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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. 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

9. 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

10. 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

11. 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

12. 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

13. Genetic variants linked to education predict longevity

Author: Chris Power, Gail Davies, Ilaria Gandin, Panagiotis Deloukas, Jennifer E. Huffman, Pascal Timshel, Albert V. Smith, A. Kong, Paul Lichtenstein, Joseph K. Pickrell, Philipp Koellinger, P. L. De Jager, Reedik Mägi, G. B. Chen, Neil Pendleton, B. V. Halldórsson, George Dedoussis, Antti-Pekka Sarin, Natalia Pervjakova, Veikko Salomaa, Simona Vaccargiu, Ozren Polasek, K. H. Jöckel, Elisabeth Steinhagen-Thiessen, Y. Milaneschi, Jessica D. Faul, Patricia A. Boyle, Patrik K. E. Magnusson, Igor Rudan, Christopher P. Nelson, Vilmundur Gudnason, John Attia, Jürgen Wellmann, Kristi Läll, Konstantin Strauch, Stuart J. Ritchie, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, R. de Vlaming, Liisa Keltigangas-Jarvinen, Thomas Meitinger, Riccardo E. Marioni, Anu Loukola, Barbera Franke, Reinhold Schmidt, Maël Lebreton, Sven Oskarsson, E. Mihailov, Harm-Jan Westra, David R. Weir, Aldi T. Kraja, Niek Verweij, Peter M. Visscher, Hans-Jörgen Grabe, Johannes H. Brandsma, Mark Adams, R. J. Scott, G. Thorleifsson, Tõnu Esko, Mika Kähönen, Saskia P. Hagenaars, Patrick Turley, Johannes Waage, Peter Lichtner, Dragana Vuckovic, Antonietta Robino, Henry Völzke, Lydia Quaye, C. de Leeuw, Marika Kaakinen, Wei Zhao, Abdel Abdellaoui, Reka Nagy, Pedro Marques-Vidal, Johan G. Eriksson, Alan F. Wright, Andres Metspalu, Lavinia Paternoster, Momoko Horikoshi, Jan A. Staessen, Tarunveer S. Ahluwalia, Tian Liu, Martin Kroh, Aldo Rustichini, Giorgia Girotto, Cristina Venturini, Lili Milani, Jennifer A. Smith, Ginevra Biino, Tessel E. Galesloot, Michael A. Horan, Gerardus A. Meddens, James F. Wilson, Francesco Cucca, Peter Vollenweider, Erika Salvi, P. J. van der Most, Jari Lahti, Campbell A, David Laibson, Andrew Bakshi, Wolfgang Hoffmann, Tomi Mäki-Opas, Andreas J. Forstner, C M van Duijn, Nicholas G. Martin, Jonathan Marten, Ute Bültmann, Olli T. Raitakari, David A. Bennett, A.G. Uitterlinden, J. E. De Neve, Ingrid B. Borecki, WD Hill, Bo Jacobsson, Antti Latvala, Katri Räikkönen, Michael B. Miller, Jonathan P. Beauchamp, S. J. van der Lee, Ilja Demuth, Stavroula Kanoni, Veronique Vitart, Elina Hyppönen, N. Eklund, Francesco P. Cappuccio, Robert F. Krueger, Maria Pina Concas, Jaime Derringer, F. J.A. Van Rooij, Helena Schmidt, Patrick J. F. Groenen, Valur Emilsson, Rico Rueedi, Aysu Okbay, Georg Homuth, Edith Hofer, W. E. R. Ollier, Hannah Campbell, Paolo Gasparini, Mark Alan Fontana, Magnus Johannesson, Seppo Koskinen, Christopher F. Chabris, Jouke-Jan Hottenga, Christine Meisinger, Kari Stefansson, Jun Ding, Tia Sorensen, Brenda W.J.H. Penninx, Michelle N. Meyer, James J. Lee, Diego Vozzi, Gonneke Willemsen, K. Petrovic, Sarah E. Medland, Mary F. Feitosa, Henning Tiemeier, L. J. Launer, William G. Iacono, Massimo Mangino, Tune H. Pers, S. E. Baumeister, Christopher Oldmeadow, Grant W. Montgomery, Marjo-Riitta Järvelin, Jaakko Kaprio, Catharine R. Gale, S.F.W. Meddens, Kevin Thom, Klaus Berger, Pablo V. Gejman, Lude Franke, Gyda Bjornsdottir, Daniel J. Benjamin, Steven F. Lehrer, Krista Fischer, Alan R. Sanders, S. Ulivi, Katharina E. Schraut, Tim D. Spector, Amy Hofman, Matt McGue, Terho Lehtimäki, D. C. Liewald, Hans Bisgaard, L. Eisele, Astanand Jugessur, George Davey Smith, T.B. Harris, A.R. Thurik, Cornelius A. Rietveld, David Schlessinger, Z. Kutalik, David J. Porteous, Lynne J. Hocking, N J Timpson, A. Palotie, Lambertus A. Kiemeney, Ian J. Deary, Sharon L.R. Kardia, Peter K. Joshi, Nilesh J. Samani, Michael A. Province, Börge Schmidt, Richa Gupta, Carmen Amador, Erin B. Ware, Joyce Y. Tung, Ioanna-Panagiota Kalafati, Lars Bertram, Caroline Hayward, P. van der Harst, Penelope A. Lind, Kadri Kaasik, N.A. Furlotte, Sarah E. Harris, B. St Pourcain, Susan M. Ring, Zhihong Zhu, Alexander Teumer, Behrooz Z. Alizadeh, Judith M. Vonk, Blair H. Smith, A Payton, Wouter J. Peyrot, Jacob Gratten, Douglas F. Levinson, C Gieger, Leanne M. Hall, Andrew Heath, Mario Pirastu, Peter Eibich, Nancy L. Pedersen, Ronny Myhre, Antonio Terracciano, David M. Evans, Raymond A. Poot, Uwe Völker, Dorret I. Boomsma, Clemens Baumbach, Unnur Thorsteinsdottir, Ivana Kolcic, Jia-Shu Yang, Dalton Conley, A. A. Vinkhuyzen, Danielle Posthuma, Karl-Oskar Lindgren, Olga Rostapshova, Jonas Bacelis, Daniele Cusi, Yong Qian, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Pamela A. F. Madden, David A. Hinds, David Cesarini, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Applied Economics, Epidemiology, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Aletta Jacobs School of Public Health, Public Health Research (PHR), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, EMGO - Mental health, Complex Trait Genetics, Biological Psychology, Marioni, RE, Ritchie, SJ, Joshi, PK, Hagenaars, SP, Hypponen, E, Benjamin, DJ, Social Science Genetic Association Consortium, Marioni, Re, Ritchie, Sj, Joshi, Pk, Hagenaars, Sp, Okbay, A, Fischer, K, Adams, Mj, Hill, Wd, Davies, G, Nagy, R, Amador, C, Läll, K, Metspalu, A, Liewald, Dc, Campbell, A, Wilson, Jf, Hayward, C, Esko, T, Porteous, Dj, Gale, Cr, Deary, Ij, Beauchamp, Jp, Fontana, Ma, Lee, Jj, Pers, Th, Rietveld, Ca, Turley, P, Chen, Gb, Emilsson, V, Meddens, Sf, Oskarsson, S, Pickrell, Jk, Thom, K, Timshel, P, de Vlaming, R, Abdellaoui, A, Ahluwalia, T, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Jh, Concas, MARIA PINA, Derringer, J, Furlotte, Na, Galesloot, Te, Girotto, Giorgia, 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, Sj, 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, J, Smith, Av, Poot, Ra, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N, Vuckovic, Dragana, Wellmann, J, Westra, Hj, Yang, J, Zhao, W, Zhu, Z, Alizadeh, Bz, Amin, N, Bakshi, A, Baumeister, Se, Biino, G, Bønnelykke, K, Boyle, Pa, Campbell, H, Cappuccio, Fp, De Neve, Je, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, Dm, Faul, Jd, Feitosa, Mf, Forstner, Aj, Gandin, Ilaria, Gunnarsson, B, Halldórsson, Bv, Harris, Tb, Heath, Ac, Hocking, Lj, Holliday, Eg, Homuth, G, Horan, Ma, Hottenga, Jj, de Jager, Pl, Jugessur, A, Kaakinen, Ma, Kähönen, M, Kanoni, S, Keltigangas Järvinen, L, Kiemeney, La, Kolcic, I, Koskinen, S, Kraja, At, Kroh, M, Kutalik, Z, Latvala, A, Launer, Lj, Lebreton, Mp, Levinson, Df, Lichtenstein, P, Lichtner, P, Loukola, A, Madden, Pa, Mägi, R, Mäki Opas, T, Marques Vidal, P, Meddens, Ga, Mcmahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, Gw, Myhre, R, Nelson, Cp, Nyholt, Dr, Ollier, We, Palotie, A, Paternoster, L, Pedersen, Nl, Petrovic, Ke, Räikkönen, K, Ring, Sm, Robino, Antonietta, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, Ar, Sarin, Ap, Schmidt, H, Scott, Rj, Smith, Bh, Smith, Ja, Staessen, Ja, Steinhagen Thiessen, E, Strauch, K, Terracciano, A, Tobin, Md, Ulivi, Sheila, Vaccargiu, S, Quaye, L, van Rooij, Fj, Venturini, C, Vinkhuyzen, Aa, Völker, U, Völzke, H, Vonk, Jm, Vozzi, Diego, 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, Dedoussis, Gv, van Duijn, Cm, Eriksson, Jg, Franke, B, Franke, L, Gasparini, Paolo, Gejman, Pv, Gieger, C, Grabe, Hj, Gratten, J, Groenen, Pj, Gudnason, V, van der Harst, P, Hinds, Da, Hoffmann, W, Iacono, Wg, Jacobsson, B, Järvelin, Mr, Jöckel, Kh, Kaprio, J, Kardia, Sl, Lehtimäki, T, Lehrer, Sf, Magnusson, Pk, Martin, Ng, Mcgue, M, Pendleton, N, Penninx, Bw, Perola, M, Pirastu, Nicola, Pirastu, M, Polasek, O, Posthuma, D, Power, C, Province, Ma, Samani, Nj, Schlessinger, D, Schmidt, R, Sørensen, Ti, Spector, Td, Stefansson, K, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tiemeier, H, Tung, Jy, Uitterlinden, Ag, Vitart, V, Vollenweider, P, Weir, Dr, Wright, Af, Conley, Dc, Krueger, Rf, Smith, Gd, Hofman, A, Laibson, Di, Medland, Se, Meyer, Mn, Johannesson, M, Visscher, Pm, Koellinger, Pd, Cesarini, D, and Benjamin, Dj
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Male, Parents, education: longevity: prediction: polygenic score [genetics], Multifactorial Inheritance, polygenic, Lebenserwartung, Cohort Studies, 0302 clinical medicine, Databases, Genetic, Medicine, genetics, polygenic score, longevity, education, gene, Soziales und Gesundheit, media_common, Aged, 80 and over, education, Multidisciplinary, Longevity, Middle Aged, Biobank, humanities, 3. Good health, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cohort, Educational Status, Female, Cohort study, Estonia, education, longevity, polygenic, Offspring, media_common.quotation_subject, Kultursektor, Prognose, Lernen, Lower risk, Education, 03 medical and health sciences, longevity, SDG 3 - Good Health and Well-being, Commentaries, Polygenic score, Journal Article, Genetics, Humans, Non-Profit-Sektor, Genetic Association Studies, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, ta1184, Genetic Variation, prediction, Educational attainment, United Kingdom, Gesundheitsstatistik, 030104 developmental biology, Genetic epidemiology, Scotland, Gesundheitszustand, Genetische Forschung, business, Prediction, Bildung, 030217 neurology & neurosurgery, Demography
Abstract: Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G, Social Science Genetic Association Consortium, Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, no. 47, pp. 13366-13371, 2016 Refereed/Peer-reviewed
Published: 2016

14. The association between lower educational attainment and depression owing to shared genetic effects?: Results in ~25,000 subjects

Author: Patricia A. Peyser, Jessica D. Faul, Patrik K. E. Magnusson, Nicholas D. Hastie, Beate St Pourcain, Marcus Ising, Gérard Waeber, Behrooz Z. Alizadeh, Judith M. Vonk, Lawrence F. Bielak, Sang Hong Lee, Wouter J. Peyrot, Thomas Illig, M. M. Weissman, Nicholas J. Timpson, George Dedoussis, Nicholas G. Martin, Tomi E. Mäkinen, Jorma Viikari, Lili Milani, Harold Snieder, Laura J. Bierut, A. C. Heath, Reinhold E. Schmidt, Mariza de Andrade, Vilmundur Gudnason, K. Petrovic, Robert M. Kirkpatrick, Marcela González Gross, William G. Iacono, Michelle N. Meyer, Henry Völzke, Marisa Loitfelder, Maria Dimitriou, Lude Franke, Robert F. Krueger, E. J. C. G. van den Oord, Sven Cichon, Michael Conlon O'Donovan, Ian W. Craig, Shawn N. Murphy, Danielle Posthuma, Brenda W.J.H. Penninx, Aarno Palotie, Roy Thurik, Panos Deloukas, Matt McGue, M. Preisig, Patricia A. Boyle, Osorio Meirelles, Ben A. Oostra, Klaus Berger, G. M. Montgomery, Sharon L.R. Kardia, Peter K. Joshi, K. Stefansson, Paul Lichtenstein, Andrew Heath, Andrea Schulz, Dena G. Hernandez, Debbie A Lawlor, S. P. Hamilton, James B. Potash, Z. Kutalik, Elisabeth Widen, Emil L. Sigurdsson, Rudolf S N Fehrmann, Matthias Nauck, Mikael Landén, Kurt Lohman, S.D. Gordon, Lefkos T. Middleton, Caroline Hayward, Anjali K. Henders, Philipp Koellinger, Jeffrey A. Boatman, G van Grootheest, M. Daly, Jian Yang, Peter Vollenweider, Penelope A. Lind, Stacy Steinberg, Frank J. A. van Rooij, Florian Holsboer, Hkon K. Gjessing, Erkki Vartiainen, Magnus Johannesson, Jingmei Li, David Laibson, Henrik Grönberg, Tõnu Esko, Ivana Kolcic, Niina Eklund, Kelly S. Benke, Henning Tiemeier, Isaac S. Kohane, Nicolas W. Martin, Ronny Myhre, Frans G. Zitman, Arpana Agrawal, James F. Wilson, Michael R. Barnes, Lei Yu, Thorgeir E. Thorgeirsson, Franois Bastardot, Katri Räikkönen, William Lawson, Willem A. Nolen, M. Rietschel, René Breuer, Bertram Müller-Myhsok, James A. Knowles, Grant W. Montgomery, Eva Reinmaa, Rudolf Uher, Andreas Mielck, Luigi Ferrucci, S. E. Medland, Yuri Milaneschi, Philip L. De Jager, Manfred Uhr, A. E. Farmer, Cornelia M. van Duijn, Samuli Ripatti, Marja-Liisa Nuotio, Manuel Mattheisen, Sebastian E. Baumeister, David R. Van Wagoner, Martin Preisig, Fernando Rivadeneira, Peter Lichtner, Christopher Oldmeadow, Hreinn Stefansson, Ian B. Hickie, Darina Czamara, Elizabeth G. Holliday, Astanand Jugessur, Carla A. Ibrahim-Verbaas, Jaime Derringer, Vivian S. Gainer, P. Muglia, Daniel J. Benjamin, Patrick K.E. Magnusson, Patience J. Gallagher, Jennifer A. Smith, Lynn Cherkas, Pamela A. F. Madden, David A. Bennett, Zoltán Kutalik, George Davey-Smith, Gudny Eiriksdottir, Jens Treutlein, N. Craddock, Juliette Harris, Antti Latvala, Roy H. Perlis, Markus M. Noethen, Jan-Emmanuel De Neve, Stanley I. Shyn, J.H. Smit, Dalton Conley, Adriaan Hofman, Jari Lahti, Patrick J. F. Groenen, Jüri Allik, Albert V. Smith, Ozren Polasek, Susan M. Ring, Thomas Bettecken, Michele L. Pergadia, Patrick J. McGrath, Katherine E. Tansey, Stephan Ripke, Hogni Oskarsson, Peng Lin, Douglas F. Levinson, Matthijs J. H. M. van der Loos, Melissa E. Garcia, Jonathan P. Beauchamp, Rodney J. Scott, Zhihong Zhu, Michel Guipponi, Lyle J. Palmer, Alexander Teumer, William Coryell, Stefan Kloiber, Gonneke Willemsen, John Frank, Victor M. Castro, Andrew M. McIntosh, John M. Starr, Antonio Terracciano, Mika Kähönen, Marco Masala, Markus Perola, André G. Uitterlinden, Sutapa Mukherjee, Alexander Viktorin, Lenore J. Launer, Elisabeth B. Binder, William A. Scheftner, Christel M. Middeldorp, D. H. R. Blackwood, I. Jones, Thais S. Rizzi, A. Teumer, Cornelius A. Rietveld, Aldo Rustichini, Guy Lewis, Susan L. Slager, David M. Evans, Dorret I. Boomsma, Harry Campbell, Susanne Churchill, Johan G. Eriksson, Alan F. Wright, Dan V. Iosifescu, W. Maier, Francesco Cucca, Federica Tozzi, David R. Weir, Eva Albrecht, L. Milani, Jennifer R. Harris, Min A. Jhun, Marjo-Riitta Järvelin, Martin F. Elderson, Ute Bültmann, Olli T. Raitakari, Konstantin Shakhbazov, Krista Fischer, Thomas G. Schulze, T. Jung-Ying, P. Lichtenstein, Terho Lethimäki, Jeffrey B. Weilburg, Rolf Holle, Bo Jacobsson, Pedro Marques Vidal, Jordan W. Smoller, Stavroula Kanoni, Kati Kristiansson, Sergey Goryachev, Michael Steffens, Peter M. Visscher, Toshiko Tanaka, Donald J. MacIntyre, Witte J.G. Hoogendijk, David Schlessinger, Ian J. Deary, Harm-Jan Westra, Erik Ingelsson, E.J.C. de Geus, Franziska Degenhardt, Lydia Quaye, John Barnard, David C. Liewald, John P. Rice, Christopher F. Chabris, P. McGuffin, Tamara B. Harris, C. M. Lewis, Gail Davies, Enda M. Byrne, H.-Erich Wichmann, Sara Hägg, David Cesarini, Najaf Amin, Juha Karjalainen, Dale R. Nyholt, Christian Gieger, Per Hall, Ania Korszun, Neale Bm, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Christina Holzapfel, Jae Hoon Sul, Christiaan de Leeuw, Antti-Pekka Sarin, Ida Surakka, Veikko Salomaa, Mina K. Chung, N. L. Pedersen, Gerome Breen, P. A. F. Madden, Martin A. Kohli, J Kaprio, John Attia, Jing Shi, Gibran Hemani, Rauli Svento, Veronique Vitart, Susanne Lucae, L. A. Jones, Jouke-Jan Hottenga, Daniel S. Evans, Hans-Jörgen Grabe, Yongmei Liu, Danyu Lin, Albert Hofman, George McMahon, Naomi R. Wray, Stefan Herms, Stefania Bandinelli, W. Hoffmann, P.F. Sullivan, Susanne Hoefels, Michael B. Miller, Alan W. McLean, Igor Rudan, Jürgen Wellmann, Anu Realo, Maurizio Fava, Matthew Kowgier, Marika Kaakinen, Helena Schmidt, Faculteit Medische Wetenschappen/UMCG, Peyrot, WJ, Lee, SH, Milaneschi, Y, Abdellaoui, A, Penninx, BWJH, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Social Science Genetic Association Consortium, Psychiatry, NCA - Neurobiology of mental health, EMGO - Mental health, Applied Economics, Biological Psychology, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (Corporate Collaborator), Social Science Genetic Association Consortium Corporate Collaborator, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium Corporate Collaborator, Lewis, C.M., Hamilton, S.P., Weissman, M.M., Breen, G., Blackwood, D.H., Cichon, S., Heath, A.C., Holsboer, F., Madden, P.A., McGuffin, P., Muglia, P., Pergadia, M.L., Lin, D., Müller-Myhsok, B., Steinberg, S., Grabe, H.J., Lichtenstein, P., Magnusson, P., Perlis, R.H., Preisig, M., Smoller, J.W., Stefansson, K., Uher, R., Kutalik, Z., Tansey, K.E., Teumer, A., Viktorin, A., Barnes, M.R., Bettecken, T., Binder, E.B., Breuer, R., Castro, V.M., Churchill, S.E., Coryell, W.H., Craddock, N., Craig, I.W., Czamara, D., Degenhardt, F., Farmer, A.E., Fava, M., Frank, J., Gainer, V.S., Gallagher, P.J., Gordon, S.D., Goryachev, S., Gross, M., Guipponi, M., Henders, A.K., Herms, S., Hickie, I.B., Hoefels, S., Hoogendijk, W., Iosifescu, D.V., Ising, M., Jones, I., Jones, L., Jung-Ying, T., Knowles, J.A., Kohane, I.S., Kohli, M.A., Korszun, A., Landen, M., Lawson, W.B., Lewis, G., Macintyre, D., Maier, W., Mattheisen, M., McGrath, P.J., McIntosh, A., McLean, A., Middeldorp, C.M., Middleton, L., Montgomery, G.M., Murphy, S.N., Nauck, M., Nolen, W.A., Nyholt, D.R., O'Donovan, M., Oskarsson, H., Pedersen, N., Scheftner, W.A., Schulz, A., Schulze, T.G., Shyn, S.I., Sigurdsson, E., Slager, S.L., Smit, J.H., Stefansson, H., Steffens, M., Thorgeirsson, T., Tozzi, F., Treutlein, J., Uhr, M., van den Oord, E.J., Van Grootheest, G., Völzke, H., Weilburg, J.B., Willemsen, G., Zitman, F.G., Neale, B., Daly, M., Sullivan, P.F., Agrawal, A., Albrecht, E., Alizadeh, B.Z., Allik, J., Amin, N., Attia, J.R., Bandinelli, S., Barnard, J., Bastardot, F., Baumeister, S.E., Beauchamp, J., Benjamin, D.J., Benke, K.S., Bennett, D.A., Berger, K., Bielak, L.F., Bierut, L.J., Boatman, J.A., Boyle, P.A., Bültmann, U., Campbell, H., Cesarini, D., Chabris, C.F., Cherkas, L., Chung, M.K., Conley, D., Cucca, F., Davey-Smith, G., Davies, G., de Andrade, M., De Jager, P.L., de Leeuw, C., De Neve, J.E., Deary, I.J., Dedoussis, G.V., Deloukas, P., Derringer, J., Dimitriou, M., Eiriksdottir, G., Eklund, N., Elderson, M.F., Eriksson, J.G., Evans, D.S., Evans, D.M., Faul, J.D., Fehrmann, R., Ferrucci, L., Fischer, K., Franke, L., Garcia, M.E., Gieger, C., Gjessing, H.K., Groenen, P.J., Grönberg, H., Gudnason, V., Hägg, S., Hall, P., Harris, J.R., Harris, J.M., Harris, T.B., Hastie, N.D., Hayward, C., Hernandez, D.G., Hoffmann, W., Hofman, A., Holle, R., Holliday, E.G., Holzapfel, C., Iacono, W.G., Ibrahim-Verbaas, C.A., Illig, T., Ingelsson, E., Jacobsson, B., Järvelin, M.R., Jhun, M.A., Johannesson, M., Joshi, P.K., Jugessur, A., Kaakinen, M., Kähönen, M., Kanoni, S., Kaprio, J., Kardia, S.L., Karjalainen, J., Kirkpatrick, R.M., Koellinger, P.D., Kolcic, I., Kowgier, M., Kristiansson, K., Krueger, R.F., Lahti, J., Laibson, D., Latvala, A., Launer, L.J., Lawlor, D.A., Lethimäki, T., Li, J., Lichtner, P.K., Liewald, D.C., Lin, P., Lind, P.A., Liu, Y., Lohman, K., Loitfelder, M., Magnusson, P.K., Mäkinen, T.E., Vidal, P.M., Martin, N.W., Masala, M., McGue, M., McMahon, G., Meirelles, O., Meyer, M.N., Mielck, A., Milani, L., Miller, M.B., Montgomery, G.W., Mukherjee, S., Myhre, R., Nuotio, M.L., Oldmeadow, C.J., Oostra, B.A., Palmer, L.J., Palotie, A., Perola, M., Petrovic, K.E., Peyser, P.A., Polašek, O., Posthuma, D., Quaye, L., Räikkönen, K., Raitakari, O.T., Realo, A., Reinmaa, E., Rice, J.P., Ring, S.M., Ripatti, S., Rivadeneira, F., Rizzi, T.S., Rudan, I., Rustichini, A., Salomaa, V., Sarin, A.P., Schlessinger, D., Schmidt, H., Schmidt, R., Scott, R.J., Shakhbazov, K., Smith, A.V., Smith, J.A., Snieder, H., Pourcain, B.S., Starr, J.M., Sul, J.H., Surakka, I., Svento, R., Tanaka, T., Terracciano, A., Thurik, A.R., Tiemeier, H., Timpson, N.J., Uitterlinden, A.G., van der Loos, M.J., van Duijn, C.M., van Rooij, F.J., Van Wagoner, D.R., Vartiainen, E., Viikari, J., Visscher, P.M., Vitart, V., Vollenweider, P.K., Vonk, J.M., Waeber, G., Weir, D.R., Wellmann, J., Westra, H.J., Wichmann, H.E., Widen, E., Wilson, J.F., Wright, A.F., Yang, J., Yu, L., and Zhao, W.
Subjects: Netherlands Twin Register (NTR), Male, Genome-wide association study, Logistic regression, Cohort Studies, Odds Ratio, pleiotropic genetic effects, Netherlands, Psychiatry, education.field_of_study, Likelihood Functions, Single Nucleotide, Middle Aged, Psychiatry and Mental health, educational attainment, depression, Major depressive disorder, Educational Status, Regression Analysis, Female, Psychology, Adult, Estonia, medicine.medical_specialty, Biochemistry & Molecular Biology, Aged, Depressive Disorder, Major/epidemiology, Depressive Disorder, Major/genetics, Depressive Disorder, Major/psychology, Estonia/epidemiology, Gene-Environment Interaction, Genetic Association Studies, Genotype, Humans, Netherlands/epidemiology, Polymorphism, Single Nucleotide/genetics, Psychiatric Status Rating Scales, Concordance, Population, SNP, Single-nucleotide polymorphism, Genetic correlation, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, mental disorders, medicine, Polymorphism, education, Molecular Biology, Depressive Disorder, Depressive Disorder, Major, major depressive disorder, ta1184, Neurosciences, Major, Odds ratio, medicine.disease, ta3124, Neurosciences & Neurology, polymorphisms, Demography
Abstract: An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on similar to 120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. Refereed/Peer-reviewed
Published: 2015

15. On the interpretation of transcriptome-wide association studies.

Author: de Leeuw C, Werme J, Savage JE, Peyrot WJ, and Posthuma D
Subjects: Chromosome Mapping, Computer Simulation, Data Analysis, Genome-Wide Association Study, Transcriptome genetics
Abstract: Transcriptome-wide association studies (TWAS) aim to detect relationships between gene expression and a phenotype, and are commonly used for secondary analysis of genome-wide association study (GWAS) results. Results from TWAS analyses are often interpreted as indicating a genetic relationship between gene expression and a phenotype, but this interpretation is not consistent with the null hypothesis that is evaluated in the traditional TWAS framework. In this study we provide a mathematical outline of this TWAS framework, and elucidate what interpretations are warranted given the null hypothesis it actually tests. We then use both simulations and real data analysis to assess the implications of misinterpreting TWAS results as indicative of a genetic relationship between gene expression and the phenotype. Our simulation results show considerably inflated type 1 error rates for TWAS when interpreted this way, with 41% of significant TWAS associations detected in the real data analysis found to have insufficient statistical evidence to infer such a relationship. This demonstrates that in current implementations, TWAS cannot reliably be used to investigate genetic relationships between gene expression and a phenotype, but that local genetic correlation analysis can serve as a potential alternative., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 de Leeuw et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2023
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16. Genome-wide association studies of polygenic risk score-derived phenotypes may lead to inflated false positive rates.

Author: Uffelmann E, Posthuma D, and Peyrot WJ
Subjects: Humans, Biological Specimen Banks, Phenotype, Risk Factors, United Kingdom, Genome-Wide Association Study, Alzheimer Disease
Published: 2023
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17. [What can genetic research teach us about the overlap and differences between psychiatric disorders?]

Author: Peyrot WJ, Nivard MG, and de Leeuw CA
Subjects: Genetic Research, Humans, Mental Disorders genetics
Abstract: Background: Genetic research has made continuous progress in the past years, as a results of the rapidly growing sample sizes and development of novel analytical tools.
AIM: To present the latest developments in research into the genetic overlap and differences between psychiatric disorders.
METHOD: Description of findings from recent literature.
RESULTS: First of all, psychiatric disorders differ in their heritability, and consequently impact of environmental factors. Second, some disorders show high concordance in direction of genetic effects, while other disorders have rather different effects. Using these genetic (dis)similarities, subgroups of psychiatric disorders can also be defined.
CONCLUSION: Genetic research is developing at rapid pace, and much more will be learned about the genetic overlap and differences between psychiatric disorders in the next years. The big promise -and challenge- will be to integrate genetic research with research of environmental factors, other biological measures and more detailed phenotypic information.
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Published: 2022

18. A role for vitamin D and omega-3 fatty acids in major depression? An exploration using genomics.

Author: Milaneschi Y, Peyrot WJ, Nivard MG, Mbarek H, Boomsma DI, and W J H Penninx B
Subjects: Adult, Depressive Disorder, Major drug therapy, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Multifactorial Inheritance, Pharmacogenetics, Depressive Disorder, Major genetics, Fatty Acids, Omega-3 therapeutic use, Vitamin D therapeutic use
Abstract: Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. In individual-level data analyses, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e - 20, PRS n3-PUFA p = 9.3e - 6, PRS MDD p = 1.4e - 4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data analyses, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). Applying genomics tools indicated that shared genetic risk or direct causality between 25-OH-D, n3-PUFA, and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.
Published: 2019
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19. 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, Åslund 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 Jr, Breslau N, and Bierut LJ
Subjects: Cooperative Behavior, Gene-Environment Interaction, Genetic Predisposition to Disease, Genotype, Humans, Life Change Events, Stress, Psychological genetics, Depression genetics, Depression psychology, Serotonin Plasma Membrane Transport Proteins genetics, Stress, Psychological complications
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
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20. Correction: 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 L, Workalemahu T, Heard-Costa NL, den Hoed M, Ahluwalia TS, Qi Q, Ngwa JS, Renström F, Quaye L, Eicher JD, Hayes JE, Cornelis M, Kutalik Z, Lim E, Luan J, Huffman JE, Zhang W, Zhao W, Griffin PJ, Haller T, Ahmad S, 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, Lyytikäinen LP, Huppertz C, Willemsen G, Peyrot WJ, Wu Y, Kristiansson K, Demirkan A, Fornage M, Hassinen M, Bielak LF, Cadby G, Tanaka T, Mägi R, van der Most PJ, Jackson AU, Bragg-Gresham JL, Vitart V, Marten J, Navarro P, Bellis C, Pasko D, Johansson Å, Snitker S, Cheng YC, Eriksson J, Lim U, Aadahl M, Adair LS, Amin N, 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, Dörr M, Ebeling T, Eiriksdottir G, Esko T, Faul JD, Fu M, Færch K, Gieger C, Gläser 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-Kähönen N, James AL, Jansson JO, Jhun MA, Juonala M, Kinnunen L, Koistinen HA, Kolcic I, Komulainen P, Kuusisto J, Kvaløy K, Kähönen M, Lakka TA, Launer LJ, Lehne B, Lindgren CM, Lorentzon M, Luben R, Marre M, Milaneschi Y, Monda KL, Montgomery GW, De Moor MHM, Mulas A, Müller-Nurasyid M, Musk AW, Männikkö R, Männistö S, Narisu N, Nauck M, Nettleton JA, Nolte IM, Oldehinkel AJ, 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, Stančáková A, Sternfeld B, Swift AJ, Tammelin T, Tan ST, Thorand B, Thuillier D, Vandenput L, Vestergaard H, van Vliet-Ostaptchouk JV, Vohl MC, Völker U, Waeber G, Walker M, Wild S, Wong A, Wright AF, Zillikens MC, Zubair N, Haiman CA, Lemarchand L, Gyllensten U, Ohlsson C, Hofman A, Rivadeneira F, Uitterlinden AG, Pérusse L, Wilson JF, Hayward C, Polasek O, Cucca F, Hveem K, Hartman CA, Tönjes A, Bandinelli S, Palmer LJ, Kardia SLR, Rauramaa R, Sørensen TIA, Tuomilehto J, Salomaa V, Penninx BWJH, de Geus EJC, Boomsma DI, Lehtimäki T, Mangino M, Laakso M, Bouchard C, Martin NG, Kuh D, Liu Y, Linneberg A, März W, Strauch K, Kivimäki M, Harris TB, Gudnason V, Völzke H, Qi L, Järvelin 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, van Duijn CM, 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 Kilpeläinen TO
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1006528.].
Published: 2017
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21. 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 L, Workalemahu T, Heard-Costa NL, den Hoed M, Ahluwalia TS, Qi Q, Ngwa JS, Renström F, Quaye L, Eicher JD, Hayes JE, Cornelis M, Kutalik Z, Lim E, Luan J, Huffman JE, Zhang W, Zhao W, Griffin PJ, Haller T, Ahmad S, 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, Lyytikäinen LP, Huppertz C, Willemsen G, Peyrot WJ, Wu Y, Kristiansson K, Demirkan A, Fornage M, Hassinen M, Bielak LF, Cadby G, Tanaka T, Mägi R, van der Most PJ, Jackson AU, Bragg-Gresham JL, Vitart V, Marten J, Navarro P, Bellis C, Pasko D, Johansson Å, Snitker S, Cheng YC, Eriksson J, Lim U, Aadahl M, Adair LS, Amin N, 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, Dörr M, Ebeling T, Eiriksdottir G, Esko T, Faul JD, Fu M, Færch K, Gieger C, Gläser 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-Kähönen N, James AL, Jansson JO, Jhun MA, Juonala M, Kinnunen L, Koistinen HA, Kolcic I, Komulainen P, Kuusisto J, Kvaløy K, Kähönen M, Lakka TA, Launer LJ, Lehne B, Lindgren CM, Lorentzon M, Luben R, Marre M, Milaneschi Y, Monda KL, Montgomery GW, De Moor MHM, Mulas A, Müller-Nurasyid M, Musk AW, Männikkö R, Männistö S, Narisu N, Nauck M, Nettleton JA, Nolte IM, Oldehinkel AJ, 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, Stančáková A, Sternfeld B, Swift AJ, Tammelin T, Tan ST, Thorand B, Thuillier D, Vandenput L, Vestergaard H, van Vliet-Ostaptchouk JV, Vohl MC, Völker U, Waeber G, Walker M, Wild S, Wong A, Wright AF, Zillikens MC, Zubair N, Haiman CA, Lemarchand L, Gyllensten U, Ohlsson C, Hofman A, Rivadeneira F, Uitterlinden AG, Pérusse L, Wilson JF, Hayward C, Polasek O, Cucca F, Hveem K, Hartman CA, Tönjes A, Bandinelli S, Palmer LJ, Kardia SLR, Rauramaa R, Sørensen TIA, Tuomilehto J, Salomaa V, Penninx BWJH, de Geus EJC, Boomsma DI, Lehtimäki T, Mangino M, Laakso M, Bouchard C, Martin NG, Kuh D, Liu Y, Linneberg A, März W, Strauch K, Kivimäki M, Harris TB, Gudnason V, Völzke H, Qi L, Järvelin 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, van Duijn CM, 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 Kilpeläinen TO
Subjects: Adiposity physiology, Body Mass Index, Epigenomics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Obesity physiopathology, Waist Circumference, Waist-Hip Ratio, Adiposity genetics, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Exercise, Obesity genetics
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Published: 2017
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22. Genetic effects influencing risk for major depressive disorder in China and Europe.

Author: Bigdeli TB, Ripke S, Peterson RE, Trzaskowski M, Bacanu SA, Abdellaoui A, Andlauer TF, Beekman AT, Berger K, Blackwood DH, Boomsma DI, Breen G, Buttenschøn HN, Byrne EM, Cichon S, Clarke TK, Couvy-Duchesne B, Craddock N, de Geus EJ, Degenhardt F, Dunn EC, Edwards AC, Fanous AH, Forstner AJ, Frank J, Gill M, Gordon SD, Grabe HJ, Hamilton SP, Hardiman O, Hayward C, Heath AC, Henders AK, Herms S, Hickie IB, Hoffmann P, Homuth G, Hottenga JJ, Ising M, Jansen R, Kloiber S, Knowles JA, Lang M, Li QS, Lucae S, MacIntyre DJ, Madden PA, Martin NG, McGrath PJ, McGuffin P, McIntosh AM, Medland SE, Mehta D, Middeldorp CM, Milaneschi Y, Montgomery GW, Mors O, Müller-Myhsok B, Nauck M, Nyholt DR, Nöthen MM, Owen MJ, Penninx BW, Pergadia ML, Perlis RH, Peyrot WJ, Porteous DJ, Potash JB, Rice JP, Rietschel M, Riley BP, Rivera M, Schoevers R, Schulze TG, Shi J, Shyn SI, Smit JH, Smoller JW, Streit F, Strohmaier J, Teumer A, Treutlein J, Van der Auwera S, van Grootheest G, van Hemert AM, Völzke H, Webb BT, Weissman MM, Wellmann J, Willemsen G, Witt SH, Levinson DF, Lewis CM, Wray NR, Flint J, Sullivan PF, and Kendler KS
Subjects: Bayes Theorem, Case-Control Studies, China, Europe, Female, Genetic Predisposition to Disease, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Asian People genetics, Depressive Disorder, Major genetics, White People genetics
Abstract: Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log 10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
Published: 2017
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23. Genome-wide association study identifies 74 loci associated with educational attainment.

Author: Okbay A, Beauchamp JP, Fontana MA, Lee JJ, Pers TH, Rietveld CA, Turley P, Chen GB, Emilsson V, Meddens SF, Oskarsson S, Pickrell JK, Thom K, Timshel P, de Vlaming R, Abdellaoui A, Ahluwalia TS, Bacelis J, Baumbach C, Bjornsdottir G, Brandsma JH, Pina Concas M, 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 SJ, deLeeuw 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 J, Smith AV, Poot RA, St Pourcain B, Teumer A, Thorleifsson G, Verweij N, Vuckovic D, Wellmann J, Westra HJ, Yang J, Zhao W, Zhu Z, Alizadeh BZ, Amin N, Bakshi A, Baumeister SE, Biino G, Bønnelykke 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, Halldórsson BV, Harris TB, Heath AC, Hocking LJ, Holliday EG, Homuth G, Horan MA, Hottenga JJ, de Jager PL, Joshi PK, Jugessur A, Kaakinen MA, Kähönen M, Kanoni S, Keltigangas-Järvinen L, Kiemeney LA, Kolcic I, Koskinen S, Kraja AT, Kroh M, Kutalik Z, Latvala A, Launer LJ, Lebreton MP, Levinson DF, Lichtenstein P, Lichtner P, Liewald DC, Loukola A, Madden PA, Mägi R, Mäki-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 WE, Palotie A, Paternoster L, Pedersen NL, Petrovic KE, Porteous DJ, Räikkönen K, Ring SM, Robino A, Rostapshova O, Rudan I, Rustichini A, Salomaa V, Sanders AR, Sarin AP, Schmidt H, 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 FJ, Venturini C, Vinkhuyzen AA, Völker U, Völzke 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, Bültmann U, Chabris CF, Cucca F, Cusi D, Deary IJ, Dedoussis GV, van Duijn CM, Eriksson JG, Franke B, Franke L, Gasparini P, Gejman PV, Gieger C, Grabe HJ, Gratten J, Groenen PJ, Gudnason V, van der Harst P, Hayward C, Hinds DA, Hoffmann W, Hyppönen E, Iacono WG, Jacobsson B, Järvelin MR, Jöckel KH, Kaprio J, Kardia SL, Lehtimäki T, Lehrer SF, Magnusson PK, Martin NG, McGue M, Metspalu A, Pendleton N, Penninx BW, Perola M, Pirastu N, Pirastu M, Polasek O, Posthuma D, Power C, Province MA, Samani NJ, Schlessinger D, Schmidt R, Sørensen TI, Spector TD, Stefansson K, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tiemeier H, Tung JY, Uitterlinden AG, Vitart V, Vollenweider P, Weir DR, Wilson JF, Wright AF, Conley DC, Krueger RF, Davey Smith G, Hofman A, Laibson DI, Medland SE, Meyer MN, Yang J, Johannesson M, Visscher PM, Esko T, Koellinger PD, Cesarini D, and Benjamin DJ
Subjects: Alzheimer Disease genetics, Bipolar Disorder genetics, Cognition, Computational Biology, Gene-Environment Interaction, Humans, Molecular Sequence Annotation, Schizophrenia genetics, United Kingdom, Brain metabolism, Educational Status, Fetus metabolism, Gene Expression Regulation genetics, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
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. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample 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
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24. Polygenic dissection of major depression clinical heterogeneity.

Author: Milaneschi Y, Lamers F, Peyrot WJ, Abdellaoui A, Willemsen G, Hottenga JJ, Jansen R, Mbarek H, Dehghan A, Lu C, Boomsma DI, and Penninx BW
Subjects: Adult, Bipolar Disorder genetics, Bipolar Disorder metabolism, Body Mass Index, C-Reactive Protein metabolism, Depressive Disorder, Major metabolism, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Meta-Analysis as Topic, Middle Aged, Multifactorial Inheritance genetics, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides metabolism, Depressive Disorder, Major genetics
Abstract: The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.
Published: 2016
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25. Disease and Polygenic Architecture: Avoid Trio Design and Appropriately Account for Unscreened Control Subjects for Common Disease.

Author: Peyrot WJ, Boomsma DI, Penninx BW, and Wray NR
Subjects: Alleles, Depressive Disorder, Major diagnosis, Depressive Disorder, Major genetics, Gene Frequency, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Genetic Association Studies methods
Abstract: Genome-wide association studies (GWASs) are an optimal design for discovery of disease risk loci for diseases whose underlying genetic architecture includes many common causal loci of small effect (a polygenic architecture). We consider two designs that deserve careful consideration if the true underlying genetic architecture of the trait is polygenic: parent-offspring trios and unscreened control subjects. We assess these designs in terms of quantification of the total contribution of genome-wide genetic markers to disease risk (SNP heritability) and power to detect an associated risk allele. First, we show that trio designs should be avoided when: (1) the disease has a lifetime risk > 1%; (2) trio probands are ascertained from families with more than one affected sibling under which scenario the SNP heritability can drop by more than 50% and power can drop as much as from 0.9 to 0.15 for a sample of 20,000 subjects; or (3) assortative mating occurs (spouse correlation of the underlying liability to the disorder), which decreases the SNP heritability but not the power to detect a single locus in the trio design. Some studies use unscreened rather than screened control subjects because these can be easier to collect; we show that the estimated SNP heritability should then be scaled by dividing by (1 - K × u)(2) for disorders with population prevalence K and proportion of unscreened control subjects u. When omitting to scale appropriately, the SNP heritability of, for example, major depressive disorder (K = 0.15) would be underestimated by 28% when none of the control subjects are screened., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2016
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26. The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects.

Author: Peyrot WJ, Lee SH, Milaneschi Y, Abdellaoui A, Byrne EM, Esko T, de Geus EJ, Hemani G, Hottenga JJ, Kloiber S, Levinson DF, Lucae S, Martin NG, Medland SE, Metspalu A, Milani L, Noethen MM, Potash JB, Rietschel M, Rietveld CA, Ripke S, Shi J, Willemsen G, Zhu Z, Boomsma DI, Wray NR, and Penninx BW
Subjects: Adult, Aged, Cohort Studies, Estonia epidemiology, Female, Gene-Environment Interaction, Genetic Association Studies, Genotype, Humans, Likelihood Functions, Male, Middle Aged, Netherlands epidemiology, Odds Ratio, Psychiatric Status Rating Scales, Regression Analysis, Depressive Disorder, Major epidemiology, Depressive Disorder, Major genetics, Depressive Disorder, Major psychology, Educational Status, Polymorphism, Single Nucleotide genetics
Abstract: An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14,949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15,138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884,105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120,000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status.
Published: 2015
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27. Effect of polygenic risk scores on depression in childhood trauma.

Author: Peyrot WJ, Milaneschi Y, Abdellaoui A, Sullivan PF, Hottenga JJ, Boomsma DI, and Penninx BW
Subjects: Adult, Case-Control Studies, Child, Depressive Disorder, Major genetics, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Male, Middle Aged, Netherlands epidemiology, Risk Assessment, Risk Factors, Adult Survivors of Child Abuse statistics & numerical data, Child Abuse statistics & numerical data, Depressive Disorder, Major epidemiology
Abstract: Background: Research on gene × environment interaction in major depressive disorder (MDD) has thus far primarily focused on candidate genes, although genetic effects are known to be polygenic., Aims: To test whether the effect of polygenic risk scores on MDD is moderated by childhood trauma., Method: The study sample consisted of 1645 participants with a DSM-IV diagnosis of MDD and 340 screened controls from The Netherlands. Chronic or remitted episodes (severe MDD) were present in 956 participants. The occurrence of childhood trauma was assessed with the Childhood Trauma Interview and the polygenic risk scores were based on genome-wide meta-analysis results from the Psychiatric Genomics Consortium., Results: The polygenic risk scores and childhood trauma independently affected MDD risk, and evidence was found for interaction as departure from both multiplicativity and additivity, indicating that the effect of polygenic risk scores on depression is increased in the presence of childhood trauma. The interaction effects were similar in predicting all MDD risk and severe MDD risk, and explained a proportion of variation in MDD risk comparable to the polygenic risk scores themselves., Conclusions: The interaction effect found between polygenic risk scores and childhood trauma implies that (1) studies on direct genetic effect on MDD gain power by focusing on individuals exposed to childhood trauma, and that (2) individuals with both high polygenic risk scores and exposure to childhood trauma are particularly at risk for developing MDD., (Royal College of Psychiatrists.)
Published: 2014
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28. Collaborative stepped care v. care as usual for common mental disorders: 8-month, cluster randomised controlled trial.

Author: Oosterbaan DB, Verbraak MJ, Terluin B, Hoogendoorn AW, Peyrot WJ, Muntingh A, and van Balkom AJ
Subjects: Adult, Anxiety Disorders psychology, Depressive Disorder psychology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Primary Health Care, Treatment Outcome, Anxiety Disorders therapy, Cognitive Behavioral Therapy methods, Depressive Disorder therapy, Patient Care Team, Self Care
Abstract: Background: Thus far collaborative stepped care (CSC) studies have not incorporated self-help as a first step., Aims: To evaluate the effectiveness of CSC in the treatment of common mental disorders., Method: An 8-month cluster randomised controlled trial comparing CSC to care as usual (CAU) (Dutch Trial Register identifier NTR1224). The CSC consisted of a stepped care approach guided by a psychiatric nurse in primary care with the addition of antidepressants dependent on the severity of the disorder, followed by cognitive-behavioural therapy in mental healthcare., Results: Twenty general practitioners (GPs) and 8 psychiatric nurses were randomised to provide CSC or CAU. The GPs recruited 163 patients of whom 85% completed the post-test measurements. At 4-month mid-test CSC was superior to CAU: 74.7% (n = 68) v. 50.8% (n = 31) responders (P = 0.003). At 8-month post-test and 12-month follow-up no significant differences were found as the patients in the CAU group improved as well., Conclusions: Treatment within a CSC model resulted in an earlier treatment response compared with CAU.
Published: 2013
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28 results on '"Peyrot, WJ"'

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

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

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

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

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

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

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

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

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

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

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

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

13. Genetic variants linked to education predict longevity

14. The association between lower educational attainment and depression owing to shared genetic effects?: Results in ~25,000 subjects

15. On the interpretation of transcriptome-wide association studies.

16. Genome-wide association studies of polygenic risk score-derived phenotypes may lead to inflated false positive rates.

17. [What can genetic research teach us about the overlap and differences between psychiatric disorders?]

18. A role for vitamin D and omega-3 fatty acids in major depression? An exploration using genomics.

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

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

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

22. Genetic effects influencing risk for major depressive disorder in China and Europe.

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

24. Polygenic dissection of major depression clinical heterogeneity.

25. Disease and Polygenic Architecture: Avoid Trio Design and Appropriately Account for Unscreened Control Subjects for Common Disease.

26. The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects.

27. Effect of polygenic risk scores on depression in childhood trauma.

28. Collaborative stepped care v. care as usual for common mental disorders: 8-month, cluster randomised controlled trial.

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28 results on '"Peyrot, WJ"'

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