Search

Your search keyword '"Peyrot, WJ"' showing total 13 results
Start Over Author "Peyrot, WJ" Publication Type Electronic Resources
13 results on '"Peyrot, WJ"'

1. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Author

Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, Borglum, AD, Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, and Borglum, AD

Abstract

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Published
2020

2. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

Author

Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, Sullivan, PF, Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, and Sullivan, PF

Abstract

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

Published
2020

3. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy

Author

Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF

Abstract

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression; disorder severity and unfavorable treatment outcomes are shown to be influenced by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment and response/nonresponse are associated with an increased genetic burden for major depression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressive episode underwent ECT. MD-PRS were calculated for these inpatients and a separate population-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on summary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases: n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higher MD-PRS. MD-PRS in population-based depression self-reporters were intermediate between ECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response (50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate that ECT cohorts show an increased genetic burden for MD and are consistent with the hypothesis that treatment-resistant MD patients represent a subgroup with an increased genetic risk for MD. Larger samples are needed to better substantiate these findings.

Published
2019

4. Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Author

Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, Sullivan, PF, Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, and Sullivan, PF

Abstract

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10-6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

Published
2019

5. Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Author

Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF

Abstract

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.

Published
2019

6. Quantifying between-cohort and between-sex genetic heterogeneity in major depressive disorder

Author

Trzaskowski, M, Mehta, D, Peyrot, WJ, Hawkes, D, Davies, D, Howard, DM, Kemper, KE, Sidorenko, J, Maier, R, Ripke, S, Mattheisen, M, Baune, BT, Grabe, HJ, Heath, AC, Jones, L, Jones, I, Madden, PAF, McIntosh, AM, Breen, G, Lewis, CM, Borglum, AD, Sullivan, PF, Martin, NG, Kendler, KS, Levinson, DF, Wray, NR, Trzaskowski, M, Mehta, D, Peyrot, WJ, Hawkes, D, Davies, D, Howard, DM, Kemper, KE, Sidorenko, J, Maier, R, Ripke, S, Mattheisen, M, Baune, BT, Grabe, HJ, Heath, AC, Jones, L, Jones, I, Madden, PAF, McIntosh, AM, Breen, G, Lewis, CM, Borglum, AD, Sullivan, PF, Martin, NG, Kendler, KS, Levinson, DF, and Wray, NR

Abstract

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD.

Published
2019

7. Collaborative meta-Analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

Author

Culverhouse, RC, Saccone, NL, Horton, AC, Ma, Y, Anstey, KJ, Banaschewski, T, Burmeister, M, Cohen-Woods, S, Etain, B, Fisher, HL, Goldman, N, Guillaume, S, Horwood, J, Juhasz, G, Lester, KJ, Mandelli, L, Middeldorp, CM, Olié, E, Villafuerte, S, Air, TM, Araya, R, Bowes, L, Burns, R, Byrne, EM, Coffey, C, Coventry, WL, Gawronski, KAB, Glei, D, Hatzimanolis, A, Hottenga, JJ, Jaussent, I, Jawahar, C, Jennen-Steinmetz, C, Kramer, JR, Lajnef, M, Little, K, Zu Schwabedissen, HM, Nauck, M, Nederhof, E, Petschner, P, Peyrot, WJ, Schwahn, C, Sinnamon, G, Stacey, D, Tian, Y, Toben, C, Van Der Auwera, S, Wainwright, N, Wang, JC, Willemsen, G, Anderson, IM, Arolt, V, Aslund, C, Bagdy, G, Baune, BT, Bellivier, F, Boomsma, DI, Courtet, P, Dannlowski, U, De Geus, EJC, Deakin, JFW, Easteal, S, Eley, T, Fergusson, DM, Goate, AM, Gonda, X, Grabe, HJ, Holzman, C, Johnson, EO, Kennedy, M, Laucht, M, Martin, NG, Munafò, MR, Nilsson, KW, Oldehinkel, AJ, Olsson, CA, Ormel, J, Otte, C, Patton, GC, Penninx, BWJH, Ritchie, K, Sarchiapone, M, Scheid, JM, Serretti, A, Smit, JH, Stefanis, NC, Surtees, PG, Völzke, H, Weinstein, M, Whooley, M, Nurnberger, JI, Breslau, N, Bierut, LJ, Culverhouse, RC, Saccone, NL, Horton, AC, Ma, Y, Anstey, KJ, Banaschewski, T, Burmeister, M, Cohen-Woods, S, Etain, B, Fisher, HL, Goldman, N, Guillaume, S, Horwood, J, Juhasz, G, Lester, KJ, Mandelli, L, Middeldorp, CM, Olié, E, Villafuerte, S, Air, TM, Araya, R, Bowes, L, Burns, R, Byrne, EM, Coffey, C, Coventry, WL, Gawronski, KAB, Glei, D, Hatzimanolis, A, Hottenga, JJ, Jaussent, I, Jawahar, C, Jennen-Steinmetz, C, Kramer, JR, Lajnef, M, Little, K, Zu Schwabedissen, HM, Nauck, M, Nederhof, E, Petschner, P, Peyrot, WJ, Schwahn, C, Sinnamon, G, Stacey, D, Tian, Y, Toben, C, Van Der Auwera, S, Wainwright, N, Wang, JC, Willemsen, G, Anderson, IM, Arolt, V, Aslund, C, Bagdy, G, Baune, BT, Bellivier, F, Boomsma, DI, Courtet, P, Dannlowski, U, De Geus, EJC, Deakin, JFW, Easteal, S, Eley, T, Fergusson, DM, Goate, AM, Gonda, X, Grabe, HJ, Holzman, C, Johnson, EO, Kennedy, M, Laucht, M, Martin, NG, Munafò, MR, Nilsson, KW, Oldehinkel, AJ, Olsson, CA, Ormel, J, Otte, C, Patton, GC, Penninx, BWJH, Ritchie, K, Sarchiapone, M, Scheid, JM, Serretti, A, Smit, JH, Stefanis, NC, Surtees, PG, Völzke, H, Weinstein, M, Whooley, M, Nurnberger, JI, Breslau, N, and Bierut, LJ

Abstract

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-Analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-Analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-Analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Published
2018

8. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

Author

Culverhouse, RC, Saccone, NL, Horton, AC, Ma, Y, Anstey, KJ, Banaschewski, T, Burmeister, M, Cohen-Woods, S, Etain, B, Fisher, HL, Goldman, N, Guillaume, S, Horwood, J, Juhasz, G, Lester, KJ, Mandelli, L, Middeldorp, CM, Olie, E, Villafuerte, S, Air, TM, Araya, R, Bowes, L, Burns, R, Byrne, EM, Coffey, C, Coventry, WL, Gawronski, KAB, Glei, D, Hatzimanolis, A, Hottenga, J-J, Jaussent, I, Jawahar, C, Jennen-Steinmetz, C, Kramer, JR, Lajnef, M, Little, K, zu Schwabedissen, HM, Nauck, M, Nederhof, E, Petschner, P, Peyrot, WJ, Schwahn, C, Sinnamon, G, Stacey, D, Tian, Y, Toben, C, Van der Auwera, S, Wainwright, N, Wang, J-C, Willemsen, G, Anderson, IM, Arolt, V, Aslund, C, Bagdy, G, Baune, BT, Bellivier, F, Boomsma, DI, Courtet, P, Dannlowski, U, de Geus, EJC, Deakin, JFW, Easteal, S, Eley, T, Fergusson, DM, Goate, AM, Gonda, X, Grabe, HJ, Holzman, C, Johnson, EO, Kennedy, M, Laucht, M, Martin, NG, Munafo, MR, Nilsson, KW, Oldehinkel, AJ, Olsson, CA, Ormel, J, Otte, C, Patton, GC, Penninx, BWJH, Ritchie, K, Sarchiapone, M, Scheid, JM, Serretti, A, Smit, JH, Stefanis, NC, Surtees, PG, Voelzke, H, Weinstein, M, Whooley, M, Nurnberger, JI, Breslau, N, Bierut, LJ, Culverhouse, RC, Saccone, NL, Horton, AC, Ma, Y, Anstey, KJ, Banaschewski, T, Burmeister, M, Cohen-Woods, S, Etain, B, Fisher, HL, Goldman, N, Guillaume, S, Horwood, J, Juhasz, G, Lester, KJ, Mandelli, L, Middeldorp, CM, Olie, E, Villafuerte, S, Air, TM, Araya, R, Bowes, L, Burns, R, Byrne, EM, Coffey, C, Coventry, WL, Gawronski, KAB, Glei, D, Hatzimanolis, A, Hottenga, J-J, Jaussent, I, Jawahar, C, Jennen-Steinmetz, C, Kramer, JR, Lajnef, M, Little, K, zu Schwabedissen, HM, Nauck, M, Nederhof, E, Petschner, P, Peyrot, WJ, Schwahn, C, Sinnamon, G, Stacey, D, Tian, Y, Toben, C, Van der Auwera, S, Wainwright, N, Wang, J-C, Willemsen, G, Anderson, IM, Arolt, V, Aslund, C, Bagdy, G, Baune, BT, Bellivier, F, Boomsma, DI, Courtet, P, Dannlowski, U, de Geus, EJC, Deakin, JFW, Easteal, S, Eley, T, Fergusson, DM, Goate, AM, Gonda, X, Grabe, HJ, Holzman, C, Johnson, EO, Kennedy, M, Laucht, M, Martin, NG, Munafo, MR, Nilsson, KW, Oldehinkel, AJ, Olsson, CA, Ormel, J, Otte, C, Patton, GC, Penninx, BWJH, Ritchie, K, Sarchiapone, M, Scheid, JM, Serretti, A, Smit, JH, Stefanis, NC, Surtees, PG, Voelzke, H, Weinstein, M, Whooley, M, Nurnberger, JI, Breslau, N, and Bierut, LJ

Abstract

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Published
2018

9. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author

de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, Shi, J, de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, and Shi, J

Abstract

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

Published
2018

10. Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD

Author

Van der Auwera, S, Peyrot, WJ, Milaneschi, Y, Hertel, J, Baune, B, Breen, G, Byrne, E, Dunn, EC, Fisher, H, Homuth, G, Levinson, D, Lewis, C, Mills, N, Mullins, N, Nauck, M, Pistis, G, Preisig, M, Rietschel, M, Ripke, S, Sullivan, P, Teumer, A, Voelzke, H, Boomsma, DI, Wray, NR, Penninx, B, Grabe, H, Van der Auwera, S, Peyrot, WJ, Milaneschi, Y, Hertel, J, Baune, B, Breen, G, Byrne, E, Dunn, EC, Fisher, H, Homuth, G, Levinson, D, Lewis, C, Mills, N, Mullins, N, Nauck, M, Pistis, G, Preisig, M, Rietschel, M, Ripke, S, Sullivan, P, Teumer, A, Voelzke, H, Boomsma, DI, Wray, NR, Penninx, B, and Grabe, H

Abstract

Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impact on GxE in MDD using a common approach in 3944 subjects of European ancestry from the Psychiatric Genomics Consortium who had completed the Childhood Trauma Questionnaire. (3) We subsequently used the genome-wide SNP data for a genome-wide case-control GxE model and GxE case-only analyses testing for an enrichment of associated SNPs. No genome-wide significant hits and no consistency among the signals of the different analytic approaches could be observed. This is the largest study for systematic GxE interaction analysis in MDD in subjects of European ancestry to date. Most of the known candidate genes/variants could not be supported. Thus, their impact on GxE interaction in MDD may be questionable. Our results underscore the need for larger samples, more extensive assessment of environmental exposures, and greater efforts to investigate new methodological approaches in GxE models for MDD.

Published
2018

11. Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

Author

Graff, M, Scott, RA, Justice, AE, Young, KL, Feitosa, MF, Barata, L, Winkler, TW, Chu, AY, Mahajan, A, Hadley, D, Xue, LT, Workalemahu, T, Heard-Costa, NL, den Hoed, M, Ahluwalia, TS, Qi, QB, Ngwa, JS, Renstrom, F, Quaye, L, Eicher, JD, Hayes, J E, Cornelis, M, Kutalik, Z, Lim, E, Luan, J, Huffman, JE, Zhang, WH, Zhao, W, Griffin, PJ, Haller, T, Ahmad, Shahzad, Marques-Vidal, PM, Bien, S, Yengo, L, Teumer, A, Smith, AV, Kumari, M, Harder, MN, Justesen, JM, Kleber, ME, Hollensted, M, Lohman, K, Rivera, NV, Whitfield, JB, Zhao, JH, Stringham, HM, Lyytikainen, LP, Huppertz, C, Willemsen, G, Peyrot, WJ, Wu, Fenny, Kristiansson, K, Demirkan, Ayse, Fornage, M, Hassinen, M, Bielak, LF, Cadby, G, Tanaka, T, Magl, R, van der Most, PJ, Jackson, AU, Bragg-Gresham, JL, Vitart, V, Marten, J, Navarro, P, Bellis, C, Pasko, D, Johansson, A, Snitker, S, Cheng, YC, Eriksson, J, Lim, U, Aadahl, M, Adair, LS, Amin, Najaf, Balkau, B, Auvinen, J, Beilby, J, Bergman, RN, Bergmann, S, Bertoni, AG, Blangero, J, Bonnefond, A, Bonnycastle, LL, Borja, JB, Brage, S, Busonero, F, Buyske, S, Campbell, H, Chines, PS, Collins, FS, Corre, T, Smith, GD, Delgado, GE, Dueker, N, Dorr, M, Ebeling, T, Eiriksdottir, G, Esko, T, Faul, JD, Fu, M, Faerch, K, Gieger, C, Glaser, S, Gong, J, Gordon-Larsen, P, Grallert, H, Grammer, TB, Grarup, N, Van Grootheest, G, Harald, K, Hastie, ND, Havulinna, AS, Hernandez, D, Hindorff, L, Hocking, LJ, Holmens, OL, Holzapfel, C, Hottenga, JJ, Huang, J, Huang, T, Hui, J, Huth, C, Hutri-Kahonen, N, James, AL, Jansson, JO, Jhun, MA, Juonala, M, Kinnunen, L, Koistinen, HA, Kolcic, I, Komulainen, P, Kuusisto, J, Kvaloy, K, Kahonen, M, Lakka, TA, Launer, LJ, Lehne, B, Lindgren, CM, Lorentzon, M, Luben, R, Marre, M (Michel), Milaneschi, Y, Monda, KL, Montgomery, GW, de Moor, MHM, Mulas, A, Muller-Nurasyid, M, Musk, AW, Mannikko, R, Mannisto, S, Narisu, N, Nauck, M, Nettleton, JA, Nolte, IM, Oldehinkel, AJ (A.), Olden, M, Ong, KK, Padmanabhan, S, Paternoster, L, Perez, J, Perola, M, Peters, A, Peters, U, Peyser, PA, Prokopenko, I, Puolijoki, H, Raitakari, OT, Rankinen, T, Rasmussen-Torvik, LJ, Rawal, R, Ridker, PM, Rose, LM, Rudan, I, Sarti, C, Sarzynski, MA, Savonen, K, Scott, WR, Sanna, S, Shuldiner, AR, Sidney, S, Silbernagel, G, Smith, BH, Smith, JA, Snieder, H, Stancakova, A, Sternfeld, B, Swift, AJ, Tammelin, T, Tan, ST, Thorand, B, Thuillier, D, Vandenput, L, Vestergaard, H, van Vliet-Ostaptchouk, JV, Vohl, MC, Volker, U, Waeber, G, Walker, M, Wild, S, Wong, A, Wright, AF, Zillikens, M.C., Zubair, N, Haiman, CA, LeMarchand, L, Gyllensten, U, Ohlsson, C, Ohlsson, CC, Hofman, Bert, Rivadeneira, Fernando, Uitterlinden, André, Perusse, L, Wilson, JF, Hayward, C, Polasek, O, Cucca, F, Hveem, K, Hartman, CA, Tonjes, A, Bandinelli, S, Palmer, LJ, Kardia, SLR, Rauramaa, R, Sorensen, TIA, Tuomilehto, J, Salomaa, V, Penninx, B, de Geus, EJC, Boomsma, DI, Lehtimaki, T, Mangino, M, Laakso, M, Bouchard, C, Martin, NG, Kuh, D, Liu, YM, Linneberg, A, Marz, W, Strauch, K, Kivimaki, M, Harris, TB, Gudnason, V, Volzke, H, Qi, L, Jarvelin, MR, Chambers, JC, Kooner, JS, Froguel, P, Kooperberg, C, Vollenweider, P, Hallmans, G, Hansen, T, Pedersen, O, Metspalu, A, Wareham, NJ, Langenberg, C, Weir, DR, Porteous, DJ, Boerwinkle, E, Chasman, DI, Abecasis, GR, Barroso, I, McCarthy, MI, Frayling, TM, O'Connell, JR, Duijn, Cornelia, Boehnke, M, Heid, IM, Mohlke, KL, Strachan, DP, Fox, CS, Liu, CT, Hirschhorn, JN, Klein, RJ, Johnson, AD, Borecki, IB, Franks, PW, North, KE, Cupples, LA, Loos, RJF, Kilpelainen, TO, Graff, M, Scott, RA, Justice, AE, Young, KL, Feitosa, MF, Barata, L, Winkler, TW, Chu, AY, Mahajan, A, Hadley, D, Xue, LT, Workalemahu, T, Heard-Costa, NL, den Hoed, M, Ahluwalia, TS, Qi, QB, Ngwa, JS, Renstrom, F, Quaye, L, Eicher, JD, Hayes, J E, Cornelis, M, Kutalik, Z, Lim, E, Luan, J, Huffman, JE, Zhang, WH, Zhao, W, Griffin, PJ, Haller, T, Ahmad, Shahzad, Marques-Vidal, PM, Bien, S, Yengo, L, Teumer, A, Smith, AV, Kumari, M, Harder, MN, Justesen, JM, Kleber, ME, Hollensted, M, Lohman, K, Rivera, NV, Whitfield, JB, Zhao, JH, Stringham, HM, Lyytikainen, LP, Huppertz, C, Willemsen, G, Peyrot, WJ, Wu, Fenny, Kristiansson, K, Demirkan, Ayse, Fornage, M, Hassinen, M, Bielak, LF, Cadby, G, Tanaka, T, Magl, R, van der Most, PJ, Jackson, AU, Bragg-Gresham, JL, Vitart, V, Marten, J, Navarro, P, Bellis, C, Pasko, D, Johansson, A, Snitker, S, Cheng, YC, Eriksson, J, Lim, U, Aadahl, M, Adair, LS, Amin, Najaf, Balkau, B, Auvinen, J, Beilby, J, Bergman, RN, Bergmann, S, Bertoni, AG, Blangero, J, Bonnefond, A, Bonnycastle, LL, Borja, JB, Brage, S, Busonero, F, Buyske, S, Campbell, H, Chines, PS, Collins, FS, Corre, T, Smith, GD, Delgado, GE, Dueker, N, Dorr, M, Ebeling, T, Eiriksdottir, G, Esko, T, Faul, JD, Fu, M, Faerch, K, Gieger, C, Glaser, S, Gong, J, Gordon-Larsen, P, Grallert, H, Grammer, TB, Grarup, N, Van Grootheest, G, Harald, K, Hastie, ND, Havulinna, AS, Hernandez, D, Hindorff, L, Hocking, LJ, Holmens, OL, Holzapfel, C, Hottenga, JJ, Huang, J, Huang, T, Hui, J, Huth, C, Hutri-Kahonen, N, James, AL, Jansson, JO, Jhun, MA, Juonala, M, Kinnunen, L, Koistinen, HA, Kolcic, I, Komulainen, P, Kuusisto, J, Kvaloy, K, Kahonen, M, Lakka, TA, Launer, LJ, Lehne, B, Lindgren, CM, Lorentzon, M, Luben, R, Marre, M (Michel), Milaneschi, Y, Monda, KL, Montgomery, GW, de Moor, MHM, Mulas, A, Muller-Nurasyid, M, Musk, AW, Mannikko, R, Mannisto, S, Narisu, N, Nauck, M, Nettleton, JA, Nolte, IM, Oldehinkel, AJ (A.), Olden, M, Ong, KK, Padmanabhan, S, Paternoster, L, Perez, J, Perola, M, Peters, A, Peters, U, Peyser, PA, Prokopenko, I, Puolijoki, H, Raitakari, OT, Rankinen, T, Rasmussen-Torvik, LJ, Rawal, R, Ridker, PM, Rose, LM, Rudan, I, Sarti, C, Sarzynski, MA, Savonen, K, Scott, WR, Sanna, S, Shuldiner, AR, Sidney, S, Silbernagel, G, Smith, BH, Smith, JA, Snieder, H, Stancakova, A, Sternfeld, B, Swift, AJ, Tammelin, T, Tan, ST, Thorand, B, Thuillier, D, Vandenput, L, Vestergaard, H, van Vliet-Ostaptchouk, JV, Vohl, MC, Volker, U, Waeber, G, Walker, M, Wild, S, Wong, A, Wright, AF, Zillikens, M.C., Zubair, N, Haiman, CA, LeMarchand, L, Gyllensten, U, Ohlsson, C, Ohlsson, CC, Hofman, Bert, Rivadeneira, Fernando, Uitterlinden, André, Perusse, L, Wilson, JF, Hayward, C, Polasek, O, Cucca, F, Hveem, K, Hartman, CA, Tonjes, A, Bandinelli, S, Palmer, LJ, Kardia, SLR, Rauramaa, R, Sorensen, TIA, Tuomilehto, J, Salomaa, V, Penninx, B, de Geus, EJC, Boomsma, DI, Lehtimaki, T, Mangino, M, Laakso, M, Bouchard, C, Martin, NG, Kuh, D, Liu, YM, Linneberg, A, Marz, W, Strauch, K, Kivimaki, M, Harris, TB, Gudnason, V, Volzke, H, Qi, L, Jarvelin, MR, Chambers, JC, Kooner, JS, Froguel, P, Kooperberg, C, Vollenweider, P, Hallmans, G, Hansen, T, Pedersen, O, Metspalu, A, Wareham, NJ, Langenberg, C, Weir, DR, Porteous, DJ, Boerwinkle, E, Chasman, DI, Abecasis, GR, Barroso, I, McCarthy, MI, Frayling, TM, O'Connell, JR, Duijn, Cornelia, Boehnke, M, Heid, IM, Mohlke, KL, Strachan, DP, Fox, CS, Liu, CT, Hirschhorn, JN, Klein, RJ, Johnson, AD, Borecki, IB, Franks, PW, North, KE, Cupples, LA, Loos, RJF, and Kilpelainen, TO

Published
2017

12. Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations

Author

Gratten, J, Wray, NR, Peyrot, WJ, McGrath, JJ, Visscher, PM, Goddard, ME, Gratten, J, Wray, NR, Peyrot, WJ, McGrath, JJ, Visscher, PM, and Goddard, ME

Abstract

The offspring of older fathers have higher risk of psychiatric disorders such as schizophrenia and autism. Paternal-age-related de novo mutations are widely assumed to be the underlying causal mechanism, and, although such mutations must logically make some contribution, there are alternative explanations (for example, elevated liability to psychiatric illness may delay fatherhood). We used population genetic models based on empirical observations of key parameters (for example, mutation rate, prevalence, and heritability) to assess the genetic relationship between paternal age and risk of psychiatric illness. These models suggest that age-related mutations are unlikely to explain much of the increased risk of psychiatric disorders in children of older fathers. Conversely, a model incorporating a weak correlation between age at first child and liability to psychiatric illness matched epidemiological observations. Our results suggest that genetic risk factors shared by older fathers and their offspring are a credible alternative explanation to de novo mutations for risk to children of older fathers.

Published
2016

13. Genome-wide association study identifies 74 loci associated with educational attainment

Author

Okbay, Aysu, Beauchamp, JP, Fontana, MA, Lee, JJ, Pers, TH, Rietveld, Niels, Turley, P, Chen, GB, Emilsson, V, Meddens, SFW, Oskarsson, S, Pickrell, JK, Thom, K, Timshel, P, Vlaming, Ronald, Abdellaoui, A, Ahluwalia, TS, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Johan, Concas, MP, Derringer, J, Furlotte, NA, Galesloot, TE, Girotto, G, Gupta, R, Hall, LM, Harris, SE, Hofer, E, Horikoshi, M, Huffman, JE, Kaasik, K, Kalafati, IP, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sven, de Leeuw, C, Lind, PA, Lindgren, KO, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, MB, van der Most, PJ, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, WJ, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, KE, Shi, JX, Smith, AV, Poot, Raymond, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N (Niek), Vuckovic, D, Wellmann, J, Westra, HJ, Yang, JY, Zhao, W, Zhu, ZH, Alizadeh, BZ, Amin, Najaf, Bakshi, A, Baumeister, SE, Biino, G, Bonnelykke, K, Boyle, PA, Campbell, H, Cappuccio, FP, Davies, G, De Neve, JE, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, DM, Faul, JD, Feitosa, MF, Forstner, AJ, Gandin, I, Gunnarsson, B, Halldorsson, BV, Harris, TB, Heath, AC, Hocking, LJ, Holliday, EG, Homuth, G, Horan, MA, Hottenga, JJ, De Jager, PL, Joshi, PK, Jugessur, A, Kaakinen, MA, Kahonen, M, Kanoni, S, Keltigangas-Jarvinen, L, Kiemeney, LALM, Kolcic, I, Koskinen, S, Kraja, AT, Kroh, M, Kutalik, Z, Latvala, A, Launer, LJ, Lebreton, MP, Levinson, DF, Lichtenstein, P, Lichtner, P, Liewald, DCM, Loukola, A, Madden, PA, Magi, R, Maki-Opas, T, Marioni, RE, Marques-Vidal, P, Meddens, GA, McMahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, GW, Myhre, R, Nelson, CP, Nyholt, DR, Ollier, WER, Palotie, A, Paternoster, L, Pedersen, NL, Petrovic, KE, Porteous, DJ, Raikkonen, K, Ring, SM, Robino, A, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, AR, Sarin, AP, Schmidt, Heléna, Scott, RJ, Smith, BH, Smith, JA, Staessen, JA, Steinhagen-Thiessen, E, Strauch, K, Terracciano, A, Tobin, MD, Ulivi, S, Vaccargiu, S, Quaye, L, van Rooij, FJA, Venturini, C, Vinkhuyzen, AAE, Volker, U, Volzke, H, Vonk, JM, Vozzi, D, Waage, J, Ware, EB, Willemsen, G, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Bisgaard, H, Boomsma, DI, Borecki, IB, Bultmann, U, Chabris, CF, Cucca, F, Cusi, D, Deary, IJ, Dedoussis, GV, Duijn, Cornelia, Eriksson, JG, Franke, B, Franke, L, Gasparini, P, Gejman, PV, Gieger, C, Grabe, HJ, Gratten, J, Groenen, Patrick, Gudnason, V, van der Harst, P, Hayward, C, Hinds, DA, Hoffmann, W, Hyppnen, E, Iacono, WG, Jacobsson, B, Jarvelin, MR, Jockel, KH, Kaprio, J, Kardia, SLR, Lehtimaki, T, Lehrer, SF, Magnusson, PKE, Martin, NG, McGue, M, Metspalu, A, Pendleton, N, Penninx, BWJH, Perola, M, Pirastu, N, Pirastu, M, Polasek, O, Posthuma, Daniëlle, Power, C, Province, MA, Samani, NJ, Schlessinger, D, Schmidt, R, Sorensen, TIA, Spector, TD, Stefansson, K, Thorsteinsdottir, U, Thurik, Roy, Timpson, NJ, Tiemeier, Henning, Tung, JY, Uitterlinden, André, Vitart, V, Vollenweider, P, Weir, DR, Wilson, JF, Wright, AF, Conley, DC, Krueger, RF, Smith, GD, Hofman, Bert, Laibson, DI, Medland, SE, Meyer, MN, Yang, Jiaqi, Johannesson, M, Visscher, PM, Esko, T, Koellinger, PD, Cesarini, D, Benjamin, DJ, Okbay, Aysu, Beauchamp, JP, Fontana, MA, Lee, JJ, Pers, TH, Rietveld, Niels, Turley, P, Chen, GB, Emilsson, V, Meddens, SFW, Oskarsson, S, Pickrell, JK, Thom, K, Timshel, P, Vlaming, Ronald, Abdellaoui, A, Ahluwalia, TS, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Johan, Concas, MP, Derringer, J, Furlotte, NA, Galesloot, TE, Girotto, G, Gupta, R, Hall, LM, Harris, SE, Hofer, E, Horikoshi, M, Huffman, JE, Kaasik, K, Kalafati, IP, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sven, de Leeuw, C, Lind, PA, Lindgren, KO, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, MB, van der Most, PJ, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, WJ, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, KE, Shi, JX, Smith, AV, Poot, Raymond, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N (Niek), Vuckovic, D, Wellmann, J, Westra, HJ, Yang, JY, Zhao, W, Zhu, ZH, Alizadeh, BZ, Amin, Najaf, Bakshi, A, Baumeister, SE, Biino, G, Bonnelykke, K, Boyle, PA, Campbell, H, Cappuccio, FP, Davies, G, De Neve, JE, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, DM, Faul, JD, Feitosa, MF, Forstner, AJ, Gandin, I, Gunnarsson, B, Halldorsson, BV, Harris, TB, Heath, AC, Hocking, LJ, Holliday, EG, Homuth, G, Horan, MA, Hottenga, JJ, De Jager, PL, Joshi, PK, Jugessur, A, Kaakinen, MA, Kahonen, M, Kanoni, S, Keltigangas-Jarvinen, L, Kiemeney, LALM, Kolcic, I, Koskinen, S, Kraja, AT, Kroh, M, Kutalik, Z, Latvala, A, Launer, LJ, Lebreton, MP, Levinson, DF, Lichtenstein, P, Lichtner, P, Liewald, DCM, Loukola, A, Madden, PA, Magi, R, Maki-Opas, T, Marioni, RE, Marques-Vidal, P, Meddens, GA, McMahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, GW, Myhre, R, Nelson, CP, Nyholt, DR, Ollier, WER, Palotie, A, Paternoster, L, Pedersen, NL, Petrovic, KE, Porteous, DJ, Raikkonen, K, Ring, SM, Robino, A, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, AR, Sarin, AP, Schmidt, Heléna, Scott, RJ, Smith, BH, Smith, JA, Staessen, JA, Steinhagen-Thiessen, E, Strauch, K, Terracciano, A, Tobin, MD, Ulivi, S, Vaccargiu, S, Quaye, L, van Rooij, FJA, Venturini, C, Vinkhuyzen, AAE, Volker, U, Volzke, H, Vonk, JM, Vozzi, D, Waage, J, Ware, EB, Willemsen, G, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Bisgaard, H, Boomsma, DI, Borecki, IB, Bultmann, U, Chabris, CF, Cucca, F, Cusi, D, Deary, IJ, Dedoussis, GV, Duijn, Cornelia, Eriksson, JG, Franke, B, Franke, L, Gasparini, P, Gejman, PV, Gieger, C, Grabe, HJ, Gratten, J, Groenen, Patrick, Gudnason, V, van der Harst, P, Hayward, C, Hinds, DA, Hoffmann, W, Hyppnen, E, Iacono, WG, Jacobsson, B, Jarvelin, MR, Jockel, KH, Kaprio, J, Kardia, SLR, Lehtimaki, T, Lehrer, SF, Magnusson, PKE, Martin, NG, McGue, M, Metspalu, A, Pendleton, N, Penninx, BWJH, Perola, M, Pirastu, N, Pirastu, M, Polasek, O, Posthuma, Daniëlle, Power, C, Province, MA, Samani, NJ, Schlessinger, D, Schmidt, R, Sorensen, TIA, Spector, TD, Stefansson, K, Thorsteinsdottir, U, Thurik, Roy, Timpson, NJ, Tiemeier, Henning, Tung, JY, Uitterlinden, André, Vitart, V, Vollenweider, P, Weir, DR, Wilson, JF, Wright, AF, Conley, DC, Krueger, RF, Smith, GD, Hofman, Bert, Laibson, DI, Medland, SE, Meyer, MN, Yang, Jiaqi, Johannesson, M, Visscher, PM, Esko, T, Koellinger, PD, Cesarini, D, and Benjamin, DJ

Abstract

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample(1,2) of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results