion

AU - Maier, W.

AU - Mallet, J.

AU - Malloy, P.

AU - Mattheisen, M.

AU - Mattingsdal, M.

AU - McGhee, K. A.

AU - McGrath, J. J.

AU - McIntosh, A.

AU - McLean, D. E.

AU - McQuillin, A.

AU - Melle, I.

AU - Michie, P. T.

AU - Milanova, V.

AU - Mors, O.

AU - Mortensen, P. B.

AU - Moskvina, V.

AU - Muglia, P.

AU - Myin-Germeys, I.

AU - Nertney, D. A.

AU - Nestadt, Gerald

AU - Nielsen, J.

AU - Nikolov, I.

AU - Nordentoft, M.

AU - Norton, N.

AU - Nöthen, M. M.

AU - O'Dushlaine, C. T.

AU - Olincy, A.

AU - Olsen, L.

AU - O'Neill, F.

AU - Ørntoft, T. F.

AU - Owen, M. J.

AU - Pantelis, C.

AU - Papadimitriou, G.

AU - Pato, M. T.

AU - Peltonen, L.

AU - Petursson, H.

AU - Pickard, B.

AU - Pimm, J.

AU - Pulver, Ann E

AU - Puri, V.

AU - Quested, D.

AU - Quinn, E. M.

AU - Rasmussen, H. B.

AU - Réthelyi, J. M.

AU - Ribble, R.

AU - Rietschel, M.

AU - Riley, B. P.

AU - Ruggeri, M.

AU - Schall, U.

AU - Schulze, T. G.

AU - Schwab, S. G.

AU - Scott, R. J.

AU - Shi, J.

AU - Sigurdsson, E.

AU - Silverman, J. M.

AU - Spencer, C. C.

AU - Stefansson, K.

AU - Strange, A.

AU - Strengman, E.

AU - Stroup, T.

AU - Suvisaari, J.

AU - Terenius, L.

AU - Thirumalai, S.

AU - Thygesen, J. H.

AU - Timm, S.

AU - Toncheva, D.

AU - van den Oord, E.

AU - van Os, J.

AU - van Winkel, R.

AU - Veldink, J.

AU - Walsh, D.

AU - Wang, A. G.

AU - Wiersma, D.

AU - Wildenauer, D. B.

AU - Williams, H. J.

AU - Williams, N. M.

AU - Wormley, B.

AU - Zammit, S.

AU - Sullivan, P. F.

AU - O'Donovan, M. C.

AU - Daly, M. J.

AU - Gejman, P.

AU - Barroso, I.

AU - Blackwell, J. M.

AU - Bramon, E.

AU - Casas, J. P.

AU - Deloukas, P.

AU - Duncanson, A.

AU - Jankowski, J.

AU - Markus, H. S.

AU - Mathew, C. G.

AU - Palmer, C. N.

AU - Plomin, R.

AU - Rautanen, A.

AU - Sawcer, S. J.

AU - Trembath, R. C.

AU - Viswanathan, A. C.

AU - Wood, N. W.

AU - Band, G.

AU - Bellenguez, C.

AU - Freeman, C.

AU - Hellenthal, G.

AU - Giannoulatou, E.

AU - Pirinen, M.

AU - Pearson, R.

AU - Su, Z.

AU - Vukcevic, D.

AU - Langford, C.

AU - Hunt, S. E.

AU - Edkins, S.

AU - Gwilliam, R.

AU - Blackburn, H.

AU - Bumpstead, S. J.

AU - Dronov, S.

AU - Gillman, M.

AU - Gray, E.

AU - Hammond, N.

AU - Jayakumar, A.

AU - McCann, O. T.

AU - Liddle, J.

AU - Potter, S. C.

AU - Ravindrarajah, R.

AU - Ricketts, M.

AU - Waller, M.

AU - Weston, P.

AU - Widaa, S.

AU - Whittaker, P.

PY - 2014/7/1

Y1 - 2014/7/1

N2 - IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.

AB - IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.

UR - http://www.scopus.com/inward/record.url?scp=84903956920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903956920&partnerID=8YFLogxK

U2 - 10.1001/jamapsychiatry.2014.528

DO - 10.1001/jamapsychiatry.2014.528

M3 - Article

C2 - 24828433

AN - SCOPUS:84903956920

VL - 71

SP - 778

EP - 785

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 7

ER -