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1. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

Author: Schmaal, L, Hibar, DP, Sämann, PG, Hall, GB, Baune, BT, Jahanshad, N, Cheung, JW, van Erp, TGM, Bos, D, Ikram, MA, Vernooij, MW, Niessen, WJ, Tiemeier, H, Hofman, A, Wittfeld, K, Grabe, HJ, Janowitz, D, Bülow, R, Selonke, M, Völzke, H, Grotegerd, D, Dannlowski, U, Arolt, V, Opel, N, Heindel, W, Kugel, H, Hoehn, D, Czisch, M, Couvy-Duchesne, B, Rentería, ME, Strike, LT, Wright, MJ, Mills, NT, de Zubicaray, GI, McMahon, KL, Medland, SE, Martin, NG, Gillespie, NA, Goya-Maldonado, R, Gruber, O, Krämer, B, Hatton, SN, Lagopoulos, J, Hickie, IB, Frodl, T, Carballedo, A, Frey, EM, van Velzen, LS, Penninx, BWJH, van Tol, M-J, van der Wee, NJ, Davey, CG, Harrison, BJ, Mwangi, B, Cao, B, Soares, JC, Veer, IM, Walter, H, Schoepf, D, Zurowski, B, Konrad, C, Schramm, E, Normann, C, Schnell, K, Sacchet, MD, Gotlib, IH, MacQueen, GM, Godlewska, BR, Nickson, T, McIntosh, AM, Papmeyer, M, Whalley, HC, Hall, J, Sussmann, JE, Li, M, Walter, M, Aftanas, L, Brack, I, Bokhan, NA, Thompson, PM, and Veltman, DJ
Subjects: Biological Psychology, Biomedical and Clinical Sciences, Clinical Sciences, Psychology, Major Depressive Disorder, Serious Mental Illness, Neurosciences, Biomedical Imaging, Depression, Basic Behavioral and Social Science, Mental Health, Brain Disorders, Clinical Research, Pediatric, Behavioral and Social Science, 2.3 Psychological, social and economic factors, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Adolescent, Adult, Brain, Cerebral Cortex, Depressive Disorder, Major, Female, Frontal Lobe, Gray Matter, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Prefrontal Cortex, Temporal Lobe, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.
Published: 2017

2. Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group.

Author: Rentería, ME, Schmaal, L, Hibar, DP, Couvy-Duchesne, B, Strike, LT, Mills, NT, de Zubicaray, GI, McMahon, KL, Medland, SE, Gillespie, NA, Hatton, SN, Lagopoulos, J, Veltman, DJ, van der Wee, N, van Erp, TGM, Wittfeld, K, Grabe, HJ, Block, A, Hegenscheid, K, Völzke, H, Veer, IM, Walter, H, Schnell, K, Schramm, E, Normann, C, Schoepf, D, Konrad, C, Zurowski, B, Godlewska, BR, Cowen, PJ, Penninx, BWJH, Jahanshad, N, Thompson, PM, Wright, MJ, Martin, NG, Christensen, H, and Hickie, IB
Subjects: Brain, Humans, Magnetic Resonance Imaging, Prevalence, Risk Factors, Suicide, Depressive Disorder, Major, Adult, Aged, Middle Aged, Female, Male, Young Adult, Suicidal Ideation, Neuroimaging, Depressive Disorder, Major, Psychology, Clinical Sciences, Public Health and Health Services
Abstract: The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.
Published: 2017

3. Response to Dr Fried & Dr Kievit, and Dr Malhi et al.

Author: Schmaal, L, Veltman, DJ, van Erp, TGM, Sämann, PG, Frodl, T, Jahanshad, N, Loehrer, E, Vernooij, MW, Niessen, WJ, Ikram, MA, Wittfeld, K, Grabe, HJ, Block, A, Hegenscheid, K, Hoehn, D, Czisch, M, Lagopoulos, J, Hatton, SN, Hickie, IB, Goya-Maldonado, R, Krämer, B, Gruber, O, Couvy-Duchesne, B, Rentería, ME, Strike, LT, Wright, MJ, de Zubicaray, GI, McMahon, KL, Medland, SE, Gillespie, NA, Hall, GB, van Velzen, LS, van Tol, M-J, van der Wee, NJ, Veer, IM, Walter, H, Schramm, E, Normann, C, Schoepf, D, Konrad, C, Zurowski, B, McIntosh, AM, Whalley, HC, Sussmann, JE, Godlewska, BR, Fischer, FH, Penninx, BWJH, Thompson, PM, and Hibar, DP
Subjects: Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Published: 2016

4. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

Author: Schmaal, L, Veltman, DJ, van Erp, TGM, Sämann, PG, Frodl, T, Jahanshad, N, Loehrer, E, Tiemeier, H, Hofman, A, Niessen, WJ, Vernooij, MW, Ikram, MA, Wittfeld, K, Grabe, HJ, Block, A, Hegenscheid, K, Völzke, H, Hoehn, D, Czisch, M, Lagopoulos, J, Hatton, SN, Hickie, IB, Goya-Maldonado, R, Krämer, B, Gruber, O, Couvy-Duchesne, B, Rentería, ME, Strike, LT, Mills, NT, de Zubicaray, GI, McMahon, KL, Medland, SE, Martin, NG, Gillespie, NA, Wright, MJ, Hall, GB, MacQueen, GM, Frey, EM, Carballedo, A, van Velzen, LS, van Tol, MJ, van der Wee, NJ, Veer, IM, Walter, H, Schnell, K, Schramm, E, Normann, C, Schoepf, D, Konrad, C, Zurowski, B, Nickson, T, McIntosh, AM, Papmeyer, M, Whalley, HC, Sussmann, JE, Godlewska, BR, Cowen, PJ, Fischer, FH, Rose, M, Penninx, BWJH, Thompson, PM, and Hibar, DP
Subjects: Brain, Hippocampus, Humans, Magnetic Resonance Imaging, Case-Control Studies, Depressive Disorder, Major, Adult, Middle Aged, Female, Male, Neuroimaging, major depressive disorder, structural volumes, ENIGMA consortium, meta-analysis, hippocampus, Depressive Disorder, Major, Psychiatry, Medical and Health Sciences, Biological Sciences, Psychology and Cognitive Sciences
Abstract: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Published: 2016

5. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Author: Stringer, S, Minică, CC, Verweij, KJH, Mbarek, H, Bernard, M, Derringer, J, van Eijk, KR, Isen, JD, Loukola, A, Maciejewski, DF, Mihailov, E, van der Most, PJ, Sánchez-Mora, C, Roos, L, Sherva, R, Walters, R, Ware, JJ, Abdellaoui, A, Bigdeli, TB, Branje, SJT, Brown, SA, Bruinenberg, M, Casas, M, Esko, T, Garcia-Martinez, I, Gordon, SD, Harris, JM, Hartman, CA, Henders, AK, Heath, AC, Hickie, IB, Hickman, M, Hopfer, CJ, Hottenga, JJ, Huizink, AC, Irons, DE, Kahn, RS, Korhonen, T, Kranzler, HR, Krauter, K, van Lier, PAC, Lubke, GH, Madden, PAF, Mägi, R, McGue, MK, Medland, SE, Meeus, WHJ, Miller, MB, Montgomery, GW, Nivard, MG, Nolte, IM, Oldehinkel, AJ, Pausova, Z, Qaiser, B, Quaye, L, Ramos-Quiroga, JA, Richarte, V, Rose, RJ, Shin, J, Stallings, MC, Stiby, AI, Wall, TL, Wright, MJ, Koot, HM, Paus, T, Hewitt, JK, Ribasés, M, Kaprio, J, Boks, MP, Snieder, H, Spector, T, Munafò, MR, Metspalu, A, Gelernter, J, Boomsma, DI, Iacono, WG, Martin, NG, Gillespie, NA, Derks, EM, and Vink, JM
Subjects: Humans, Marijuana Abuse, Carrier Proteins, Potassium Channels, Cell Adhesion Molecules, Membrane Proteins, Marijuana Smoking, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Young Adult, CD56 Antigen, Potassium Channels, Sodium-Activated, and over, Sodium-Activated, Antigens, CD56, Genetics, Tobacco, Substance Abuse, Human Genome, Drug Abuse, Brain Disorders, Pediatric Research Initiative, Tobacco Smoke and Health, Prevention, Biotechnology, Clinical Research, 2.1 Biological and endogenous factors, Mental Health, Psychology, Clinical Sciences, Public Health and Health Services
Abstract: Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P
Published: 2016

6. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Author: Schijven, D, Postema, MC, Fukunaga, M, Matsumoto, J, Miura, K, de Zwarte, SMC, van Haren, NEM, Cahn, W, Hulshoff Pol, HE, Kahn, RS, Ayesa-Arriola, R, Ortiz-García de la Foz, V, Tordesillas-Gutierrez, D, Vázquez-Bourgon, J, Crespo-Facorro, B, Alnæs, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jönsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quidé, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ, Green, MJ, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS, Weickert, TW, de Haan, L, Brosch, K, Pfarr, J-K, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadić, I, Krämer, B, Gruber, O, Satterthwaite, TD, Bustillo, J, Mathalon, DH, Preda, A, Calhoun, VD, Ford, JM, Potkin, SG, Chen, J, Tan, Y, Wang, Z, Xiang, H, Fan, F, Bernardoni, F, Ehrlich, S, Fuentes-Claramonte, P, Garcia-Leon, MA, Guerrero-Pedraza, A, Salvador, R, Sarró, S, Pomarol-Clotet, E, Ciullo, V, Piras, F, Vecchio, D, Banaj, N, Spalletta, G, Michielse, S, van Amelsvoort, T, Dickie, EW, Voineskos, AN, Sim, K, Ciufolini, S, Dazzan, P, Murray, RM, Kim, W-S, Chung, Y-C, Andreou, C, Schmidt, A, Borgwardt, S, McIntosh, AM, Whalley, HC, Lawrie, SM, du Plessis, S, Luckhoff, HK, Scheffler, F, Emsley, R, Grotegerd, D, Lencer, R, Dannlowski, U, Edmond, JT, Rootes-Murdy, K, Stephen, JM, Mayer, AR, Antonucci, LA, Fazio, L, Pergola, G, Bertolino, A, Díaz-Caneja, CM, Janssen, J, Lois, NG, Arango, C, Tomyshev, AS, Lebedeva, I, Cervenka, S, Sellgren, CM, Georgiadis, F, Kirschner, M, Kaiser, S, Hajek, T, Skoch, A, Spaniel, F, Kim, M, Kwak, YB, Oh, S, Kwon, JS, James, A, Bakker, G, Knöchel, C, Stäblein, M, Oertel, V, Uhlmann, A, Howells, FM, Stein, DJ, Temmingh, HS, Diaz-Zuluaga, AM, Pineda-Zapata, JA, López-Jaramillo, C, Homan, S, Ji, E, Surbeck, W, Homan, P, Fisher, SE, Franke, B, Glahn, DC, Gur, RC, Hashimoto, R, Jahanshad, N, Luders, E, Medland, SE, Thompson, PM, Turner, JA, van Erp, TGM, Francks, C, Schijven, D, Postema, MC, Fukunaga, M, Matsumoto, J, Miura, K, de Zwarte, SMC, van Haren, NEM, Cahn, W, Hulshoff Pol, HE, Kahn, RS, Ayesa-Arriola, R, Ortiz-García de la Foz, V, Tordesillas-Gutierrez, D, Vázquez-Bourgon, J, Crespo-Facorro, B, Alnæs, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jönsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quidé, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ, Green, MJ, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS, Weickert, TW, de Haan, L, Brosch, K, Pfarr, J-K, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadić, I, Krämer, B, Gruber, O, Satterthwaite, TD, Bustillo, J, Mathalon, DH, Preda, A, Calhoun, VD, Ford, JM, Potkin, SG, Chen, J, Tan, Y, Wang, Z, Xiang, H, Fan, F, Bernardoni, F, Ehrlich, S, Fuentes-Claramonte, P, Garcia-Leon, MA, Guerrero-Pedraza, A, Salvador, R, Sarró, S, Pomarol-Clotet, E, Ciullo, V, Piras, F, Vecchio, D, Banaj, N, Spalletta, G, Michielse, S, van Amelsvoort, T, Dickie, EW, Voineskos, AN, Sim, K, Ciufolini, S, Dazzan, P, Murray, RM, Kim, W-S, Chung, Y-C, Andreou, C, Schmidt, A, Borgwardt, S, McIntosh, AM, Whalley, HC, Lawrie, SM, du Plessis, S, Luckhoff, HK, Scheffler, F, Emsley, R, Grotegerd, D, Lencer, R, Dannlowski, U, Edmond, JT, Rootes-Murdy, K, Stephen, JM, Mayer, AR, Antonucci, LA, Fazio, L, Pergola, G, Bertolino, A, Díaz-Caneja, CM, Janssen, J, Lois, NG, Arango, C, Tomyshev, AS, Lebedeva, I, Cervenka, S, Sellgren, CM, Georgiadis, F, Kirschner, M, Kaiser, S, Hajek, T, Skoch, A, Spaniel, F, Kim, M, Kwak, YB, Oh, S, Kwon, JS, James, A, Bakker, G, Knöchel, C, Stäblein, M, Oertel, V, Uhlmann, A, Howells, FM, Stein, DJ, Temmingh, HS, Diaz-Zuluaga, AM, Pineda-Zapata, JA, López-Jaramillo, C, Homan, S, Ji, E, Surbeck, W, Homan, P, Fisher, SE, Franke, B, Glahn, DC, Gur, RC, Hashimoto, R, Jahanshad, N, Luders, E, Medland, SE, Thompson, PM, Turner, JA, van Erp, TGM, and Francks, C
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023

7. Multi-trait genetic analysis identifies auto-immune loci associated with cutaneous melanoma

Author: Liyanage, U, MacGregor, S, Bishop, DT, Shi, J, An, J, Ong, JS, Han, X, Scolyer, RA, Martin, NG, Medland, SE, Byrne, EM, Green, AC, Saw, RPM, Thompson, JF, Stretch, J, Spillane, A, Jiang, Y, Tian, C, 23andMe Research Team, Gordon, SG, Duffy, DL, Olsen, CM, Whiteman, DC, Long, GV, Iles, MM, Landi, MT, and Law, MH
Abstract: Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including with its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multi-trait analysis of GWAS (MTAG). We used bivariate LD-score regression to identify traits that are genetically correlated with clinically-confirmed cutaneous melanoma, and then used publicly available GWAS for these traits in a MTAG. MTAG allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci; 19 of them were not previously reported in the input cutaneous melanoma GWAS-meta-analysis. 55 of these loci were replicated (P < 0.05/74), Bonferroni corrected P -value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the new cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP, and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.
Published: 2022

8. Genetic variants associated with longitudinal changes in brain structure across the lifespan

Author: Brouwer, RM, Klein, M, Grasby, KL, Schnack, HG, Jahanshad, N, Teeuw, J, Thomopoulos, SI, Sprooten, E, Franz, CE, Gogtay, N, Kremen, WS, Panizzon, MS, Olde Loohuis, LM, Whelan, CD, Aghajani, M, Alloza, C, Alanaes, D, Artiges, E, Ayesa-Arriola, R, Barker, GJ, Bastin, ME, Blok, E, Boen, E, Breukelaar, IA, Bright, JK, Buimer, EEL, Bulow, R, Cannon, DM, Ciufolini, S, Crossley, NA, Damatac, CG, Dazzan, P, de Mol, CL, de Zwarte, SMC, Desrivieres, S, Diaz-Caneja, CM, Doan, NT, Dohm, K, Froehner, JH, Goltermann, J, Grigis, A, Grotegerd, D, Han, LKM, Harris, MA, Hartman, CA, Heany, SJ, Heindel, W, Heslenfeld, DJ, Hohmann, S, Ittermann, B, Jansen, PR, Janssen, J, Jia, T, Jiang, J, Jockwitz, C, Karali, T, Keeser, D, Koevoets, MGJC, Lenroot, RK, Malchow, B, Mandl, RCW, Medel, V, Meinert, S, Morgan, CA, Muehleisen, TW, Nabulsi, L, Opel, N, de la Foz, VO-G, Overs, BJ, Paillere Martinot, M-L, Redlich, R, Marques, TR, Repple, J, Roberts, G, Roshchupkin, GV, Setiaman, N, Shumskaya, E, Stein, F, Sudre, G, Takahashi, S, Thalamuthu, A, Tordesillas-Gutierrez, D, van der Lugt, A, van Haren, NEM, Wardlaw, JM, Wen, W, Westeneng, H-J, Wittfeld, K, Zhu, AH, Zugman, A, Armstrong, NJ, Bonfiglio, G, Bralten, J, Dalvie, S, Davies, G, Di Forti, M, Ding, L, Donohoe, G, Forstner, AJ, Gonzalez-Penas, J, Guimaraes, JPOFT, Homuth, G, Hottenga, J-J, Knol, MJ, Kwok, JBJ, Le Hellard, S, Mather, KA, Milaneschi, Y, Morris, DW, Noethen, MM, Papiol, S, Rietschel, M, Santoro, ML, Steen, VM, Stein, JL, Streit, F, Tankard, RM, Teumer, A, van 't Ent, D, van der Meer, D, van Eijk, KR, Vassos, E, Vazquez-Bourgon, J, Witt, SH, Adams, HHH, Agartz, I, Ames, D, Amunts, K, Andreassen, OA, Arango, C, Banaschewski, T, Baune, BT, Belangero, SI, Bokde, ALW, Boomsma, DI, Bressan, RA, Brodaty, H, Buitelaar, JK, Cahn, W, Caspers, S, Cichon, S, Crespo-Facorro, B, Cox, SR, Dannlowski, U, Elvsashagen, T, Espeseth, T, Falkai, PG, Fisher, SE, Flor, H, Fullerton, JM, Garavan, H, Gowland, PA, Grabe, HJ, Hahn, T, Heinz, A, Hillegers, M, Hoare, J, Hoekstra, PJ, Ikram, MA, Jackowski, AP, Jansen, A, Jonsson, EG, Kahn, RS, Kircher, T, Korgaonkar, MS, Krug, A, Lemaitre, H, Malt, UF, Martinot, J-L, McDonald, C, Mitchell, PB, Muetzel, RL, Murray, RM, Nees, F, Nenadic, I, Oosterlaan, J, Ophoff, RA, Pan, PM, Penninx, BWJH, Poustka, L, Sachdev, PS, Salum, GA, Schofield, PR, Schumann, G, Shaw, P, Sim, K, Smolka, MN, Stein, DJ, Trollor, JN, van den Berg, LH, Veldink, JH, Walter, H, Westlye, LT, Whelan, R, White, T, Wright, MJ, Medland, SE, Franke, B, Thompson, PM, Hulshoff Pol, HE, Brouwer, RM, Klein, M, Grasby, KL, Schnack, HG, Jahanshad, N, Teeuw, J, Thomopoulos, SI, Sprooten, E, Franz, CE, Gogtay, N, Kremen, WS, Panizzon, MS, Olde Loohuis, LM, Whelan, CD, Aghajani, M, Alloza, C, Alanaes, D, Artiges, E, Ayesa-Arriola, R, Barker, GJ, Bastin, ME, Blok, E, Boen, E, Breukelaar, IA, Bright, JK, Buimer, EEL, Bulow, R, Cannon, DM, Ciufolini, S, Crossley, NA, Damatac, CG, Dazzan, P, de Mol, CL, de Zwarte, SMC, Desrivieres, S, Diaz-Caneja, CM, Doan, NT, Dohm, K, Froehner, JH, Goltermann, J, Grigis, A, Grotegerd, D, Han, LKM, Harris, MA, Hartman, CA, Heany, SJ, Heindel, W, Heslenfeld, DJ, Hohmann, S, Ittermann, B, Jansen, PR, Janssen, J, Jia, T, Jiang, J, Jockwitz, C, Karali, T, Keeser, D, Koevoets, MGJC, Lenroot, RK, Malchow, B, Mandl, RCW, Medel, V, Meinert, S, Morgan, CA, Muehleisen, TW, Nabulsi, L, Opel, N, de la Foz, VO-G, Overs, BJ, Paillere Martinot, M-L, Redlich, R, Marques, TR, Repple, J, Roberts, G, Roshchupkin, GV, Setiaman, N, Shumskaya, E, Stein, F, Sudre, G, Takahashi, S, Thalamuthu, A, Tordesillas-Gutierrez, D, van der Lugt, A, van Haren, NEM, Wardlaw, JM, Wen, W, Westeneng, H-J, Wittfeld, K, Zhu, AH, Zugman, A, Armstrong, NJ, Bonfiglio, G, Bralten, J, Dalvie, S, Davies, G, Di Forti, M, Ding, L, Donohoe, G, Forstner, AJ, Gonzalez-Penas, J, Guimaraes, JPOFT, Homuth, G, Hottenga, J-J, Knol, MJ, Kwok, JBJ, Le Hellard, S, Mather, KA, Milaneschi, Y, Morris, DW, Noethen, MM, Papiol, S, Rietschel, M, Santoro, ML, Steen, VM, Stein, JL, Streit, F, Tankard, RM, Teumer, A, van 't Ent, D, van der Meer, D, van Eijk, KR, Vassos, E, Vazquez-Bourgon, J, Witt, SH, Adams, HHH, Agartz, I, Ames, D, Amunts, K, Andreassen, OA, Arango, C, Banaschewski, T, Baune, BT, Belangero, SI, Bokde, ALW, Boomsma, DI, Bressan, RA, Brodaty, H, Buitelaar, JK, Cahn, W, Caspers, S, Cichon, S, Crespo-Facorro, B, Cox, SR, Dannlowski, U, Elvsashagen, T, Espeseth, T, Falkai, PG, Fisher, SE, Flor, H, Fullerton, JM, Garavan, H, Gowland, PA, Grabe, HJ, Hahn, T, Heinz, A, Hillegers, M, Hoare, J, Hoekstra, PJ, Ikram, MA, Jackowski, AP, Jansen, A, Jonsson, EG, Kahn, RS, Kircher, T, Korgaonkar, MS, Krug, A, Lemaitre, H, Malt, UF, Martinot, J-L, McDonald, C, Mitchell, PB, Muetzel, RL, Murray, RM, Nees, F, Nenadic, I, Oosterlaan, J, Ophoff, RA, Pan, PM, Penninx, BWJH, Poustka, L, Sachdev, PS, Salum, GA, Schofield, PR, Schumann, G, Shaw, P, Sim, K, Smolka, MN, Stein, DJ, Trollor, JN, van den Berg, LH, Veldink, JH, Walter, H, Westlye, LT, Whelan, R, White, T, Wright, MJ, Medland, SE, Franke, B, Thompson, PM, and Hulshoff Pol, HE
Abstract: Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.
Published: 2022

9. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author: Howe, LJ, Nivard, MG, Morris, TT, Hansen, AF, Rasheed, H, Cho, Y, Chittoor, G, Ahlskog, R, Lind, PA, Palviainen, T, van der Zee, MD, Cheesman, R, Mangino, M, Wang, Y, Li, S, Klaric, L, Ratliff, SM, Bielak, LF, Nygaard, M, Giannelis, A, Willoughby, EA, Reynolds, CA, Balbona, JV, Andreassen, OA, Ask, H, Baras, A, Bauer, CR, Boomsma, DI, Campbell, A, Campbell, H, Chen, Z, Christofidou, P, Corfield, E, Dahm, CC, Dokuru, DR, Evans, LM, de Geus, EJC, Giddaluru, S, Gordon, SD, Harden, KP, Hill, WD, Hughes, A, Kerr, SM, Kim, Y, Kweon, H, Latvala, A, Lawlor, DA, Li, L, Lin, K, Magnus, P, Magnusson, PKE, Mallard, TT, Martikainen, P, Mills, MC, Njolstad, PR, Overton, JD, Pedersen, NL, Porteous, DJ, Reid, J, Silventoinen, K, Southey, MC, Stoltenberg, C, Tucker-Drob, EM, Wright, MJ, Hewitt, JK, Keller, MC, Stallings, MC, Lee, JJ, Christensen, K, Kardia, SLR, Peyser, PA, Smith, JA, Wilson, JF, Hopper, JL, Hagg, S, Spector, TD, Pingault, J-B, Plomin, R, Havdahl, A, Bartels, M, Martin, NG, Oskarsson, S, Justice, AE, Millwood, IY, Hveem, K, Naess, O, Willer, CJ, Asvold, BO, Koellinger, PD, Kaprio, J, Medland, SE, Walters, RG, Benjamin, DJ, Turley, P, Evans, DM, Smith, GD, Hayward, C, Brumpton, B, Hemani, G, Davies, NM, Howe, LJ, Nivard, MG, Morris, TT, Hansen, AF, Rasheed, H, Cho, Y, Chittoor, G, Ahlskog, R, Lind, PA, Palviainen, T, van der Zee, MD, Cheesman, R, Mangino, M, Wang, Y, Li, S, Klaric, L, Ratliff, SM, Bielak, LF, Nygaard, M, Giannelis, A, Willoughby, EA, Reynolds, CA, Balbona, JV, Andreassen, OA, Ask, H, Baras, A, Bauer, CR, Boomsma, DI, Campbell, A, Campbell, H, Chen, Z, Christofidou, P, Corfield, E, Dahm, CC, Dokuru, DR, Evans, LM, de Geus, EJC, Giddaluru, S, Gordon, SD, Harden, KP, Hill, WD, Hughes, A, Kerr, SM, Kim, Y, Kweon, H, Latvala, A, Lawlor, DA, Li, L, Lin, K, Magnus, P, Magnusson, PKE, Mallard, TT, Martikainen, P, Mills, MC, Njolstad, PR, Overton, JD, Pedersen, NL, Porteous, DJ, Reid, J, Silventoinen, K, Southey, MC, Stoltenberg, C, Tucker-Drob, EM, Wright, MJ, Hewitt, JK, Keller, MC, Stallings, MC, Lee, JJ, Christensen, K, Kardia, SLR, Peyser, PA, Smith, JA, Wilson, JF, Hopper, JL, Hagg, S, Spector, TD, Pingault, J-B, Plomin, R, Havdahl, A, Bartels, M, Martin, NG, Oskarsson, S, Justice, AE, Millwood, IY, Hveem, K, Naess, O, Willer, CJ, Asvold, BO, Koellinger, PD, Kaprio, J, Medland, SE, Walters, RG, Benjamin, DJ, Turley, P, Evans, DM, Smith, GD, Hayward, C, Brumpton, B, Hemani, G, and Davies, NM
Abstract: Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
Published: 2022

10. Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts

Author: Silventoinen, K, Li, W, Jelenkovic, A, Sund, R, Yokoyama, Y, Aaltonen, S, Piirtola, M, Sugawara, M, Tanaka, M, Matsumoto, S, Baker, LA, Tuvblad, C, Tynelius, P, Rasmussen, F, Craig, JM, Saffery, R, Willemsen, G, Bartels, M, van Beijsterveldt, CEM, Martin, NG, Medland, SE, Montgomery, GW, Lichtenstein, P, Krueger, RF, McGue, M, Pahlen, S, Christensen, K, Skytthe, A, Kyvik, KO, Saudino, KJ, Dubois, L, Boivin, M, Brendgen, M, Dionne, G, Vitaro, F, Ullemar, V, Almqvist, C, Magnusson, PKE, Corley, RP, Huibregtse, BM, Knafo-Noam, A, Mankuta, D, Abramson, L, Haworth, CMA, Plomin, R, Bjerregaard-Andersen, M, Beck-Nielsen, H, Sodemann, M, Duncan, GE, Buchwald, D, Burt, SA, Klump, KL, Llewellyn, CH, Fisher, A, Boomsma, D, Sorensen, TIA, Kaprio, J, Silventoinen, K, Li, W, Jelenkovic, A, Sund, R, Yokoyama, Y, Aaltonen, S, Piirtola, M, Sugawara, M, Tanaka, M, Matsumoto, S, Baker, LA, Tuvblad, C, Tynelius, P, Rasmussen, F, Craig, JM, Saffery, R, Willemsen, G, Bartels, M, van Beijsterveldt, CEM, Martin, NG, Medland, SE, Montgomery, GW, Lichtenstein, P, Krueger, RF, McGue, M, Pahlen, S, Christensen, K, Skytthe, A, Kyvik, KO, Saudino, KJ, Dubois, L, Boivin, M, Brendgen, M, Dionne, G, Vitaro, F, Ullemar, V, Almqvist, C, Magnusson, PKE, Corley, RP, Huibregtse, BM, Knafo-Noam, A, Mankuta, D, Abramson, L, Haworth, CMA, Plomin, R, Bjerregaard-Andersen, M, Beck-Nielsen, H, Sodemann, M, Duncan, GE, Buchwald, D, Burt, SA, Klump, KL, Llewellyn, CH, Fisher, A, Boomsma, D, Sorensen, TIA, and Kaprio, J
Abstract: BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.
Published: 2022

11. Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts

Author: Silventoinen, K, Piirtola, M, Jelenkovic, A, Sund, R, Tarnoki, AD, Tarnoki, DL, Medda, E, Nistico, L, Toccaceli, V, Honda, C, Inui, F, Tomizawa, R, Watanabe, M, Sakai, N, Gatz, M, Butler, DA, Lee, J, Lee, SJ, Sung, J, Franz, CE, Kremen, WS, Lyons, MJ, Derom, CA, Vlietinck, RF, Loos, RJF, Tynelius, P, Rasmussen, F, Martin, NG, Medland, SE, Montgomery, GW, Brandt, I, Nilsen, TS, Harris, JR, Tyler, J, Hopper, JL, Magnusson, PKE, Pedersen, NL, Aslan, AKD, Ordonana, JR, Sanchez-Romera, JF, Colodro-Conde, L, Rebato, E, Zhang, D, Pang, Z, Tan, Q, Silberg, JL, Maes, HH, Boomsma, D, Sorensen, TIA, Korhonen, T, Kaprio, J, Silventoinen, K, Piirtola, M, Jelenkovic, A, Sund, R, Tarnoki, AD, Tarnoki, DL, Medda, E, Nistico, L, Toccaceli, V, Honda, C, Inui, F, Tomizawa, R, Watanabe, M, Sakai, N, Gatz, M, Butler, DA, Lee, J, Lee, SJ, Sung, J, Franz, CE, Kremen, WS, Lyons, MJ, Derom, CA, Vlietinck, RF, Loos, RJF, Tynelius, P, Rasmussen, F, Martin, NG, Medland, SE, Montgomery, GW, Brandt, I, Nilsen, TS, Harris, JR, Tyler, J, Hopper, JL, Magnusson, PKE, Pedersen, NL, Aslan, AKD, Ordonana, JR, Sanchez-Romera, JF, Colodro-Conde, L, Rebato, E, Zhang, D, Pang, Z, Tan, Q, Silberg, JL, Maes, HH, Boomsma, D, Sorensen, TIA, Korhonen, T, and Kaprio, J
Abstract: We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.
Published: 2022

12. Lifetime prevalence and correlates of perinatal depression in a case-cohort study of depression

Author: Kiewa, J, Meltzer-Brody, S, Milgrom, J, Bennett, E, Mackle, T, Guintivano, J, Hickie, IB, Colodro-Conde, L, Medland, SE, Martin, N, Wray, N, Byrne, E, Kiewa, J, Meltzer-Brody, S, Milgrom, J, Bennett, E, Mackle, T, Guintivano, J, Hickie, IB, Colodro-Conde, L, Medland, SE, Martin, N, Wray, N, and Byrne, E
Abstract: OBJECTIVES: This study sought to evaluate the prevalence, timing of onset and duration of symptoms of depression in the perinatal period (PND) in women with depression, according to whether they had a history of depression prior to their first perinatal period. We further sought to identify biopsychosocial correlates of perinatal symptoms in women with depression. DESIGN AND SETTING: The Australian Genetics of Depression Study is an online case cohort study of the aetiology of depression. For a range of variables, women with depression who report significant perinatal depressive symptoms were compared with women with lifetime depression who did not experience perinatal symptoms. PARTICIPANTS: In a large sample of parous women with major depressive disorder (n=7182), we identified two subgroups of PND cases with and without prior depression history (n=2261; n=878, respectively). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was a positive screen for PND on the lifetime version of the Edinburgh Postnatal Depression Scale. Descriptive measures reported lifetime prevalence, timing of onset and duration of PND symptoms. There were no secondary outcome measures. RESULTS: The prevalence of PND among parous women was 70%. The majority of women reported at least one perinatal episode with symptoms both antenatally and postnatally. Of women who experienced depression prior to first pregnancy, PND cases were significantly more likely to report more episodes of depression (OR=1.15 per additional depression episode, 95% CI 1.13 to 1.17, p<0.001), non-European ancestry (OR 1.5, 95% CI 1.0 to 2.1, p=0.03), severe nausea during pregnancy (OR 1.3, 95% CI 1.1 to 1.6, p=0.006) and emotional abuse (OR 1.4, 95% CI 1.1 to 1.7, p=0.005). CONCLUSIONS: The majority of parous women with lifetime depression in this study experienced PND, associated with more complex, severe depression. Results highlight the importance of perinatal assessments of depressive symptoms, part
Published: 2022

13. The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes

Author: Mitchell, BL, Campos, A, Whiteman, DC, Olsen, CM, Gordon, SD, Walker, AJ, Dean, OM, Berk, M, Hickie, IB, Medland, SE, Wray, NR, Martin, NG, Byrne, EM, Mitchell, BL, Campos, A, Whiteman, DC, Olsen, CM, Gordon, SD, Walker, AJ, Dean, OM, Berk, M, Hickie, IB, Medland, SE, Wray, NR, Martin, NG, and Byrne, EM
Abstract: BACKGROUND: Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery-often achieved with a trade-off in the depth of phenotyping. METHODS: The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest publicly available depression genome-wide association study to date and subsequently used polygenic scores to investigate genetic heterogeneity across various clinical subtypes of MDD. RESULTS: We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We found that a polygenic score for depression explained 5.7% of variance in MDD liability in our sample. Finally, we found strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course, and various subtypes of MDD. CONCLUSIONS: Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with the discovery of novel loci, we provide support for differential pathways to illness models that recognize the overlap with other common psychiatric disorders as well as pathophysiological differences.
Published: 2022

14. A saturated map of common genetic variants associated with human height

Author: Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, Hirschhorn, JN, Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, and Hirschhorn, JN
Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Published: 2022

15. Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non-perinatal depression

Author: Kiewa, J, Meltzer-Brody, S, Milgrom, J, Guintivano, J, Hickie, IB, Whiteman, DC, Olsen, CM, Colodro-Conde, L, Medland, SE, Martin, NG, Wray, NR, Byrne, EM, Kiewa, J, Meltzer-Brody, S, Milgrom, J, Guintivano, J, Hickie, IB, Whiteman, DC, Olsen, CM, Colodro-Conde, L, Medland, SE, Martin, NG, Wray, NR, and Byrne, EM
Abstract: BACKGROUND: Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case-control study investigated genetic differences between PND and MDD outside the perinatal period (non-perinatal depression or NPD). METHODS: We conducted a genome-wide association study using PND cases (Edinburgh Postnatal Depression Scale score ≥ 13) from the Australian Genetics of Depression Study 2018 data (n = 3804) and screened controls (n = 6134). Results of gene-set enrichment analysis were compared with those of women with non-PND. For six psychiatric disorders/traits, genetic correlations with PND were evaluated, and logistic regression analysis reported polygenic score (PGS) association with both PND and NPD. RESULTS: Genes differentially expressed in ovarian tissue were significantly enriched (stdBeta = 0.07, p = 3.3e-04), but were not found to be associated with NPD. The genetic correlation between PND and MDD was 0.93 (SE = 0.07; p = 3.5e-38). Compared with controls, PGS for MDD are higher for PND cases (odds ratio [OR] = 1.8, confidence interval [CI] = [1.7-1.8], p = 9.5e-140) than for NPD cases (OR = 1.6, CI = [1.5-1.7], p = 1.2e-49). Highest risk is for those reporting both antenatal and postnatal depression, irrespective of prior MDD history. CONCLUSIONS: PND has a high genetic overlap with MDD, but points of distinction focus on differential expression in ovarian tissue and higher MDD PGS, particularly for women experiencing both antenatal and postpartum PND.
Published: 2022

16. Australian Parkinson's Genetics Study (APGS): Pilot (n=1532)

Author: Bivol, S, Mellick, GD, Gratten, J, Parker, R, Mulcahy, A, Mosley, PE, Poortvliet, PC, Campos, AI, Mitchell, BL, Garcia-Marin, LM, Cross, S, Ferguson, M, Lind, PA, Loesch-Mdzewska, Danuta, Visscher, PM, Medland, SE, Scherzer, CR, Martin, NG, and Rentería, ME
Subjects: 110999 Neurosciences not elsewhere classified, FOS: Clinical medicine, 111799 Public Health and Health Services not elsewhere classified, 110399 Clinical Sciences not elsewhere classified, FOS: Health sciences, Uncategorized
Abstract: Purpose Parkinson's disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinson's Genetics Study seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic and environmental basis of PD susceptibility, symptoms and progression. Participants In the pilot phase reported here, 1819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme records. The average age at the time of the questionnaire was 64±6 years. We collected patient-reported information and sociodemographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred and thirty-two participants (84.2%) met all inclusion criteria, and 1499 provided a DNA sample via traditional post. Findings to date 65% of participants were men, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions. Future plans We plan to recruit sex-matched and age-matched unaffected controls, genotype all participants and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.
Published: 2022
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17. Brain Correlates of Suicide Attempt in 18,925 Participants Across 18 International Cohorts

Author: Campos, A, Thompson, PM, Veltman, DJ, Pozzi, E, van Veltzen, LS, Jahanshad, N, Adams, MJ, Baune, BT, Berger, K, Brosch, K, Bulow, R, Connolly, CG, Dannlowski, U, Davey, CG, de Zubicaray, G, Dima, D, Erwin-Grabner, T, Evans, JW, Fu, CHY, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Grotegerd, D, Harris, MA, Harrison, BJ, Hatton, SN, Hermesdorf, M, Hickie, IB, Ho, TC, Kircher, T, Krug, A, Lagopoulos, J, Lemke, H, McMahon, K, MacMaster, FP, Martin, NG, McIntosh, AM, Medland, SE, Meinert, S, Meller, T, Nenadic, I, Opel, N, Redlich, R, Reneman, L, Repple, J, Sacchet, MD, Schmitt, S, Schrantee, A, Sim, K, Singh, A, Stein, F, Strike, LT, van Der Wee, NJA, van Der Werff, SJA, Volzke, H, Waltemate, L, Whalley, HC, Wittfeld, K, Wright, MJ, Yang, TT, Zarate, CA, Schmaal, L, Renteria, ME, Campos, A, Thompson, PM, Veltman, DJ, Pozzi, E, van Veltzen, LS, Jahanshad, N, Adams, MJ, Baune, BT, Berger, K, Brosch, K, Bulow, R, Connolly, CG, Dannlowski, U, Davey, CG, de Zubicaray, G, Dima, D, Erwin-Grabner, T, Evans, JW, Fu, CHY, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Grotegerd, D, Harris, MA, Harrison, BJ, Hatton, SN, Hermesdorf, M, Hickie, IB, Ho, TC, Kircher, T, Krug, A, Lagopoulos, J, Lemke, H, McMahon, K, MacMaster, FP, Martin, NG, McIntosh, AM, Medland, SE, Meinert, S, Meller, T, Nenadic, I, Opel, N, Redlich, R, Reneman, L, Repple, J, Sacchet, MD, Schmitt, S, Schrantee, A, Sim, K, Singh, A, Stein, F, Strike, LT, van Der Wee, NJA, van Der Werff, SJA, Volzke, H, Waltemate, L, Whalley, HC, Wittfeld, K, Wright, MJ, Yang, TT, Zarate, CA, Schmaal, L, and Renteria, ME
Abstract: BACKGROUND: Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior. METHODS: Here, we pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (nonattempters with depression), and healthy control subjects. RESULTS: We identified 25 regions of interest with statistically significant (false discovery rate < .05) differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe. CONCLUSIONS: This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidal behaviors may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk.
Published: 2021

18. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, Perry, JRB, Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, and Perry, JRB
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021

19. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author: Sonderby, IE, van der Meer, D, Moreau, C, Kaufmann, T, Walters, GB, Ellegaard, M, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Buelow, R, Boen, R, Cahn, W, Calhoun, VD, Caspers, S, Ching, CRK, Cichon, S, Ciufolini, S, Crespo-Facorro, B, Curran, JE, Dale, AM, Dalvie, S, Dazzan, P, de Geus, EJC, de Zubicaray, GI, de Zwarte, SMC, Desrivieres, S, Doherty, JL, Donohoe, G, Draganski, B, Ehrlich, S, Eising, E, Espeseth, T, Fejgin, K, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Ge, T, Glahn, DC, Grabe, HJ, Groenewold, NA, Gustafsson, O, Haavik, J, Haberg, AK, Hall, J, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Holmes, AJ, Homuth, G, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jahanshad, N, Jockwitz, C, Johansson, S, Joensson, EG, Jorgensen, NR, Kikuchi, M, Knowles, EEM, Kumar, K, Le Hellard, S, Leu, C, Linden, DEJ, Liu, J, Lundervold, A, Lundervold, AJ, Maillard, AM, Martin, NG, Martin-Brevet, S, Mather, KA, Mathias, SR, McMahon, KL, McRae, AF, Medland, SE, Meyer-Lindenberg, A, Moberget, T, Modenato, C, Sanchez, JM, Morris, DW, Muehleisen, TW, Murray, RM, Nielsen, J, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, GB, Prieto, C, Quinlan, EB, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Schork, AJ, Schumann, G, Shin, J, Shumskaya, E, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Suzuki, IK, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, van 't Ent, D, van den Bree, MBM, Vanderhaeghen, P, Vassos, E, Wen, W, Wittfeld, K, Wright, MJ, Agartz, I, Djurovic, S, Westlye, LT, Stefansson, H, Stefansson, K, Jacquemont, S, Thompson, PM, Andreassen, OA, Sonderby, IE, van der Meer, D, Moreau, C, Kaufmann, T, Walters, GB, Ellegaard, M, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Buelow, R, Boen, R, Cahn, W, Calhoun, VD, Caspers, S, Ching, CRK, Cichon, S, Ciufolini, S, Crespo-Facorro, B, Curran, JE, Dale, AM, Dalvie, S, Dazzan, P, de Geus, EJC, de Zubicaray, GI, de Zwarte, SMC, Desrivieres, S, Doherty, JL, Donohoe, G, Draganski, B, Ehrlich, S, Eising, E, Espeseth, T, Fejgin, K, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Ge, T, Glahn, DC, Grabe, HJ, Groenewold, NA, Gustafsson, O, Haavik, J, Haberg, AK, Hall, J, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Holmes, AJ, Homuth, G, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jahanshad, N, Jockwitz, C, Johansson, S, Joensson, EG, Jorgensen, NR, Kikuchi, M, Knowles, EEM, Kumar, K, Le Hellard, S, Leu, C, Linden, DEJ, Liu, J, Lundervold, A, Lundervold, AJ, Maillard, AM, Martin, NG, Martin-Brevet, S, Mather, KA, Mathias, SR, McMahon, KL, McRae, AF, Medland, SE, Meyer-Lindenberg, A, Moberget, T, Modenato, C, Sanchez, JM, Morris, DW, Muehleisen, TW, Murray, RM, Nielsen, J, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, GB, Prieto, C, Quinlan, EB, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Schork, AJ, Schumann, G, Shin, J, Shumskaya, E, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Suzuki, IK, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, van 't Ent, D, van den Bree, MBM, Vanderhaeghen, P, Vassos, E, Wen, W, Wittfeld, K, Wright, MJ, Agartz, I, Djurovic, S, Westlye, LT, Stefansson, H, Stefansson, K, Jacquemont, S, Thompson, PM, and Andreassen, OA
Abstract: Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
Published: 2021

20. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, Ruderfer, DM, Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, and Ruderfer, DM
Abstract: BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2021

21. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JR, Qiao, Z, Als, TD, Bigdeli, TB, Borte, S, Bryois, J, Charney, AW, Drange, OK, Gandal, MJ, Hagenaars, SP, Ikeda, M, Kamitaki, N, Kim, M, Krebs, K, Panagiotaropoulou, G, Schilder, BM, Sloofman, LG, Steinberg, S, Trubetskoy, V, Winsvold, BS, Won, H-H, Abramova, L, Adorjan, K, Agerbo, E, Al Eissa, M, Albani, D, Alliey-Rodriguez, N, Anjorin, A, Antilla, V, Antoniou, A, Awasthi, S, Baek, JH, Baekvad-Hansen, M, Bass, N, Bauer, M, Beins, EC, Bergen, SE, Birner, A, Pedersen, CB, Boen, E, Boks, MP, Bosch, R, Brum, M, Brumpton, BM, Brunkhorst-Kanaan, N, Budde, M, Bybjerg-Grauholm, J, Byerley, W, Cairns, M, Casas, M, Cervantes, P, Clarke, T-K, Cruceanu, C, Cuellar-Barboza, A, Cunningham, J, Curtis, D, Czerski, PM, Dale, AM, Dalkner, N, David, FS, Degenhardt, F, Djurovic, S, Dobbyn, AL, Douzenis, A, Elvsashagen, T, Escott-Price, V, Ferrier, IN, Fiorentino, A, Foroud, TM, Forty, L, Frank, J, Frei, O, Freimer, NB, Frisen, L, Gade, K, Garnham, J, Gelernter, J, Pedersen, MG, Gizer, IR, Gordon, SD, Gordon-Smith, K, Greenwood, TA, Grove, J, Guzman-Parra, J, Ha, K, Haraldsson, M, Hautzinger, M, Heilbronner, U, Hellgren, D, Herms, S, Hoffmann, P, Holmans, PA, Huckins, L, Jamain, S, Johnson, JS, Kalman, JL, Kamatani, Y, Kennedy, JL, Kittel-Schneider, S, Knowles, JA, Kogevinas, M, Koromina, M, Kranz, TM, Kranzler, HR, Kubo, M, Kupka, R, Kushner, SA, Lavebratt, C, Lawrence, J, Leber, M, Lee, H-J, Lee, PH, Levy, SE, Lewis, C, Liao, C, Lucae, S, Lundberg, M, MacIntyre, DJ, Maier, W, Maihofer, A, Malaspina, D, Maratou, E, Martinsson, L, Mattheisen, M, McCarroll, SA, McGregor, NW, McGuffin, P, McKay, JD, Medeiros, H, Medland, SE, Millischer, V, Montgomery, GW, Moran, JL, Morris, DW, Muhleisen, TW, O'Brien, N, O'Donovan, C, Loohuis, LMO, Oruc, L, Papiol, S, Pardinas, AF, Perry, A, Pfennig, A, Porichi, E, Potash, JB, Quested, D, Raj, T, Rapaport, MH, DePaulo, JR, Regeer, EJ, Rice, JP, Rivas, F, Rivera, M, Roth, J, Roussos, P, Ruderfer, DM, Sanchez-Mora, C, Schulte, EC, Senner, F, Sharp, S, Shilling, PD, Sigurdsson, E, Sirignano, L, Slaney, C, Smeland, OB, Sobell, JL, Hansen, CS, Artigas, MS, Spijker, AT, Stein, DJ, Strauss, JS, Swiatkowska, B, Terao, C, Thorgeirsson, TE, Toma, C, Tooney, P, Tsermpini, E-E, Vawter, MP, Vedder, H, Walters, JTR, Witt, SH, Xi, S, Xu, W, Yang, JMK, Young, AH, Young, H, Zandi, PP, Zhou, H, Zillich, L, Adolfsson, R, Agartz, I, Alda, M, Alfredsson, L, Babadjanova, G, Backlund, L, Baune, BT, Bellivier, F, Bengesser, S, Berrettini, WH, Blackwood, DHR, Boehnke, M, Borglum, AD, Breen, G, Carr, VJ, Catts, S, Corvin, A, Craddock, N, Dannlowski, U, Dikeos, D, Esko, T, Etain, B, Ferentinos, P, Frye, M, Fullerton, JM, Gawlik, M, Gershon, ES, Goes, F, Green, MJ, Grigoroiu-Serbanescu, M, Hauser, J, Henskens, F, Hillert, J, Hong, KS, Hougaard, DM, Hultman, CM, Hveem, K, Iwata, N, Jablensky, A, Jones, I, Jones, LA, Kahn, RS, Kelsoe, JR, Kirov, G, Landen, M, Leboyer, M, Lewis, CM, Li, QS, Lissowska, J, Lochner, C, Loughland, C, Martin, NG, Mathews, CA, Mayoral, F, McElroy, SL, McIntosh, AM, McMahon, FJ, Melle, I, Michie, P, Milani, L, Mitchell, PB, Morken, G, Mors, O, Mortensen, PB, Mowry, B, Muller-Myhsok, B, Myers, RM, Neale, BM, Nievergelt, CM, Nordentoft, M, Nothen, MM, ODonovan, MC, Oedegaard, KJ, Olsson, T, Owen, MJ, Paciga, SA, Pantelis, C, Pato, C, Pato, MT, Patrinos, GP, Perlis, RH, Posthuma, D, Ramos-Quiroga, JA, Reif, A, Reininghaus, EZ, Ribases, M, Rietschel, M, Ripke, S, Rouleau, GA, Saito, T, Schall, U, Schalling, M, Schofield, PR, Schulze, TG, Scott, LJ, Scott, RJ, Serretti, A, Weickert, CS, Smoller, JW, Stefansson, H, Stefansson, K, Stordal, E, Streit, F, Sullivan, PF, Turecki, G, Vaaler, AE, Vieta, E, Vincent, JB, Waldman, ID, Weickert, TW, Werge, T, Wray, NR, Zwart, J, Biernacka, JM, Nurnberger, J, Cichon, S, Edenberg, HJ, Stahl, EA, McQuillin, A, Di Florio, A, Ophoff, RA, Andreassen, OA, Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JR, Qiao, Z, Als, TD, Bigdeli, TB, Borte, S, Bryois, J, Charney, AW, Drange, OK, Gandal, MJ, Hagenaars, SP, Ikeda, M, Kamitaki, N, Kim, M, Krebs, K, Panagiotaropoulou, G, Schilder, BM, Sloofman, LG, Steinberg, S, Trubetskoy, V, Winsvold, BS, Won, H-H, Abramova, L, Adorjan, K, Agerbo, E, Al Eissa, M, Albani, D, Alliey-Rodriguez, N, Anjorin, A, Antilla, V, Antoniou, A, Awasthi, S, Baek, JH, Baekvad-Hansen, M, Bass, N, Bauer, M, Beins, EC, Bergen, SE, Birner, A, Pedersen, CB, Boen, E, Boks, MP, Bosch, R, Brum, M, Brumpton, BM, Brunkhorst-Kanaan, N, Budde, M, Bybjerg-Grauholm, J, Byerley, W, Cairns, M, Casas, M, Cervantes, P, Clarke, T-K, Cruceanu, C, Cuellar-Barboza, A, Cunningham, J, Curtis, D, Czerski, PM, Dale, AM, Dalkner, N, David, FS, Degenhardt, F, Djurovic, S, Dobbyn, AL, Douzenis, A, Elvsashagen, T, Escott-Price, V, Ferrier, IN, Fiorentino, A, Foroud, TM, Forty, L, Frank, J, Frei, O, Freimer, NB, Frisen, L, Gade, K, Garnham, J, Gelernter, J, Pedersen, MG, Gizer, IR, Gordon, SD, Gordon-Smith, K, Greenwood, TA, Grove, J, Guzman-Parra, J, Ha, K, Haraldsson, M, Hautzinger, M, Heilbronner, U, Hellgren, D, Herms, S, Hoffmann, P, Holmans, PA, Huckins, L, Jamain, S, Johnson, JS, Kalman, JL, Kamatani, Y, Kennedy, JL, Kittel-Schneider, S, Knowles, JA, Kogevinas, M, Koromina, M, Kranz, TM, Kranzler, HR, Kubo, M, Kupka, R, Kushner, SA, Lavebratt, C, Lawrence, J, Leber, M, Lee, H-J, Lee, PH, Levy, SE, Lewis, C, Liao, C, Lucae, S, Lundberg, M, MacIntyre, DJ, Maier, W, Maihofer, A, Malaspina, D, Maratou, E, Martinsson, L, Mattheisen, M, McCarroll, SA, McGregor, NW, McGuffin, P, McKay, JD, Medeiros, H, Medland, SE, Millischer, V, Montgomery, GW, Moran, JL, Morris, DW, Muhleisen, TW, O'Brien, N, O'Donovan, C, Loohuis, LMO, Oruc, L, Papiol, S, Pardinas, AF, Perry, A, Pfennig, A, Porichi, E, Potash, JB, Quested, D, Raj, T, Rapaport, MH, DePaulo, JR, Regeer, EJ, Rice, JP, Rivas, F, Rivera, M, Roth, J, Roussos, P, Ruderfer, DM, Sanchez-Mora, C, Schulte, EC, Senner, F, Sharp, S, Shilling, PD, Sigurdsson, E, Sirignano, L, Slaney, C, Smeland, OB, Sobell, JL, Hansen, CS, Artigas, MS, Spijker, AT, Stein, DJ, Strauss, JS, Swiatkowska, B, Terao, C, Thorgeirsson, TE, Toma, C, Tooney, P, Tsermpini, E-E, Vawter, MP, Vedder, H, Walters, JTR, Witt, SH, Xi, S, Xu, W, Yang, JMK, Young, AH, Young, H, Zandi, PP, Zhou, H, Zillich, L, Adolfsson, R, Agartz, I, Alda, M, Alfredsson, L, Babadjanova, G, Backlund, L, Baune, BT, Bellivier, F, Bengesser, S, Berrettini, WH, Blackwood, DHR, Boehnke, M, Borglum, AD, Breen, G, Carr, VJ, Catts, S, Corvin, A, Craddock, N, Dannlowski, U, Dikeos, D, Esko, T, Etain, B, Ferentinos, P, Frye, M, Fullerton, JM, Gawlik, M, Gershon, ES, Goes, F, Green, MJ, Grigoroiu-Serbanescu, M, Hauser, J, Henskens, F, Hillert, J, Hong, KS, Hougaard, DM, Hultman, CM, Hveem, K, Iwata, N, Jablensky, A, Jones, I, Jones, LA, Kahn, RS, Kelsoe, JR, Kirov, G, Landen, M, Leboyer, M, Lewis, CM, Li, QS, Lissowska, J, Lochner, C, Loughland, C, Martin, NG, Mathews, CA, Mayoral, F, McElroy, SL, McIntosh, AM, McMahon, FJ, Melle, I, Michie, P, Milani, L, Mitchell, PB, Morken, G, Mors, O, Mortensen, PB, Mowry, B, Muller-Myhsok, B, Myers, RM, Neale, BM, Nievergelt, CM, Nordentoft, M, Nothen, MM, ODonovan, MC, Oedegaard, KJ, Olsson, T, Owen, MJ, Paciga, SA, Pantelis, C, Pato, C, Pato, MT, Patrinos, GP, Perlis, RH, Posthuma, D, Ramos-Quiroga, JA, Reif, A, Reininghaus, EZ, Ribases, M, Rietschel, M, Ripke, S, Rouleau, GA, Saito, T, Schall, U, Schalling, M, Schofield, PR, Schulze, TG, Scott, LJ, Scott, RJ, Serretti, A, Weickert, CS, Smoller, JW, Stefansson, H, Stefansson, K, Stordal, E, Streit, F, Sullivan, PF, Turecki, G, Vaaler, AE, Vieta, E, Vincent, JB, Waldman, ID, Weickert, TW, Werge, T, Wray, NR, Zwart, J, Biernacka, JM, Nurnberger, J, Cichon, S, Edenberg, HJ, Stahl, EA, McQuillin, A, Di Florio, A, Ophoff, RA, and Andreassen, OA
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2021

22. Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color

Author: Simcoe, M, Valdes, A, Liu, F, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, W, Kraft, P, Hammond, CJ, Shi, Y, Chen, Y, Zeng, C, Klaver, CCW, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Han, J, Mackey, DA, Martin, NG, Cheng, C-Y, Hinds, DA, Spector, TD, Kayser, M, Hysi, PG, Simcoe, M, Valdes, A, Liu, F, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, W, Kraft, P, Hammond, CJ, Shi, Y, Chen, Y, Zeng, C, Klaver, CCW, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Han, J, Mackey, DA, Martin, NG, Cheng, C-Y, Hinds, DA, Spector, TD, Kayser, M, and Hysi, PG
Abstract: Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
Published: 2021

23. Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets

Author: Postema, MC, Hoogman, M, Ambrosino, S, Asherson, P, Banaschewski, T, Bandeira, CE, Baranov, A, Bau, CHD, Baumeister, S, Baur-Streubel, R, Bellgrove, MA, Biederman, J, Bralten, J, Brandeis, D, Brem, S, Buitelaar, JK, Busatto, GF, Castellanos, FX, Cercignani, M, Chaim-Avancini, TM, Chantiluke, KC, Christakou, A, Coghill, D, Conzelmann, A, Cubillo, AI, Cupertino, RB, de Zeeuw, P, Doyle, AE, Durston, S, Earl, EA, Epstein, JN, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Frodl, T, Gabel, MC, Gogberashvili, T, Grevet, EH, Haavik, J, Harrison, NA, Hartman, CA, Heslenfeld, DJ, Hoekstra, PJ, Hohmann, S, Hovik, MF, Jernigan, TL, Kardatzki, B, Karkashadze, G, Kelly, C, Kohls, G, Konrad, K, Kuntsi, J, Lazaro, L, Lera-Miguel, S, Lesch, K-P, Louza, MR, Lundervold, AJ, Malpas, CB, Mattos, P, McCarthy, H, Namazova-Baranova, L, Nicolau, R, Nigg, JT, Novotny, SE, Oberwelland Weiss, E, O'Gorman Tuura, RL, Oosterlaan, J, Oranje, B, Paloyelis, Y, Pauli, P, Picon, FA, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Rosa, PGP, Rubia, K, Schrantee, A, Schweren, LJS, Seitz, J, Shaw, P, Silk, TJ, Skokauskas, N, Soliva Vila, JC, Stevens, MC, Sudre, G, Tamm, L, Tovar-Moll, F, van Erp, TGM, Vance, A, Vilarroya, O, Vives-Gilabert, Y, von Polier, GG, Walitza, S, Yoncheva, YN, Zanetti, MV, Ziegler, GC, Glahn, DC, Jahanshad, N, Medland, SE, Thompson, PM, Fisher, SE, Franke, B, Francks, C, Postema, MC, Hoogman, M, Ambrosino, S, Asherson, P, Banaschewski, T, Bandeira, CE, Baranov, A, Bau, CHD, Baumeister, S, Baur-Streubel, R, Bellgrove, MA, Biederman, J, Bralten, J, Brandeis, D, Brem, S, Buitelaar, JK, Busatto, GF, Castellanos, FX, Cercignani, M, Chaim-Avancini, TM, Chantiluke, KC, Christakou, A, Coghill, D, Conzelmann, A, Cubillo, AI, Cupertino, RB, de Zeeuw, P, Doyle, AE, Durston, S, Earl, EA, Epstein, JN, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Frodl, T, Gabel, MC, Gogberashvili, T, Grevet, EH, Haavik, J, Harrison, NA, Hartman, CA, Heslenfeld, DJ, Hoekstra, PJ, Hohmann, S, Hovik, MF, Jernigan, TL, Kardatzki, B, Karkashadze, G, Kelly, C, Kohls, G, Konrad, K, Kuntsi, J, Lazaro, L, Lera-Miguel, S, Lesch, K-P, Louza, MR, Lundervold, AJ, Malpas, CB, Mattos, P, McCarthy, H, Namazova-Baranova, L, Nicolau, R, Nigg, JT, Novotny, SE, Oberwelland Weiss, E, O'Gorman Tuura, RL, Oosterlaan, J, Oranje, B, Paloyelis, Y, Pauli, P, Picon, FA, Plessen, KJ, Ramos-Quiroga, JA, Reif, A, Reneman, L, Rosa, PGP, Rubia, K, Schrantee, A, Schweren, LJS, Seitz, J, Shaw, P, Silk, TJ, Skokauskas, N, Soliva Vila, JC, Stevens, MC, Sudre, G, Tamm, L, Tovar-Moll, F, van Erp, TGM, Vance, A, Vilarroya, O, Vives-Gilabert, Y, von Polier, GG, Walitza, S, Yoncheva, YN, Zanetti, MV, Ziegler, GC, Glahn, DC, Jahanshad, N, Medland, SE, Thompson, PM, Fisher, SE, Franke, B, and Francks, C
Abstract: OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
Published: 2021

24. Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years

Author: Dima, D, Modabbernia, A, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, Ortiz-Garcia De la Foz, V, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, Van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Williams, SCR, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, Frangou, S, Dima, D, Modabbernia, A, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, Ortiz-Garcia De la Foz, V, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, Van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Williams, SCR, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, and Frangou, S
Abstract: Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
Published: 2021

25. Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Author: Frangou, S, Modabbernia, A, Williams, SCR, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, de la Foz, VO-G, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, Dima, D, Frangou, S, Modabbernia, A, Williams, SCR, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, de la Foz, VO-G, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, and Dima, D
Abstract: Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
Published: 2021

26. Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Author: Han, LKM, Dinga, R, Hahn, T, Ching, CRK, Eyler, LT, Aftanas, L, Aghajani, M, Aleman, A, Baune, BT, Berger, K, Brak, I, Filho, GB, Carballedo, A, Connolly, CG, Couvy-Duchesne, B, Cullen, KR, Dannlowski, U, Davey, CG, Dima, D, Duran, FLS, Enneking, V, Filimonova, E, Frenzel, S, Frodl, T, Fu, CHY, Godlewska, BR, Gotlib, IH, Grabe, HJ, Groenewold, NA, Grotegerd, D, Gruber, O, Hall, GB, Harrison, BJ, Hatton, SN, Hermesdorf, M, Hickie, IB, Ho, TC, Hosten, N, Jansen, A, Kähler, C, Kircher, T, Klimes-Dougan, B, Krämer, B, Krug, A, Lagopoulos, J, Leenings, R, MacMaster, FP, MacQueen, G, McIntosh, A, McLellan, Q, McMahon, KL, Medland, SE, Mueller, BA, Mwangi, B, Osipov, E, Portella, MJ, Pozzi, E, Reneman, L, Repple, J, Rosa, PGP, Sacchet, MD, Sämann, PG, Schnell, K, Schrantee, A, Simulionyte, E, Soares, JC, Sommer, J, Stein, DJ, Steinsträter, O, Strike, LT, Thomopoulos, SI, van Tol, M-J, Veer, IM, Vermeiren, RRJM, Walter, H, van der Wee, NJA, van der Werff, SJA, Whalley, H, Winter, NR, Wittfeld, K, Wright, MJ, Wu, M-J, Völzke, H, Yang, TT, Zannias, V, de Zubicaray, GI, Zunta-Soares, GB, Abé, C, Alda, M, Andreassen, OA, Bøen, E, Bonnin, CM, Canales-Rodriguez, EJ, Cannon, D, Caseras, X, Chaim-Avancini, TM, Elvsåshagen, T, Favre, P, Foley, SF, Fullerton, JM, Goikolea, JM, Haarman, BCM, Hajek, T, Henry, C, Houenou, J, Howells, FM, Ingvar, M, Kuplicki, R, Lafer, B, Landén, M, Machado-Vieira, R, Malt, UF, McDonald, C, Mitchell, PB, Nabulsi, L, Otaduy, MCG, Overs, BJ, Polosan, M, Pomarol-Clotet, E, Radua, J, Rive, MM, Roberts, G, Ruhe, HG, Salvador, R, Sarró, S, Satterthwaite, TD, Savitz, J, Schene, AH, Schofield, PR, Serpa, MH, Sim, K, Soeiro-de-Souza, MG, Sutherland, AN, Temmingh, HS, Timmons, GM, Uhlmann, A, Vieta, E, Wolf, DH, Zanetti, MV, Jahanshad, N, Thompson, PM, Veltman, DJ, Penninx, BWJH, Marquand, AF, Cole, JH, Schmaal, L, Han, LKM, Dinga, R, Hahn, T, Ching, CRK, Eyler, LT, Aftanas, L, Aghajani, M, Aleman, A, Baune, BT, Berger, K, Brak, I, Filho, GB, Carballedo, A, Connolly, CG, Couvy-Duchesne, B, Cullen, KR, Dannlowski, U, Davey, CG, Dima, D, Duran, FLS, Enneking, V, Filimonova, E, Frenzel, S, Frodl, T, Fu, CHY, Godlewska, BR, Gotlib, IH, Grabe, HJ, Groenewold, NA, Grotegerd, D, Gruber, O, Hall, GB, Harrison, BJ, Hatton, SN, Hermesdorf, M, Hickie, IB, Ho, TC, Hosten, N, Jansen, A, Kähler, C, Kircher, T, Klimes-Dougan, B, Krämer, B, Krug, A, Lagopoulos, J, Leenings, R, MacMaster, FP, MacQueen, G, McIntosh, A, McLellan, Q, McMahon, KL, Medland, SE, Mueller, BA, Mwangi, B, Osipov, E, Portella, MJ, Pozzi, E, Reneman, L, Repple, J, Rosa, PGP, Sacchet, MD, Sämann, PG, Schnell, K, Schrantee, A, Simulionyte, E, Soares, JC, Sommer, J, Stein, DJ, Steinsträter, O, Strike, LT, Thomopoulos, SI, van Tol, M-J, Veer, IM, Vermeiren, RRJM, Walter, H, van der Wee, NJA, van der Werff, SJA, Whalley, H, Winter, NR, Wittfeld, K, Wright, MJ, Wu, M-J, Völzke, H, Yang, TT, Zannias, V, de Zubicaray, GI, Zunta-Soares, GB, Abé, C, Alda, M, Andreassen, OA, Bøen, E, Bonnin, CM, Canales-Rodriguez, EJ, Cannon, D, Caseras, X, Chaim-Avancini, TM, Elvsåshagen, T, Favre, P, Foley, SF, Fullerton, JM, Goikolea, JM, Haarman, BCM, Hajek, T, Henry, C, Houenou, J, Howells, FM, Ingvar, M, Kuplicki, R, Lafer, B, Landén, M, Machado-Vieira, R, Malt, UF, McDonald, C, Mitchell, PB, Nabulsi, L, Otaduy, MCG, Overs, BJ, Polosan, M, Pomarol-Clotet, E, Radua, J, Rive, MM, Roberts, G, Ruhe, HG, Salvador, R, Sarró, S, Satterthwaite, TD, Savitz, J, Schene, AH, Schofield, PR, Serpa, MH, Sim, K, Soeiro-de-Souza, MG, Sutherland, AN, Temmingh, HS, Timmons, GM, Uhlmann, A, Vieta, E, Wolf, DH, Zanetti, MV, Jahanshad, N, Thompson, PM, Veltman, DJ, Penninx, BWJH, Marquand, AF, Cole, JH, and Schmaal, L
Abstract: Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.
Published: 2021

27. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author: Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, Agrawal, A, Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, and Agrawal, A
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotyp
Published: 2021

28. Genetic variants for head size share genes and pathways with cancer

Author: Shihua Li, Melissa J. Green, Nagata M, Miyamoto S, Le Grand Q, Pourcain Bs, Grabe Hj, Catherine Helmer, William R. Reay, Nele Friedrich, Mazoyer B, Seshadri S, Per Hoffmann, Simon Haworth, Veronica Witte A, Yang Q, Max Lam, Teunissen Mw, Fang-Chi Hsu, Debette S, Murray J. Cairns, Amod Ar, Setoh K, Windham Bg, Shareefa Dalvie, Georg Homuth, Charlie S. DeCarli, Gennady V. Roshchupkin, Céline S. Reinbold, Mühleisen Tw, Nakahara S, Van der Auwera S, Xueqiu Jian, Cecil Ca, Jean-François Dartigues, Alexa S. Beiser, Stein Jl, Houlden H, Christiane Jockwitz, Moebus S, Claudia L. Satizabal, Tavia E. Evans, Matsuda F, Cora E. Lewis, Wittfeld K, Calhoun Vd, van der Lugt A, Teumer A, Pausova Z, W. T. Longstreth, Aniket Mishra, Tomáš Paus, Vernooij Mw, Medland Se, Palmer Nd, Ahmad R. Hariri, Adrian Preda, Clifford R. Jack, van Erp Tg, Amaia Carrion-Castillo, Werring Dj, Gwénaëlle Catheline, Asta Håberg, Robin Bülow, Sven Cichon, Yann Quidé, Muetzel R, Tabara Y, Sidney S, Cheung C, Brunner Hg, Annchen R. Knodt, Mosley Th, van Dam-Nolen Dh, Hostettler Ic, Jean Shin, Shapland Cy, Reut Avinun, Crivello F, Mäkitie O, Fornage M, Yoshida K, Villringer A, Lim K, Schreiner Pj, Bowden Dw, Thompson Pm, Daniel Bos, Uhlmann A, Enlund-Cerullo M, Schmidt R, Hieab H.H. Adams, Neda Jahanshad, Frauke Beyer, Gloria H.Y. Li, Fabio Macciardi, Lamballais S, Kämpe A, Judith M. Ford, Poot Ra, J. C. Bis, Yoichiro Kamatani, Ami Tsuchida, Markus Scholz, Ikram Ma, Andersson S, Lenore J. Launer, Stein Dj, Koudstaal Pj, Barry I. Freedman, Barbara Franke, Ikram Mk, Sim K, Marie-Gabrielle Duperron, Bryan Rn, Svenja Caspers, Pawlak Ma, Tonya White, Maria J. Knol, Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, and Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium
Subjects: Genetics, 0303 health sciences, education.field_of_study, biology, Population, Wnt signaling pathway, Macrocephaly, Cancer, medicine.disease, Biological pathway, 03 medical and health sciences, 0302 clinical medicine, medicine, biology.protein, PTEN, Human height, medicine.symptom, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53, PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.
Published: 2020

29. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Author: Hofer, E, Roshchupkin, GV, Adams, HHH, Knol, MJ, Lin, H, Li, S, Zare, H, Ahmad, S, Armstrong, NJ, Satizabal, CL, Bernard, M, Bis, JC, Gillespie, NA, Luciano, M, Mishra, A, Scholz, M, Teumer, A, Xia, R, Jian, X, Mosley, TH, Saba, Y, Pirpamer, L, Seiler, S, Becker, JT, Carmichael, O, Rotter, JI, Psaty, BM, Lopez, OL, Amin, N, van der Lee, SJ, Yang, Q, Himali, JJ, Maillard, P, Beiser, AS, Decarli, C, Karama, S, Lewis, L, Harris, M, Bastin, ME, Deary, IJ, Witte, AV, Beyer, F, Loeffler, M, Mather, KA, Schofield, PR, Thalamuthu, A, Kwok, JB, Wright, MJ, Ames, D, Trollor, J, Jiang, J, Brodaty, H, Wen, W, Vernooij, MW, Hofman, A, Uitterlinden, AG, Niessen, WJ, Wittfeld, K, Bülow, R, Völker, U, Pausova, Z, Pike, GB, Maingault, S, Crivello, F, Tzourio, C, Amouyel, P, Mazoyer, B, Neale, MC, Franz, CE, Lyons, MJ, Panizzon, MS, Andreassen, OA, Dale, AM, Logue, M, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Stein, JL, Thompson, PM, Medland, SE, Sachdev, PS, Kremen, WS, Wardlaw, JM, Villringer, A, van Duijn, CM, Grabe, HJ, Longstreth, WT, Fornage, M, Paus, T, Debette, S, Ikram, MA, Schmidt, H, Schmidt, R, Seshadri, S, Ching, CRK, Hofer, E, Roshchupkin, GV, Adams, HHH, Knol, MJ, Lin, H, Li, S, Zare, H, Ahmad, S, Armstrong, NJ, Satizabal, CL, Bernard, M, Bis, JC, Gillespie, NA, Luciano, M, Mishra, A, Scholz, M, Teumer, A, Xia, R, Jian, X, Mosley, TH, Saba, Y, Pirpamer, L, Seiler, S, Becker, JT, Carmichael, O, Rotter, JI, Psaty, BM, Lopez, OL, Amin, N, van der Lee, SJ, Yang, Q, Himali, JJ, Maillard, P, Beiser, AS, Decarli, C, Karama, S, Lewis, L, Harris, M, Bastin, ME, Deary, IJ, Witte, AV, Beyer, F, Loeffler, M, Mather, KA, Schofield, PR, Thalamuthu, A, Kwok, JB, Wright, MJ, Ames, D, Trollor, J, Jiang, J, Brodaty, H, Wen, W, Vernooij, MW, Hofman, A, Uitterlinden, AG, Niessen, WJ, Wittfeld, K, Bülow, R, Völker, U, Pausova, Z, Pike, GB, Maingault, S, Crivello, F, Tzourio, C, Amouyel, P, Mazoyer, B, Neale, MC, Franz, CE, Lyons, MJ, Panizzon, MS, Andreassen, OA, Dale, AM, Logue, M, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Stein, JL, Thompson, PM, Medland, SE, Sachdev, PS, Kremen, WS, Wardlaw, JM, Villringer, A, van Duijn, CM, Grabe, HJ, Longstreth, WT, Fornage, M, Paus, T, Debette, S, Ikram, MA, Schmidt, H, Schmidt, R, Seshadri, S, and Ching, CRK
Abstract: Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
Published: 2020

30. Erratum: A Neuroethics Framework for the Australian Brain Initiative (Neuron (2019) 101(3) (365–369), (S0896627319300054), (10.1016/j.neuron.2019.01.004))

Author: Carter, A, Richards, LJ, Apthorp, D, Azghadi, MR, Badcock, DR, Balleine, B, Bekkers, JM, Berk, M, Bourne, JA, Bradley, AP, Breakspear, M, Brichta, A, Carter, O, Castles, A, Chakli, K, Cohen-Woods, S, Conn, SJ, Cornish, J, Cornish, K, de Zubicaray, G, Egan, GF, Enticott, PG, Fitzgibbon, BM, Forlini, C, Fornito, A, Griffiths, L, Gullifer, J, Hall, W, Halliday, G, Hannan, AJ, Harrer, S, Harvey, A, Hatherly, C, Hickie, IB, Kennett, J, Kiernan, M, Kilpatrick, T, Kiral-Kornek, I, Korgaonkar, MS, Lawrence, AJ, Leventer, R, Levy, N, Licinio, J, Lovell, N, Mackellar, G, Malcolm, L, Mason, A, Mattingley, JB, Medland, SE, Michie, PT, Nithianantharajah, J, Parker, J, Payne, JM, Poole-Warren, L, Sah, P, Sarnyai, Z, Schofield, PR, Shimoni, O, Shum, DHK, Silk, T, Slee, M, Smith, AE, Soulis, T, Sriram, S, Stuart, GJ, Tapson, J, Thompson, MB, van Schaik, A, Vincent, NA, Vissel, B, Waters, A, Carter, A, Richards, LJ, Apthorp, D, Azghadi, MR, Badcock, DR, Balleine, B, Bekkers, JM, Berk, M, Bourne, JA, Bradley, AP, Breakspear, M, Brichta, A, Carter, O, Castles, A, Chakli, K, Cohen-Woods, S, Conn, SJ, Cornish, J, Cornish, K, de Zubicaray, G, Egan, GF, Enticott, PG, Fitzgibbon, BM, Forlini, C, Fornito, A, Griffiths, L, Gullifer, J, Hall, W, Halliday, G, Hannan, AJ, Harrer, S, Harvey, A, Hatherly, C, Hickie, IB, Kennett, J, Kiernan, M, Kilpatrick, T, Kiral-Kornek, I, Korgaonkar, MS, Lawrence, AJ, Leventer, R, Levy, N, Licinio, J, Lovell, N, Mackellar, G, Malcolm, L, Mason, A, Mattingley, JB, Medland, SE, Michie, PT, Nithianantharajah, J, Parker, J, Payne, JM, Poole-Warren, L, Sah, P, Sarnyai, Z, Schofield, PR, Shimoni, O, Shum, DHK, Silk, T, Slee, M, Smith, AE, Soulis, T, Sriram, S, Stuart, GJ, Tapson, J, Thompson, MB, van Schaik, A, Vincent, NA, Vissel, B, and Waters, A
Abstract: (Neuron 101, 365–369; February 6, 2019) In the original publication of this NeuroView, the member list for the Australian Brain Alliance was omitted. This has now been corrected online. Neuron apologizes for the error.
Published: 2020

31. Correction : A Neuroethics Framework for the Australian Brain Initiative (Neuron (2019) 101(3) (365–369), (S0896627319300054), (10.1016/j.neuron.2019.01.004))

Author: Carter, Adrian, Richards, Linda J., Apthorp, D, Azghadi, MR, Badcock, DR, Balleine, B, Bekkers, JM, Berk, Michael, Bourne, JA, Bradley, AP, Breakspear, M, Brichta, A, Carter, O, Castles, A, Chakli, K, Cohen-Woods, S, Conn, SJ, Cornish, J, Cornish, K, de Zubicaray, G, Egan, GF, Enticott, Peter, Fitzgibbon, BM, Forlini, Cynthia, Fornito, A, Griffiths, L, Gullifer, J, Hall, W, Halliday, G, Hannan, AJ, Harrer, S, Harvey, A, Hatherly, C, Hickie, IB, Kennett, J, Kiernan, M, Kilpatrick, T, Kiral-Kornek, I, Korgaonkar, MS, Lawrence, Andrew J, Leventer, R, Levy, N, Licinio, J, Lovell, N, Mackellar, G, Malcolm, L, Mason, A, Mattingley, JB, Medland, SE, Michie, PT, Nithianantharajah, J, Parker, J, Payne, JM, Poole-Warren, L, Sah, P, Sarnyai, Z, Schofield, PR, Shimoni, O, Shum, DHK, Silk, Timothy, Slee, M, Smith, AE, Soulis, T, Sriram, S, Stuart, GJ, Tapson, J, Thompson, MB, van Schaik, A, Vincent, NA, Vissel, B, Waters, A, Carter, Adrian, Richards, Linda J., Apthorp, D, Azghadi, MR, Badcock, DR, Balleine, B, Bekkers, JM, Berk, Michael, Bourne, JA, Bradley, AP, Breakspear, M, Brichta, A, Carter, O, Castles, A, Chakli, K, Cohen-Woods, S, Conn, SJ, Cornish, J, Cornish, K, de Zubicaray, G, Egan, GF, Enticott, Peter, Fitzgibbon, BM, Forlini, Cynthia, Fornito, A, Griffiths, L, Gullifer, J, Hall, W, Halliday, G, Hannan, AJ, Harrer, S, Harvey, A, Hatherly, C, Hickie, IB, Kennett, J, Kiernan, M, Kilpatrick, T, Kiral-Kornek, I, Korgaonkar, MS, Lawrence, Andrew J, Leventer, R, Levy, N, Licinio, J, Lovell, N, Mackellar, G, Malcolm, L, Mason, A, Mattingley, JB, Medland, SE, Michie, PT, Nithianantharajah, J, Parker, J, Payne, JM, Poole-Warren, L, Sah, P, Sarnyai, Z, Schofield, PR, Shimoni, O, Shum, DHK, Silk, Timothy, Slee, M, Smith, AE, Soulis, T, Sriram, S, Stuart, GJ, Tapson, J, Thompson, MB, van Schaik, A, Vincent, NA, Vissel, B, and Waters, A
Published: 2020

32. ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

Author: Thompson, PM, Jahanshad, N, Ching, CRK, Salminen, LE, Thomopoulos, SI, Bright, J, Baune, BT, Bertolin, S, Bralten, J, Bruin, WB, Buelow, R, Chen, J, Chye, Y, Dannlowski, U, de Kovel, CGF, Donohoe, G, Eyler, LT, Faraone, SV, Favre, P, Filippi, CA, Frodl, T, Garijo, D, Gil, Y, Grabe, HJ, Grasby, KL, Hajek, T, Han, LKM, Hatton, SN, Hilbert, K, Ho, TC, Holleran, L, Homuth, G, Hosten, N, Houenou, J, Ivanov, I, Jia, T, Kelly, S, Klein, M, Kwon, JS, Laansma, MA, Leerssen, J, Lueken, U, Nunes, A, Neill, JO, Opel, N, Piras, F, Postema, MC, Pozzi, E, Shatokhina, N, Soriano-Mas, C, Spalletta, G, Sun, D, Teumer, A, Tilot, AK, Tozzi, L, van der Merwe, C, Van Someren, EJW, van Wingen, GA, Voelzke, H, Walton, E, Wang, L, Winkler, AM, Wittfeld, K, Wright, MJ, Yun, J-Y, Zhang, G, Zhang-James, Y, Adhikari, BM, Agartz, I, Aghajani, M, Aleman, A, Althoff, RR, Altmann, A, Andreassen, OA, Baron, DA, Bartnik-Olson, BL, Bas-Hoogendam, J, Baskin-Sommers, AR, Bearden, CE, Berner, LA, Boedhoe, PSW, Brouwer, RM, Buitelaar, JK, Caeyenberghs, K, Cecil, CAM, Cohen, RA, Cole, JH, Conrod, PJ, De Brito, SA, de Zwarte, SMC, Dennis, EL, Desrivieres, S, Dima, D, Ehrlich, S, Esopenko, C, Fairchild, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Garavan, HP, Glahn, DC, Groenewold, NA, Gurholt, TP, Gutman, BA, Hahn, T, Harding, IH, Hernaus, D, Hibar, DP, Hillary, FG, Hoogman, M, Pol, HE, Jalbrzikowski, M, Karkashadze, GA, Klapwijk, ET, Knickmeyer, RC, Kochunov, P, Koerte, IK, Kong, X-Z, Liew, S-L, Lin, AP, Logue, MW, Luders, E, Macciardi, F, Mackey, S, Mayer, AR, McDonald, CR, McMahon, AB, Medland, SE, Modinos, G, Morey, RA, Mueller, SC, Mukherjee, P, Namazova-Baranova, L, Nir, TM, Olsen, A, Paschou, P, Pine, DS, Pizzagalli, F, Renteria, ME, Rohrer, JD, Saemann, PG, Schmaal, L, Schumann, G, Shiroishi, MS, Sisodiya, SM, Smit, DJA, Sonderby, IE, Stein, DJ, Stein, JL, Tahmasian, M, Tate, DF, Turner, JA, van den Heuvel, OA, van der Wee, NJA, van der Werf, YD, van Erp, TGM, van Haren, NEM, van Rooij, D, van Velzen, LS, Veer, IM, Veltman, DJ, Villalon-Reina, JE, Walter, H, Whelan, CD, Wilde, EA, Zarei, M, Zelman, V, Thompson, PM, Jahanshad, N, Ching, CRK, Salminen, LE, Thomopoulos, SI, Bright, J, Baune, BT, Bertolin, S, Bralten, J, Bruin, WB, Buelow, R, Chen, J, Chye, Y, Dannlowski, U, de Kovel, CGF, Donohoe, G, Eyler, LT, Faraone, SV, Favre, P, Filippi, CA, Frodl, T, Garijo, D, Gil, Y, Grabe, HJ, Grasby, KL, Hajek, T, Han, LKM, Hatton, SN, Hilbert, K, Ho, TC, Holleran, L, Homuth, G, Hosten, N, Houenou, J, Ivanov, I, Jia, T, Kelly, S, Klein, M, Kwon, JS, Laansma, MA, Leerssen, J, Lueken, U, Nunes, A, Neill, JO, Opel, N, Piras, F, Postema, MC, Pozzi, E, Shatokhina, N, Soriano-Mas, C, Spalletta, G, Sun, D, Teumer, A, Tilot, AK, Tozzi, L, van der Merwe, C, Van Someren, EJW, van Wingen, GA, Voelzke, H, Walton, E, Wang, L, Winkler, AM, Wittfeld, K, Wright, MJ, Yun, J-Y, Zhang, G, Zhang-James, Y, Adhikari, BM, Agartz, I, Aghajani, M, Aleman, A, Althoff, RR, Altmann, A, Andreassen, OA, Baron, DA, Bartnik-Olson, BL, Bas-Hoogendam, J, Baskin-Sommers, AR, Bearden, CE, Berner, LA, Boedhoe, PSW, Brouwer, RM, Buitelaar, JK, Caeyenberghs, K, Cecil, CAM, Cohen, RA, Cole, JH, Conrod, PJ, De Brito, SA, de Zwarte, SMC, Dennis, EL, Desrivieres, S, Dima, D, Ehrlich, S, Esopenko, C, Fairchild, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Garavan, HP, Glahn, DC, Groenewold, NA, Gurholt, TP, Gutman, BA, Hahn, T, Harding, IH, Hernaus, D, Hibar, DP, Hillary, FG, Hoogman, M, Pol, HE, Jalbrzikowski, M, Karkashadze, GA, Klapwijk, ET, Knickmeyer, RC, Kochunov, P, Koerte, IK, Kong, X-Z, Liew, S-L, Lin, AP, Logue, MW, Luders, E, Macciardi, F, Mackey, S, Mayer, AR, McDonald, CR, McMahon, AB, Medland, SE, Modinos, G, Morey, RA, Mueller, SC, Mukherjee, P, Namazova-Baranova, L, Nir, TM, Olsen, A, Paschou, P, Pine, DS, Pizzagalli, F, Renteria, ME, Rohrer, JD, Saemann, PG, Schmaal, L, Schumann, G, Shiroishi, MS, Sisodiya, SM, Smit, DJA, Sonderby, IE, Stein, DJ, Stein, JL, Tahmasian, M, Tate, DF, Turner, JA, van den Heuvel, OA, van der Wee, NJA, van der Werf, YD, van Erp, TGM, van Haren, NEM, van Rooij, D, van Velzen, LS, Veer, IM, Veltman, DJ, Villalon-Reina, JE, Walter, H, Whelan, CD, Wilde, EA, Zarei, M, and Zelman, V
Abstract: This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
Published: 2020

33. 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

34. Mapping Cortical and Subcortical Asymmetry in Obsessive-Compulsive Disorder: Findings From the ENIGMA Consortium

Author: Kong, X-Z, Boedhoe, PSW, Abe, Y, Alonso, P, Ameis, SH, Arnold, PD, Assogna, F, Baker, JT, Batistuzzo, MC, Benedetti, F, Beucke, JC, Bollettini, I, Bose, A, Brem, S, Brennan, BP, Buitelaar, J, Calvo, R, Cheng, Y, Cho, KIK, Dallaspezia, S, Denys, D, Ely, BA, Feusner, J, Fitzgerald, KD, Fouche, J-P, Fridgeirsson, EA, Glahn, DC, Gruner, P, Gursel, DA, Hauser, TU, Hirano, Y, Hoexter, MQ, Hu, H, Huyser, C, James, A, Jaspers-Fayer, F, Kathmann, N, Kaufmann, C, Koch, K, Kuno, M, Kvale, G, Kwon, JS, Lazaro, L, Liu, Y, Lochner, C, Marques, P, Marsh, R, Martinez-Zalacain, I, Mataix-Cols, D, Medland, SE, Menchon, JM, Minuzzi, L, Moreira, PS, Morer, A, Morgado, P, Nakagawa, A, Nakamae, T, Nakao, T, Narayanaswamy, JC, Nurmi, EL, O'Neill, J, Pariente, JC, Perriello, C, Piacentini, J, Piras, F, Pittenger, C, Reddy, YCJ, Rus-Oswald, OG, Sakai, Y, Sato, JR, Schmaal, L, Simpson, HB, Soreni, N, Soriano-Mas, C, Spalletta, G, Stern, ER, Stevens, MC, Stewart, SE, Szeszko, PR, Tolin, DF, Tsuchiyagaito, A, van Rooij, D, van Wingen, GA, Venkatasubramanian, G, Wang, Z, Yun, J-Y, Thompson, PM, Stein, DJ, van den Heuvel, OA, Francks, C, Kong, X-Z, Boedhoe, PSW, Abe, Y, Alonso, P, Ameis, SH, Arnold, PD, Assogna, F, Baker, JT, Batistuzzo, MC, Benedetti, F, Beucke, JC, Bollettini, I, Bose, A, Brem, S, Brennan, BP, Buitelaar, J, Calvo, R, Cheng, Y, Cho, KIK, Dallaspezia, S, Denys, D, Ely, BA, Feusner, J, Fitzgerald, KD, Fouche, J-P, Fridgeirsson, EA, Glahn, DC, Gruner, P, Gursel, DA, Hauser, TU, Hirano, Y, Hoexter, MQ, Hu, H, Huyser, C, James, A, Jaspers-Fayer, F, Kathmann, N, Kaufmann, C, Koch, K, Kuno, M, Kvale, G, Kwon, JS, Lazaro, L, Liu, Y, Lochner, C, Marques, P, Marsh, R, Martinez-Zalacain, I, Mataix-Cols, D, Medland, SE, Menchon, JM, Minuzzi, L, Moreira, PS, Morer, A, Morgado, P, Nakagawa, A, Nakamae, T, Nakao, T, Narayanaswamy, JC, Nurmi, EL, O'Neill, J, Pariente, JC, Perriello, C, Piacentini, J, Piras, F, Pittenger, C, Reddy, YCJ, Rus-Oswald, OG, Sakai, Y, Sato, JR, Schmaal, L, Simpson, HB, Soreni, N, Soriano-Mas, C, Spalletta, G, Stern, ER, Stevens, MC, Stewart, SE, Szeszko, PR, Tolin, DF, Tsuchiyagaito, A, van Rooij, D, van Wingen, GA, Venkatasubramanian, G, Wang, Z, Yun, J-Y, Thompson, PM, Stein, DJ, van den Heuvel, OA, and Francks, C
Abstract: BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD. METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.
Published: 2020

35. The genetic architecture of the human cerebral cortex

Author: Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, Medland, SE, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, and Medland, SE
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Published: 2020

36. Genetic and environmental variation in educational attainment: an individual-based analysis of 28 twin cohorts

Author: Silventoinen, K, Jelenkovic, A, Sund, R, Latvala, A, Honda, C, Inui, F, Tomizawa, R, Watanabe, M, Sakai, N, Rebato, E, Busjahn, A, Tyler, J, Hopper, JL, Ordonana, JR, Sanchez-Romera, JF, Colodro-Conde, L, Calais-Ferreira, L, Oliveira, VC, Ferreira, PH, Medda, E, Nistico, L, Toccaceli, V, Derom, CA, Vlietinck, RF, Loos, RJF, Siribaddana, SH, Hotopf, M, Sumathipala, A, Rijsdijk, F, Duncan, GE, Buchwald, D, Tynelius, P, Rasmussen, F, Tan, Q, Zhang, D, Pang, Z, Magnusson, PKE, Pedersen, NL, Aslan, AKD, Hwang, AE, Mack, TM, Krueger, RF, McGue, M, Pahlen, S, Brandt, I, Nilsen, TS, Harris, JR, Martin, NG, Medland, SE, Montgomery, GW, Willemsen, G, Bartels, M, van Beijsterveldt, CEM, Franz, CE, Kremen, WS, Lyons, MJ, Silberg, JL, Maes, HH, Kandler, C, Nelson, TL, Whitfield, KE, Corley, RP, Huibregtse, BM, Gatz, M, Butler, DA, Tarnoki, AD, Tarnoki, DL, Park, HA, Lee, J, Lee, SJ, Sung, J, Yokoyama, Y, Sorensen, TIA, Boomsma, D, Kaprio, J, Silventoinen, K, Jelenkovic, A, Sund, R, Latvala, A, Honda, C, Inui, F, Tomizawa, R, Watanabe, M, Sakai, N, Rebato, E, Busjahn, A, Tyler, J, Hopper, JL, Ordonana, JR, Sanchez-Romera, JF, Colodro-Conde, L, Calais-Ferreira, L, Oliveira, VC, Ferreira, PH, Medda, E, Nistico, L, Toccaceli, V, Derom, CA, Vlietinck, RF, Loos, RJF, Siribaddana, SH, Hotopf, M, Sumathipala, A, Rijsdijk, F, Duncan, GE, Buchwald, D, Tynelius, P, Rasmussen, F, Tan, Q, Zhang, D, Pang, Z, Magnusson, PKE, Pedersen, NL, Aslan, AKD, Hwang, AE, Mack, TM, Krueger, RF, McGue, M, Pahlen, S, Brandt, I, Nilsen, TS, Harris, JR, Martin, NG, Medland, SE, Montgomery, GW, Willemsen, G, Bartels, M, van Beijsterveldt, CEM, Franz, CE, Kremen, WS, Lyons, MJ, Silberg, JL, Maes, HH, Kandler, C, Nelson, TL, Whitfield, KE, Corley, RP, Huibregtse, BM, Gatz, M, Butler, DA, Tarnoki, AD, Tarnoki, DL, Park, HA, Lee, J, Lee, SJ, Sung, J, Yokoyama, Y, Sorensen, TIA, Boomsma, D, and Kaprio, J
Abstract: We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a2 = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c2 = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a2 = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a2 = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c2 = 0.31; 0.29-0.33 and c2 = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.
Published: 2020

37. 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

38. Mapping brain asymmetry in health and disease through the ENIGMA consortium

Author: Kong, X-Z, Postema, MC, Guadalupe, T, de Kovel, C, Boedhoe, PSW, Hoogman, M, Mathias, SR, van Rooij, D, Schijven, D, Glahn, DC, Medland, SE, Jahanshad, N, Thomopoulos, S, Turner, JA, Buitelaar, J, van Erp, TGM, Franke, B, Fisher, SE, van den Heuvel, OA, Schmaal, L, Thompson, PM, Francks, C, Kong, X-Z, Postema, MC, Guadalupe, T, de Kovel, C, Boedhoe, PSW, Hoogman, M, Mathias, SR, van Rooij, D, Schijven, D, Glahn, DC, Medland, SE, Jahanshad, N, Thomopoulos, S, Turner, JA, Buitelaar, J, van Erp, TGM, Franke, B, Fisher, SE, van den Heuvel, OA, Schmaal, L, Thompson, PM, and Francks, C
Abstract: Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA-Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive-compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.
Published: 2020

39. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author: Li, C, Stoma, S, Lotta, LA, Warner, S, Albrecht, E, Allione, A, Arp, PP, Broer, L, Buxton, JL, Alves, ADSC, Deelen, J, Fedko, IO, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Loe, TK, Mangino, M, Milaneschi, Y, Miraglio, B, Pervjakova, N, Russo, A, Surakka, I, van der Spek, A, Verhoeven, JE, Amin, N, Beekman, M, Blakemore, A, Canzian, F, Hamby, SE, Hottenga, J-J, Jones, PD, Jousilahti, P, Magi, R, Medland, SE, Montgomery, GW, Nyholt, DR, Perola, M, Pietilainen, KH, Salomaa, V, Sillanpaa, E, Suchiman, HE, van Heemst, D, Willemsen, G, Agudo, A, Boeing, H, Boomsma, D, Chirlaque, M-D, Fagherazzi, G, Ferrari, P, Franks, P, Gieger, C, Eriksson, JG, Gunter, M, Hagg, S, Hovatta, I, Imaz, L, Kaprio, J, Kaaks, R, Key, T, Krogh, V, Martin, NG, Melander, O, Metspalu, A, Moreno, C, Onland-Moret, NC, Nilsson, P, Ong, KK, Overvad, K, Palli, D, Panico, S, Pedersen, NL, Penninx, BWJH, Ramon Quiros, J, Riitta Jarvelin, M, Rodriguez-Barranco, M, Scott, RA, Severi, G, Slagboom, PE, Spector, TD, Tjonneland, A, Trichopoulou, A, Tumino, R, Uitterlinden, AG, van der Schouw, YT, van Duijn, CM, Weiderpass, E, Denchi, EL, Matullo, G, Butterworth, AS, Danesh, J, Samani, NJ, Wareham, NJ, Nelson, CP, Langenberg, C, Codd, V, Li, C, Stoma, S, Lotta, LA, Warner, S, Albrecht, E, Allione, A, Arp, PP, Broer, L, Buxton, JL, Alves, ADSC, Deelen, J, Fedko, IO, Gordon, SD, Jiang, T, Karlsson, R, Kerrison, N, Loe, TK, Mangino, M, Milaneschi, Y, Miraglio, B, Pervjakova, N, Russo, A, Surakka, I, van der Spek, A, Verhoeven, JE, Amin, N, Beekman, M, Blakemore, A, Canzian, F, Hamby, SE, Hottenga, J-J, Jones, PD, Jousilahti, P, Magi, R, Medland, SE, Montgomery, GW, Nyholt, DR, Perola, M, Pietilainen, KH, Salomaa, V, Sillanpaa, E, Suchiman, HE, van Heemst, D, Willemsen, G, Agudo, A, Boeing, H, Boomsma, D, Chirlaque, M-D, Fagherazzi, G, Ferrari, P, Franks, P, Gieger, C, Eriksson, JG, Gunter, M, Hagg, S, Hovatta, I, Imaz, L, Kaprio, J, Kaaks, R, Key, T, Krogh, V, Martin, NG, Melander, O, Metspalu, A, Moreno, C, Onland-Moret, NC, Nilsson, P, Ong, KK, Overvad, K, Palli, D, Panico, S, Pedersen, NL, Penninx, BWJH, Ramon Quiros, J, Riitta Jarvelin, M, Rodriguez-Barranco, M, Scott, RA, Severi, G, Slagboom, PE, Spector, TD, Tjonneland, A, Trichopoulou, A, Tumino, R, Uitterlinden, AG, van der Schouw, YT, van Duijn, CM, Weiderpass, E, Denchi, EL, Matullo, G, Butterworth, AS, Danesh, J, Samani, NJ, Wareham, NJ, Nelson, CP, Langenberg, C, and Codd, V
Abstract: Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Published: 2020

40. Comparison of Genome-Wide Association Scans for Quantitative and Observational Measures of Human Hair Curvature.

Author: Ho, YYW, Mina-Vargas, A, Zhu, G, Brims, M, McNevin, D, Montgomery, GW, Martin, NG, Medland, SE, Painter, JN, Ho, YYW, Mina-Vargas, A, Zhu, G, Brims, M, McNevin, D, Montgomery, GW, Martin, NG, Medland, SE, and Painter, JN
Abstract: Previous genetic studies on hair morphology focused on the overall morphology of the hair using data collected by self-report or researcher observation. Here, we present the first genome-wide association study (GWAS) of a micro-level quantitative measure of hair curvature. We compare these results to GWAS results obtained using a macro-level classification of observable hair curvature performed in the same sample of twins and siblings of European descent. Observational data were collected by trained observers, while quantitative data were acquired using an Optical Fibre Diameter Analyser (OFDA). The GWAS for both the observational and quantitative measures of hair curvature resulted in genome-wide significant signals at chromosome 1q21.3 close to the trichohyalin (TCHH) gene, previously shown to harbor variants associated with straight hair morphology in Europeans. All genetic variants reaching genome-wide significance for both GWAS (quantitative measure lead single-nucleotide polymorphism [SNP] rs12130862, p = 9.5 × 10-09; observational measure lead SNP rs11803731, p = 2.1 × 10-17) were in moderate to very high linkage disequilibrium (LD) with each other (minimum r2 = .45), indicating they represent the same genetic locus. Conditional analyses confirmed the presence of only one signal associated with each measure at this locus. Results from the quantitative measures reconfirmed the accuracy of observational measures.
Published: 2020

41. Replication of the association of common rs9939609 variant of FTO with increased BMI in an Australian adult twin population but no evidence for gene by environment (G × E) interaction

Author: Cornes, BK, Lind, PA, Medland, SE, Montgomery, GW, Nyholt, DR, and Martin, NG
Published: 2009

42. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Author: Liu, M, Jiang, Y, Wedow, R, Li, Y, Brazel, DM, Chen, F, Datta, G, Davila-Velderrain, J, McGuire, D, Tian, C, Zhan, X, Team, 23Andme Research, Psychiatry, Hunt All-In, Choquet, H, Docherty, AR, Faul, JD, Foerster, JR, Fritsche, LG, Gabrielsen, ME, Gordon, SD, Haessler, J, Hottenga, J-J, Huang, H, Jang, S-K, Jansen, PR, Ling, Y, Mägi, R, Matoba, N, McMahon, G, Mulas, A, Orrù, V, Palviainen, T, Pandit, A, Reginsson, GW, Skogholt, AH, Smith, JA, Taylor, AE, Turman, C, Willemsen, G, Young, H, Young, KA, Zajac, GJM, Zhao, W, Zhou, W, Bjornsdottir, G, Boardman, JD, Boehnke, M, Boomsma, DI, Chen, C, Cucca, F, Davies, GE, Eaton, CB, Ehringer, MA, Esko, T, Fiorillo, E, Gillespie, NA, Gudbjartsson, DF, Haller, T, Harris, KM, Heath, AC, Hewitt, JK, Hickie, IB, Hokanson, JE, Hopfer, CJ, Hunter, DJ, Iacono, WG, Johnson, EO, Kamatani, Y, Kardia, SLR, Keller, MC, Kellis, M, Kooperberg, C, Kraft, P, Krauter, KS, Laakso, M, Lind, PA, Loukola, A, Lutz, SM, Madden, PAF, Martin, NG, McGue, M, McQueen, MB, Medland, SE, Metspalu, A, Mohlke, KL, Nielsen, JB, Okada, Y, Peters, U, Polderman, TJC, Posthuma, D, Reiner, AP, Rice, JP, Rimm, E, Rose, RJ, Runarsdottir, V, Stallings, MC, Stančáková, A, Stefansson, H, Thai, KK, Tindle, HA, Tyrfingsson, T, Wall, TL, Weir, DR, Weisner, C, Whitfield, JB, Winsvold, BS, Yin, J, Zuccolo, L, Bierut, LJ, Hveem, K, Lee, JJ, Munafò, MR, Saccone, NL, Willer, CJ, Cornelis, MC, David, SP, Hinds, DA, Jorgenson, E, Kaprio, J, Stitzel, JA, Stefansson, K, Thorgeirsson, TE, Abecasis, G, Liu, DJ, Vrieze, S, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Methodology, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Aging & Later Life, and Human Genetics
Subjects: Male, Netherlands Twin Register (NTR), Smoking/genetics, ved/biology.organism_classification_rank.species, Alcohol, Genome-wide association study, Brain and Behaviour, chemistry.chemical_compound, 0302 clinical medicine, Tobacco Use Disorder/genetics, Tobacco/adverse effects, Genetics, 0303 health sciences, Smoking, Tobacco and Alcohol, public health, Tobacco Use Disorder, Middle Aged, 3. Good health, Phenotype, psychiatric disorders, Genetic Variation/genetics, Meta-analysis, Genome-Wide Association Study/methods, Female, Physical and Mental Health, Risk, Alcohol Drinking, psychology, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Tobacco, Humans, Model organism, Gene, 030304 developmental biology, Genetic association, ved/biology, Genetic Variation, Alcohol Drinking/genetics, Heritability, chemistry, genome-wide association studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6,7,8,9,10,11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures. © 2019. This is the authors’ accepted and refereed manuscript to the article.
Published: 2019

43. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Author: Watson HJ, Yilmaz Z, Thornton LM, Hübel C, Coleman JRI, Gaspar HA, Bryois J, Hinney A, Leppä VM, Mattheisen M, Medland SE, Ripke S, Yao S, Giusti-Rodríguez P, Anorexia Nervosa Genetics Initiative, Hanscombe KB, Purves KL, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Baker JH, Berrettini WH, Boehm I, Boni C, Perica VB, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramís G, Esko T, Estivill X, Farmer A, Favaro A, Fernández-Aranda F, Fichter MM, Fischer K, Föcker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Mayora MG, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jiménez-Murcia S, Julià A, Kalsi G, Kaminská D, Kaprio J, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klareskog L, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Munn-Chernoff MA, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Raquel Rabionet Janssen, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op 't Landt MCT, Slopien A, Sorbi S, Swiatkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell JE, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Stuber GD, Gordon S, Grove J, Henders AK, Juréus A, Kirk KM, Larsen JT, Parker R, Petersen L, Jordan J, Kennedy M, Montgomery GW, Wade TD, Birgegård A, Lichtenstein P, Norring C, Landén M, Martin NG, Mortensen PB, Sullivan PF, Breen G, and Bulik CM
Subjects: mental disorders
Abstract: Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness 1 , affecting 0.9-4% of women and 0.3% of men 2-4 , with twin-based heritability estimates of 50-60% 5 . Mortality rates are higher than those in other psychiatric disorders 6 , and outcomes are unacceptably poor 7 . Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) 8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
Published: 2019

44. A Neuroethics Framework for the Australian Brain Initiative

Author: Kennett, J, Carter, A, Bourne, JA, Hall, W, Levy, N, Mattingley, JB, Lawrence, AJ, Forlini, C, Malcolm, L, Vincent, N, Richards, LJ, Egan, GF, Breakspear, M, Cornish, K, Halliday, G, Poole-Warren, L, Sriram, S, Soulis, T, Fitzgibbon, B, Kiral-Kornek, I, Badcock, DR, Balleine, B, Bekkers, JM, Berk, M, Bradley, A, Brichta, A, Carter, O, Castles, A, Clements, J, Cornish, J, de Zubicaray, G, Enticott, PG, Fornito, A, Griffiths, L, Gullifer, J, Hannan, AJ, Harrer, S, Harvey, A, Hickie, IB, Jazwinska, L, Kiernan, M, Kilpatrick, T, Leventer, R, Licinio, J, Lovell, N, Mackellar, G, Medland, SE, Michie, PT, Nithianantharajah, J, Parker, J, Payne, JM, Rossell, S, Sah, P, Sarnyai, Z, Schofield, PR, Shum, DHK, Silk, T, Slee, M, Stuart, GJ, Tapson, J, van Schaik, A, Vissel, B, Waters, A, Apthorp, D, Cohen-Woods, S, Conn, SJ, Korgaonkar, M, Mason, A, Azghadi, MR, Shimoni, O, Smith, A, Thompson, MB, Kennett, J, Carter, A, Bourne, JA, Hall, W, Levy, N, Mattingley, JB, Lawrence, AJ, Forlini, C, Malcolm, L, Vincent, N, Richards, LJ, Egan, GF, Breakspear, M, Cornish, K, Halliday, G, Poole-Warren, L, Sriram, S, Soulis, T, Fitzgibbon, B, Kiral-Kornek, I, Badcock, DR, Balleine, B, Bekkers, JM, Berk, M, Bradley, A, Brichta, A, Carter, O, Castles, A, Clements, J, Cornish, J, de Zubicaray, G, Enticott, PG, Fornito, A, Griffiths, L, Gullifer, J, Hannan, AJ, Harrer, S, Harvey, A, Hickie, IB, Jazwinska, L, Kiernan, M, Kilpatrick, T, Leventer, R, Licinio, J, Lovell, N, Mackellar, G, Medland, SE, Michie, PT, Nithianantharajah, J, Parker, J, Payne, JM, Rossell, S, Sah, P, Sarnyai, Z, Schofield, PR, Shum, DHK, Silk, T, Slee, M, Stuart, GJ, Tapson, J, van Schaik, A, Vissel, B, Waters, A, Apthorp, D, Cohen-Woods, S, Conn, SJ, Korgaonkar, M, Mason, A, Azghadi, MR, Shimoni, O, Smith, A, and Thompson, MB
Abstract: Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.
Published: 2019

45. The CODATwins Project: The Current Status and Recent Findings of COllaborative Project of Development of Anthropometrical Measures in Twins

Author: Silventoinen, K, Jelenkovic, A, Yokoyama, Y, Sund, R, Sugawara, M, Tanaka, M, Matsumoto, S, Bogl, LH, Freitas, DL, Maia, JA, Hjelmborg, JVB, Aaltonen, S, Piirtola, M, Latvala, A, Calais-Ferreira, L, Oliveira, VC, Ferreira, PH, Ji, F, Ning, F, Pang, Z, Ordonana, JR, Sanchez-Romera, JF, Colodro-Conde, L, Burt, SA, Klump, KL, Martin, NG, Medland, SE, Montgomery, GW, Kandler, C, McAdams, TA, Eley, TC, Gregory, AM, Saudino, KJ, Dubois, L, Boivin, M, Brendgen, M, Dionne, G, Vitaro, F, Tarnoki, AD, Tarnoki, DL, Haworth, CMA, Plomin, R, Oncel, SY, Aliev, F, Medda, E, Nistico, L, Toccaceli, V, Craig, JM, Saffery, R, Siribaddana, SH, Hotopf, M, Sumathipala, A, Rijsdijk, F, Jeong, H-U, Spector, T, Mangino, M, Lachance, G, Gatz, M, Butler, DA, Gao, W, Yu, C, Li, L, Bayasgalan, G, Narandalai, D, Harden, KP, Tucker-Drob, EM, Christensen, K, Skytthe, A, Kyvik, KO, Derom, CA, Vlietinck, RF, Loos, RJF, Cozen, W, Hwang, AE, Mack, TM, He, M, Ding, X, Silberg, JL, Maes, HH, Cutler, TL, Hopper, JL, Magnusson, PKE, Pedersen, NL, Dahl Aslan, AK, Baker, LA, Tuvblad, C, Bjerregaard-Andersen, M, Beck-Nielsen, H, Sodemann, M, Ullemar, V, Almqvist, C, Tan, Q, Zhang, D, Swan, GE, Krasnow, R, Jang, KL, Knafo-Noam, A, Mankuta, D, Abramson, L, Lichtenstein, P, Krueger, RF, McGue, M, Pahlen, S, Tynelius, P, Rasmussen, F, Duncan, GE, Buchwald, D, Corley, RP, Huibregtse, BM, Nelson, TL, Whitfield, KE, Franz, CE, Kremen, WS, Lyons, MJ, Ooki, S, Brandt, I, Nilsen, TS, Harris, JR, Sung, J, Park, HA, Lee, J, Lee, SJ, Willemsen, G, Bartels, M, Van Beijsterveldt, CEM, Llewellyn, CH, Fisher, A, Rebato, E, Busjahn, A, Tomizawa, R, Inui, F, Watanabe, M, Honda, C, Sakai, N, Hur, Y-M, Sorensen, TIA, Boomsma, DI, Kaprio, J, Silventoinen, K, Jelenkovic, A, Yokoyama, Y, Sund, R, Sugawara, M, Tanaka, M, Matsumoto, S, Bogl, LH, Freitas, DL, Maia, JA, Hjelmborg, JVB, Aaltonen, S, Piirtola, M, Latvala, A, Calais-Ferreira, L, Oliveira, VC, Ferreira, PH, Ji, F, Ning, F, Pang, Z, Ordonana, JR, Sanchez-Romera, JF, Colodro-Conde, L, Burt, SA, Klump, KL, Martin, NG, Medland, SE, Montgomery, GW, Kandler, C, McAdams, TA, Eley, TC, Gregory, AM, Saudino, KJ, Dubois, L, Boivin, M, Brendgen, M, Dionne, G, Vitaro, F, Tarnoki, AD, Tarnoki, DL, Haworth, CMA, Plomin, R, Oncel, SY, Aliev, F, Medda, E, Nistico, L, Toccaceli, V, Craig, JM, Saffery, R, Siribaddana, SH, Hotopf, M, Sumathipala, A, Rijsdijk, F, Jeong, H-U, Spector, T, Mangino, M, Lachance, G, Gatz, M, Butler, DA, Gao, W, Yu, C, Li, L, Bayasgalan, G, Narandalai, D, Harden, KP, Tucker-Drob, EM, Christensen, K, Skytthe, A, Kyvik, KO, Derom, CA, Vlietinck, RF, Loos, RJF, Cozen, W, Hwang, AE, Mack, TM, He, M, Ding, X, Silberg, JL, Maes, HH, Cutler, TL, Hopper, JL, Magnusson, PKE, Pedersen, NL, Dahl Aslan, AK, Baker, LA, Tuvblad, C, Bjerregaard-Andersen, M, Beck-Nielsen, H, Sodemann, M, Ullemar, V, Almqvist, C, Tan, Q, Zhang, D, Swan, GE, Krasnow, R, Jang, KL, Knafo-Noam, A, Mankuta, D, Abramson, L, Lichtenstein, P, Krueger, RF, McGue, M, Pahlen, S, Tynelius, P, Rasmussen, F, Duncan, GE, Buchwald, D, Corley, RP, Huibregtse, BM, Nelson, TL, Whitfield, KE, Franz, CE, Kremen, WS, Lyons, MJ, Ooki, S, Brandt, I, Nilsen, TS, Harris, JR, Sung, J, Park, HA, Lee, J, Lee, SJ, Willemsen, G, Bartels, M, Van Beijsterveldt, CEM, Llewellyn, CH, Fisher, A, Rebato, E, Busjahn, A, Tomizawa, R, Inui, F, Watanabe, M, Honda, C, Sakai, N, Hur, Y-M, Sorensen, TIA, Boomsma, DI, and Kaprio, J
Abstract: The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Published: 2019

46. 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

47. 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

48. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects

Author: Middeldorp, CM, Mahajan, A, Horikoshi, M, Robertson, NR, Beaumont, RN, Bradfield, JP, Bustamante, M, Cousminer, DL, Day, FR, De Silva, NM, Guxens, M, Mook-Kanamori, DO, St Pourcain, B, Warrington, NM, Adair, LS, Ahlqvist, E, Ahluwalia, TS, Almgren, P, Ang, W, Atalay, M, Auvinen, J, Bartels, M, Beckmann, JS, Bilbao, JR, Bond, T, Borja, JB, Cavadino, A, Charoen, P, Chen, Z, Coin, L, Cooper, C, Curtin, JA, Custovic, A, Das, S, Davies, GE, Dedoussis, GV, Duijts, L, Eastwood, PR, Eliasen, AU, Elliott, P, Eriksson, JG, Estivill, X, Fadista, J, Fedko, IO, Frayling, TM, Gaillard, R, Gauderman, WJ, Geller, F, Gilliland, F, Gilsanz, V, Granell, R, Grarup, N, Groop, L, Hadley, D, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayes, MG, Hebebrand, J, Heinrich, J, Helgeland, O, Henders, AK, Henderson, J, Henriksen, TB, Hirschhorn, JN, Hivert, M-F, Hocher, B, Holloway, JW, Holt, P, Hottenga, J-J, Hypponen, E, Iniguez, C, Johansson, S, Jugessur, A, Kahonen, M, Kalkwarf, HJ, Kaprio, J, Karhunen, V, Kemp, JP, Kerkhof, M, Koppelman, GH, Korner, A, Kotecha, S, Kreiner-Moller, E, Kulohoma, B, Kumar, A, Kutalik, Z, Lahti, J, Lappe, JM, Larsson, H, Lehtimaki, T, Lewin, AM, Li, J, Lichtenstein, P, Lindgren, CM, Lindi, V, Linneberg, A, Liu, X, Liu, J, Lowe, WL, Lundstrom, S, Lyytikainen, L-P, Ma, RCW, Mace, A, Magi, R, Magnus, P, Mamun, AA, Mannikko, M, Martin, NG, Mbarek, H, McCarthy, NS, Medland, SE, Melbye, M, Melen, E, Mohlke, KL, Monnereau, C, Morgen, CS, Morris, AP, Murray, JC, Myhre, R, Najman, JM, Nivard, MG, Nohr, EA, Nolte, IM, Ntalla, I, O'Reilly, P, Oberfield, SE, Oken, E, Oldehinkel, AJ, Pahkala, K, Palviainen, T, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Pershagen, G, Pitkanen, N, Plomin, R, Power, C, Prasad, RB, Prokopenko, I, Pulkkinen, L, Raikkonen, K, Raitakari, OT, Reynolds, RM, Richmond, RC, Rivadeneira, F, Rodriguez, A, Rose, RJ, Salem, R, Santa-Marina, L, Saw, S-M, Schnurr, TM, Scott, JG, Selzam, S, Shepherd, JA, Simpson, A, Skotte, L, Sleiman, PMA, Snieder, H, Sorensen, TIA, Standl, M, Steegers, EAP, Strachan, DP, Straker, L, Strandberg, T, Taylor, M, Teo, Y-Y, Thiering, E, Torrent, M, Tyrrell, J, Uitterlinden, AG, van Beijsterveldt, T, van der Most, PJ, van Duijn, CM, Viikari, J, Vilor-Tejedor, N, Vogelezang, S, Vonk, JM, Vrijkotte, TGM, Vuoksimaa, E, Wang, CA, Watkins, WJ, Wichmann, H-E, Willemsen, G, Williams, GM, Wilson, JF, Wray, NR, Xu, S, Xu, C-J, Yaghootkar, H, Yi, L, Zafarmand, MH, Zeggini, E, Zemel, BS, Hinney, A, Lakka, TA, Whitehouse, AJO, Sunyer, J, Widen, EE, Feenstra, B, Sebert, S, Jacobsson, B, Njolstad, PR, Stoltenberg, C, Smith, GD, Lawlor, DA, Paternoster, L, Timpson, NJ, Ong, KK, Bisgaard, H, Bonnelykke, K, Jaddoe, VWV, Tiemeier, H, Jarvelin, M-R, Evans, DM, Perry, JRB, Grant, SFA, Boomsma, DI, Freathy, RM, McCarthy, MI, Felix, JF, Middeldorp, CM, Mahajan, A, Horikoshi, M, Robertson, NR, Beaumont, RN, Bradfield, JP, Bustamante, M, Cousminer, DL, Day, FR, De Silva, NM, Guxens, M, Mook-Kanamori, DO, St Pourcain, B, Warrington, NM, Adair, LS, Ahlqvist, E, Ahluwalia, TS, Almgren, P, Ang, W, Atalay, M, Auvinen, J, Bartels, M, Beckmann, JS, Bilbao, JR, Bond, T, Borja, JB, Cavadino, A, Charoen, P, Chen, Z, Coin, L, Cooper, C, Curtin, JA, Custovic, A, Das, S, Davies, GE, Dedoussis, GV, Duijts, L, Eastwood, PR, Eliasen, AU, Elliott, P, Eriksson, JG, Estivill, X, Fadista, J, Fedko, IO, Frayling, TM, Gaillard, R, Gauderman, WJ, Geller, F, Gilliland, F, Gilsanz, V, Granell, R, Grarup, N, Groop, L, Hadley, D, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayes, MG, Hebebrand, J, Heinrich, J, Helgeland, O, Henders, AK, Henderson, J, Henriksen, TB, Hirschhorn, JN, Hivert, M-F, Hocher, B, Holloway, JW, Holt, P, Hottenga, J-J, Hypponen, E, Iniguez, C, Johansson, S, Jugessur, A, Kahonen, M, Kalkwarf, HJ, Kaprio, J, Karhunen, V, Kemp, JP, Kerkhof, M, Koppelman, GH, Korner, A, Kotecha, S, Kreiner-Moller, E, Kulohoma, B, Kumar, A, Kutalik, Z, Lahti, J, Lappe, JM, Larsson, H, Lehtimaki, T, Lewin, AM, Li, J, Lichtenstein, P, Lindgren, CM, Lindi, V, Linneberg, A, Liu, X, Liu, J, Lowe, WL, Lundstrom, S, Lyytikainen, L-P, Ma, RCW, Mace, A, Magi, R, Magnus, P, Mamun, AA, Mannikko, M, Martin, NG, Mbarek, H, McCarthy, NS, Medland, SE, Melbye, M, Melen, E, Mohlke, KL, Monnereau, C, Morgen, CS, Morris, AP, Murray, JC, Myhre, R, Najman, JM, Nivard, MG, Nohr, EA, Nolte, IM, Ntalla, I, O'Reilly, P, Oberfield, SE, Oken, E, Oldehinkel, AJ, Pahkala, K, Palviainen, T, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Pershagen, G, Pitkanen, N, Plomin, R, Power, C, Prasad, RB, Prokopenko, I, Pulkkinen, L, Raikkonen, K, Raitakari, OT, Reynolds, RM, Richmond, RC, Rivadeneira, F, Rodriguez, A, Rose, RJ, Salem, R, Santa-Marina, L, Saw, S-M, Schnurr, TM, Scott, JG, Selzam, S, Shepherd, JA, Simpson, A, Skotte, L, Sleiman, PMA, Snieder, H, Sorensen, TIA, Standl, M, Steegers, EAP, Strachan, DP, Straker, L, Strandberg, T, Taylor, M, Teo, Y-Y, Thiering, E, Torrent, M, Tyrrell, J, Uitterlinden, AG, van Beijsterveldt, T, van der Most, PJ, van Duijn, CM, Viikari, J, Vilor-Tejedor, N, Vogelezang, S, Vonk, JM, Vrijkotte, TGM, Vuoksimaa, E, Wang, CA, Watkins, WJ, Wichmann, H-E, Willemsen, G, Williams, GM, Wilson, JF, Wray, NR, Xu, S, Xu, C-J, Yaghootkar, H, Yi, L, Zafarmand, MH, Zeggini, E, Zemel, BS, Hinney, A, Lakka, TA, Whitehouse, AJO, Sunyer, J, Widen, EE, Feenstra, B, Sebert, S, Jacobsson, B, Njolstad, PR, Stoltenberg, C, Smith, GD, Lawlor, DA, Paternoster, L, Timpson, NJ, Ong, KK, Bisgaard, H, Bonnelykke, K, Jaddoe, VWV, Tiemeier, H, Jarvelin, M-R, Evans, DM, Perry, JRB, Grant, SFA, Boomsma, DI, Freathy, RM, McCarthy, MI, and Felix, JF
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019

49. A network analysis approach to ADHD symptoms: More than the sum of its parts

Author: Medland, SE, Silk, TJ, Malpas, CB, Beare, R, Efron, D, Anderson, V, Hazell, P, Jongeling, B, Nicholson, JM, Sciberras, E, Medland, SE, Silk, TJ, Malpas, CB, Beare, R, Efron, D, Anderson, V, Hazell, P, Jongeling, B, Nicholson, JM, and Sciberras, E
Abstract: In interpreting attention-deficit/hyperactivity disorder (ADHD) symptoms, categorical and dimensional approaches are commonly used. Both employ binary symptom counts which give equal weighting, with little attention to the combinations and relative contributions of individual symptoms. Alternatively, symptoms can be viewed as an interacting network, revealing the complex relationship between symptoms. Using a novel network modelling approach, this study explores the relationships between the 18 symptoms in the Diagnostic Statistical Manual (DSM-5) criteria and whether network measures are useful in predicting outcomes. Participants were from a community cohort, the Children's Attention Project. DSM ADHD symptoms were recorded in a face-to-face structured parent interview for 146 medication naïve children with ADHD and 209 controls (aged 6-8 years). Analyses indicated that not all symptoms are equal. Frequencies of endorsement and configurations of symptoms varied, with certain symptoms playing a more important role within the ADHD symptom network. In total, 116,220 combinations of symptoms within a diagnosis of ADHD were identified, with 92% demonstrating a unique symptom configuration. Symptom association networks highlighted the relative importance of hyperactive/impulsive symptoms in the symptom network. In particular, the 'motoric'-type symptoms as well as interrupts as a marker of impulsivity in the hyperactive domain, as well as loses things and does not follow instructions in the inattentive domain, had high measures of centrality. Centrality-measure weighted symptom counts showed significant association with clinical but not cognitive outcomes, however the relationships were not significantly stronger than symptom count alone. The finding may help to explain heterogeneity in the ADHD phenotype.
Published: 2019

50. 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

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