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    Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
    Blokland, GAM ; Grove, J ; Chen, C-Y ; Cotsapas, C ; Tobet, S ; Handa, R ; St Clair, D ; Lencz, T ; Mowry, BJ ; Periyasamy, S ; Cairns, MJ ; Tooney, PA ; Wu, JQ ; Kelly, B ; Kirov, G ; Sullivan, PF ; Corvin, A ; Riley, BP ; Esko, T ; Milani, L ; Jonsson, EG ; Palotie, A ; Ehrenreich, H ; Begemann, M ; Steixner-Kumar, A ; Sham, PC ; Iwata, N ; Weinberger, DR ; Gejman, P ; Sanders, AR ; Buxbaum, JD ; Rujescu, D ; Giegling, I ; Konte, B ; Hartmann, AM ; Bramon, E ; Murray, RM ; Pato, MT ; Lee, J ; Melle, I ; Molden, E ; Ophoff, RA ; McQuillin, A ; Bass, NJ ; Adolfsson, R ; Malhotra, AK ; Martin, NG ; Fullerton, JM ; Mitchell, PB ; Schofield, PR ; Forstner, AJ ; Degenhardt, F ; Schaupp, S ; Comes, AL ; Kogevinas, M ; Guzman-Parra, J ; Reif, A ; Streit, F ; Sirignano, L ; Cichon, S ; Grigoroiu-Serbanescu, M ; Hauser, J ; Lissowska, J ; Mayoral, F ; Muller-Myhsok, B ; Schulze, TG ; Nothen, MM ; Rietschel, M ; Kelsoe, J ; Leboyer, M ; Jamain, S ; Etain, B ; Bellivier, F ; Vincent, JB ; Alda, M ; O'Donovan, C ; Cervantes, P ; Biernacka, JM ; Frye, M ; McElroy, SL ; Scott, LJ ; Stahl, EA ; Landen, M ; Hamshere, ML ; Smeland, OB ; Djurovic, S ; Vaaler, AE ; Andreassen, OA ; Baune, BT ; Air, T ; Preisig, M ; Uher, R ; Levinson, DF ; Weissman, MM ; Potash, JB ; Shi, J ; Knowles, JA ; Perlis, RH ; Lucae, S ; Boomsma, D ; Penninx, BWJH ; Hottenga, J-J ; de Geus, EJC ; Willemsen, G ; Milaneschi, Y ; Tiemeier, H ; Grabe, HJ ; Teumer, A ; Van der Auwera, S ; Volker, U ; Hamilton, SP ; Magnusson, PKE ; Viktorin, A ; Mehta, D ; Mullins, N ; Adams, MJ ; Breen, G ; McIntosh, AM ; Lewis, CM ; Hougaard, DM ; Nordentoft, M ; Mors, O ; Mortensen, PB ; Werge, T ; Als, TD ; Borglum, AD ; Petryshen, TL ; Smoller, JW ; Goldstein, JM (ELSEVIER SCIENCE INC, 2021-11-29)
    BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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    BILATERAL ELECTROCONVULSIVE THERAPY FOR POST-TRAUMATIC STRESS DISORDER COMORBID TO DEPRESSION
    Kavakbasi, E ; Ciftci, GM ; Baune, BT (Galenos Yayinevi, 2021-11-01)
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    Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk
    Miles, AE ; Dos Santos, FC ; Byrne, EM ; Renteria, ME ; McIntosh, AM ; Adams, MJ ; Pistis, G ; Castelao, E ; Preisig, M ; Baune, BT ; Schubert, KO ; Lewis, CM ; Jones, LA ; Jones, I ; Uher, R ; Smoller, JW ; Perlis, RH ; Levinson, DF ; Potash, JB ; Weissman, MM ; Shi, J ; Lewis, G ; Penninx, BWJH ; Boomsma, D ; Hamilton, SP ; Sibille, E ; Hariri, AR ; Nikolova, YS (SPRINGERNATURE, 2021-12)
    Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.
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    Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
    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 (NATURE PORTFOLIO, 2021-06)
    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.
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    Brain Correlates of Suicide Attempt in 18,925 Participants Across 18 International Cohorts
    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 (ELSEVIER SCIENCE INC, 2021-08-15)
    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.
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    The association between genetically determined ABO blood types and major depressive disorder
    Garvert, L ; Baune, BT ; Berger, K ; Boomsma, D ; Breen, G ; Greinacher, A ; Hamilton, SP ; Levinson, DF ; Lewis, CM ; Lucae, S ; Magnusson, PKE ; Martin, NG ; McIntosh, AM ; Mors, O ; Mueller-Myhsok, B ; Penninx, BWJH ; Perlis, RH ; Pistis, G ; Potash, JB ; Preisig, M ; Rietschel, M ; Shi, J ; Smoller, JW ; Tiemeier, H ; Uher, R ; Voelker, U ; Voelzke, H ; Weissman, MM ; Grabe, HJ ; Van der Auwera, S (ELSEVIER IRELAND LTD, 2021-05)
    ABO blood types and their corresponding antigens have long been assumed to be related to different human diseases. So far, smaller studies on the relationship between mental disorders and blood types yielded contradicting results. In this study we analyzed the association between ABO blood types and lifetime major depressive disorder (MDD). We performed a pooled analysis with data from 26 cohorts that are part of the MDD working group of the Psychiatric Genomics Consortium (PGC). The dataset included 37,208 individuals of largely European ancestry of which 41.6% were diagnosed with lifetime MDD. ABO blood types were identified using three single nucleotide polymorphisms in the ABO gene: rs505922, rs8176746 and rs8176747. Regression analyses were performed to assess associations between the individual ABO blood types and MDD diagnosis as well as putative interaction effects with sex. The models were adjusted for sex, cohort and the first ten genetic principal components. The percentage of blood type A was slightly lower in cases than controls while blood type O was more prominent in cases. However, these differences were not statistically significant. Our analyses found no evidence of an association between ABO blood types and major depressive disorder.
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    Global, regional, and national mortality among young people aged 10-24 years, 1950-2019: a systematic analysis for the Global Burden of Disease Study 2019
    Ward, JL ; Azzopardi, PS ; Francis, KL ; Santelli, JS ; Skirbekk, V ; Sawyer, SM ; Kassebaum, NJ ; Mokdad, AH ; Hay, SI ; Abd-Allah, F ; Abdoli, A ; Abdollahi, M ; Abedi, A ; Abolhassani, H ; Abreu, LG ; Abrigo, MRM ; Abu-Gharbieh, E ; Abushouk, AI ; Adebayo, OM ; Adekanmbi, V ; Adham, D ; Advani, SM ; Afshari, K ; Agrawal, A ; Ahmad, T ; Ahmadi, K ; Ahmed, AE ; Aji, B ; Akombi-Inyang, B ; Alahdab, F ; Al-Aly, Z ; Alam, K ; Alanezi, FM ; Alanzi, TM ; Alcalde-Rabanal, JE ; Alemu, BW ; Al-Hajj, S ; Alhassan, RK ; Ali, S ; Alicandro, G ; Alijanzadeh, M ; Aljunid, SM ; Almasi-Hashiani, A ; Almasri, NA ; Al-Mekhlafi, HM ; Alonso, J ; Al-Raddadi, RM ; Altirkawi, KA ; Alvis-Guzman, N ; Amare, AT ; Amini, S ; Aminorroaya, A ; Amit, AML ; Amugsi, DA ; Ancuceanu, R ; Anderlini, D ; Andrei, CL ; Androudi, S ; Ansari, F ; Ansari, I ; Antonio, CAT ; Anvari, D ; Anwer, R ; Appiah, SCY ; Arabloo, J ; Arab-Zozani, M ; Arnlov, J ; Asaad, M ; Asadi-Aliabadi, M ; Asadi-Pooya, AA ; Atout, MMW ; Ausloos, M ; Avenyo, EK ; Avila-Burgos, L ; Quintanilla, BPA ; Ayano, G ; Aynalem, YA ; Azari, S ; Azene, ZN ; Bakhshaei, MH ; Bakkannavar, SM ; Banach, M ; Banik, PC ; Barboza, MA ; Barker-Collo, SL ; Baernighausen, TW ; Basu, S ; Baune, BT ; Bayati, M ; Bedi, N ; Beghi, E ; Bekuma, TT ; Bell, AW ; Bell, ML ; Benjet, C ; Bensenor, IM ; Berhe, AK ; Berhe, K ; Berman, AE ; Bhagavathula, AS ; Bhardwaj, N ; Bhardwaj, P ; Bhattacharyya, K ; Bhattarai, S ; Bhutta, ZA ; Bijani, A ; Bikbov, B ; Biondi, A ; Birhanu, TTM ; Biswas, RK ; Bohlouli, S ; Bolla, SR ; Boloor, A ; Borschmann, R ; Boufous, S ; Bragazzi, NL ; Braithwaite, D ; Breitborde, NJK ; Brenner, H ; Britton, GB ; Burns, RA ; Nagaraja, SB ; Butt, ZA ; dos Santos, FLC ; Camera, LA ; Campos-Nonato, IR ; Campuzano Rincon, JC ; Cardenas, R ; Carreras, G ; Carrero, JJ ; Carvalho, F ; Castaldelli-Maia, JM ; Castaneda-Orjuela, CA ; Castelpietra, G ; Catala-Lopez, F ; Cerin, E ; Chandan, JS ; Chang, H-Y ; Chang, J-C ; Charan, J ; Chattu, VK ; Chaturvedi, S ; Choi, J-YJ ; Chowdhury, MAK ; Christopher, DJ ; Dinh-Toi, C ; Chung, MT ; Chung, S-C ; Cicuttini, FM ; Constantin, TV ; Costa, VM ; Dahlawi, SMA ; Dai, H ; Dai, X ; Damiani, G ; Dandona, L ; Dandona, R ; Daneshpajouhnejad, P ; Darwesh, AM ; Alberto Davila-Cervantes, C ; Davletov, K ; De la Hoz, FP ; De Leo, D ; Dervenis, N ; Desai, R ; Desalew, A ; Deuba, K ; Dharmaratne, SD ; Dhungana, GP ; Dianatinasab, M ; da Silva, DD ; Diaz, D ; Didarloo, A ; Djalalinia, S ; Dorostkar, F ; Doshi, CP ; Doshmangir, L ; Doyle, KE ; Duraes, AR ; Kalan, ME ; Ebtehaj, S ; Edvardsson, D ; El Tantawi, M ; Elgendy, IY ; El-Jaafary, SI ; Elsharkawy, A ; Eshrati, B ; Eskandarieh, S ; Esmaeilnejad, S ; Esmaeilzadeh, F ; Esteghamati, S ; Faro, A ; Farzadfar, F ; Fattahi, N ; Feigin, VL ; Ferede, TY ; Fereshtehnejad, S-M ; Fernandes, E ; Ferrara, P ; Filip, I ; Fischer, F ; Fisher, JL ; Foigt, NA ; Folayan, MO ; Fomenkov, AA ; Foroutan, M ; Fukumoto, T ; Gad, MM ; Gaidhane, AM ; Gallus, S ; Gebre, T ; Gebremedhin, KB ; Gebremeskel, GG ; Gebremeskel, L ; Gebreslassie, AA ; Gesesew, HA ; Ghadiri, K ; Ghafourifard, M ; Ghamari, F ; Ghashghaee, A ; Gilani, SA ; Gnedovskaya, EV ; Godinho, MA ; Golechha, M ; Goli, S ; Gona, PN ; Gopalani, SV ; Gorini, G ; Grivna, M ; Gubari, MIM ; Gugnani, HC ; Guimaraes, RA ; Guo, Y ; Gupta, R ; Haagsma, JA ; Hafezi-Nejad, N ; Haile, TG ; Haj-Mirzaian, A ; Haj-Mirzaian, A ; Hall, BJ ; Hamadeh, RR ; Abdullah, KH ; Hamidi, S ; Handiso, DW ; Hanif, A ; Hankey, GJ ; Haririan, H ; Maria Haro, J ; Hasaballah, AI ; Hashi, A ; Hassan, A ; Hassanipour, S ; Hassankhani, H ; Hayat, K ; Heidari-Soureshjani, R ; Herteliu, C ; Heydarpour, F ; Ho, HC ; Hole, MK ; Holla, R ; Hoogar, P ; Hosseini, M ; Hosseinzadeh, M ; Hostiuc, M ; Hostiuc, S ; Househ, M ; Hsairi, M ; Huda, TM ; Humayun, A ; Hussain, R ; Hwang, B-F ; Iavicoli, I ; Ibitoye, SE ; Ilesanmi, OS ; Ilic, IM ; Ilic, MD ; Inbaraj, LR ; Intarut, N ; Iqbal, U ; Irvani, SSN ; Islam, MM ; Islam, SMS ; Iso, H ; Ivers, RQ ; Jahani, MA ; Jakovljevic, M ; Jalali, A ; Janodia, MD ; Javaheri, T ; Jeemon, P ; Jenabi, E ; Jha, RP ; Jha, V ; Ji, JS ; Jonas, JB ; Jones, KM ; Joukar, F ; Jozwiak, JJ ; Juliusson, PB ; Jurisson, M ; Kabir, A ; Kabir, Z ; Kalankesh, LR ; Kalhor, R ; Kamyari, N ; Kanchan, T ; Karch, A ; Karimi, SE ; Kaur, S ; Kayode, GA ; Keiyoro, PN ; Khalid, N ; Khammarnia, M ; Khan, M ; Khan, MN ; Khatab, K ; Khater, MM ; Khatib, MN ; Khayamzadeh, M ; Khazaie, H ; Khoja, AT ; Kieling, C ; Kim, Y-E ; Kim, YJ ; Kimokoti, RW ; Kisa, A ; Kisa, S ; Kivimaki, M ; Koolivand, A ; Kosen, S ; Koyanagi, A ; Krishan, K ; Kugbey, N ; Kumar, GA ; Kumar, M ; Kumar, N ; Kurmi, OP ; Kusuma, D ; La Vecchia, C ; Lacey, B ; Lal, DK ; Lalloo, R ; Lan, Q ; Landires, I ; Lansingh, VC ; Larsson, AO ; Lasrado, S ; Lassi, ZS ; Lauriola, P ; Lee, PH ; Lee, SWH ; Leigh, J ; Leonardi, M ; Leung, J ; Levi, M ; Lewycka, S ; Li, B ; Li, M-C ; Li, S ; Lim, L-L ; Lim, SS ; Liu, X ; Lorkowski, S ; Lotufo, PA ; Lunevicius, R ; Maddison, R ; Mahasha, PW ; Mahdavi, MM ; Mahmoudi, M ; Majeed, A ; Maleki, A ; Malekzadeh, R ; Malta, DC ; Mamun, AA ; Mansouri, B ; Mansournia, MA ; Martinez, G ; Martinez-Raga, J ; Martins-Melo, FR ; Mason-Jones, AJ ; Masoumi, SZ ; Mathur, MR ; Maulik, PK ; McGrath, JJ ; Mehndiratta, MM ; Mehri, F ; Memiah, PTN ; Mendoza, W ; Menezes, RG ; Mengesha, EW ; Meretoja, A ; Meretoja, TJ ; Mestrovic, T ; Miazgowski, B ; Miazgowski, T ; Michalek, IM ; Miller, TR ; Mini, GK ; Mirica, A ; Mirrakhimov, EM ; Mirzaei, H ; Mirzaei, M ; Moazen, B ; Mohammad, DK ; Mohammadi, S ; Mohammadian-Hafshejani, A ; Mohammadifard, N ; Mohammadpourhodki, R ; Mohammed, S ; Monasta, L ; Moradi, G ; Moradi-Lakeh, M ; Moradzadeh, R ; Moraga, P ; Morrison, SD ; Mosapour, A ; Khaneghah, AM ; Mueller, UO ; Muriithi, MK ; Murray, CJL ; Muthupandian, S ; Naderi, M ; Nagarajan, AJ ; Naghavi, M ; Naimzada, MD ; Nangia, V ; Nayak, VC ; Nazari, J ; Ndejjo, R ; Negoi, I ; Negoi, RI ; Netsere, HB ; Nguefack-Tsague, G ; Diep, NN ; Huong, LTN ; Nie, J ; Ningrum, DNA ; Nnaji, CA ; Nomura, S ; Noubiap, JJ ; Nowak, C ; Nunez-Samudio, V ; Ogbo, FA ; Oghenetega, OB ; Oh, I-H ; Oladnabi, M ; Olagunju, AT ; Olusanya, BO ; Olusanya, JO ; Bali, AO ; Omer, MO ; Onwujekwe, OE ; Ortiz, A ; Otoiu, A ; Otstavnov, N ; Otstavnov, SS ; Overland, S ; Owolabi, MO ; Mahesh, PA ; Padubidri, JR ; Pakshir, K ; Palladino, R ; Pana, A ; Panda-Jonas, S ; Pandey, A ; Able Panelo, CI ; Park, E-K ; Patten, SB ; Peden, AE ; Filipino Pepito, VC ; Peprah, EK ; Pereira, J ; Pesudovs, K ; Hai, QP ; Phillips, MR ; Piradov, MA ; Pirsaheb, M ; Postma, MJ ; Pottoo, FH ; Pourjafar, H ; Pourshams, A ; Prada, SI ; Pupillo, E ; Syed, ZQ ; Rabiee, MH ; Rabiee, N ; Radfar, A ; Rafiee, A ; Raggi, A ; Rahim, F ; Rahimi-Movaghar, V ; Rahman, MHU ; Rahman, MA ; Ramezanzadeh, K ; Ranabhat, CL ; Rao, SJ ; Rashedi, V ; Rastogi, P ; Rathi, P ; Rawaf, DL ; Rawaf, S ; Rawal, L ; Rawassizadeh, R ; Renzaho, AMN ; Rezaei, N ; Rezaei, N ; Rezai, MS ; Riahi, SM ; Rickard, J ; Roever, L ; Ronfani, L ; Roth, GA ; Rubagotti, E ; Rumisha, SF ; Rwegerera, GM ; Sabour, S ; Sachdev, PS ; Saddik, B ; Sadeghi, E ; Moghaddam, SS ; Sagar, R ; Sahebkar, A ; Sahraian, MA ; Sajadi, SM ; Salem, MR ; Salimzadeh, H ; Samy, AM ; Sanabria, J ; Santric-Milicevic, MM ; Saraswathy, SYI ; Sarrafzadegan, N ; Sarveazad, A ; Sathish, T ; Sattin, D ; Saxena, D ; Saxena, S ; Schiavolin, S ; Schwebel, DC ; Schwendicke, F ; Senthilkumaran, S ; Sepanlou, SG ; Sha, F ; Shafaat, O ; Shahabi, S ; Shaheen, AA ; Shaikh, MA ; Shakiba, S ; Shamsi, MB ; Shannawaz, M ; Sharafi, K ; Sheikh, A ; Sheikhbahaei, S ; Shetty, BSK ; Shi, P ; Shigematsu, M ; Shin, JI ; Shiri, R ; Shuval, K ; Siabani, S ; Sigfusdottir, ID ; Sigurvinsdottir, R ; Santos Silva, DA ; Silva, JP ; Simonetti, B ; Singh, JA ; Singh, V ; Sinke, AH ; Skryabin, VY ; Slater, H ; Smith, EUR ; Sobhiyeh, MR ; Sobngwi, E ; Soheili, A ; Somefun, OD ; Sorrie, MB ; Soyiri, IN ; Sreeramareddy, CT ; Stein, DJ ; Stokes, MA ; Sudaryanto, A ; Sultan, I ; Tabares-Seisdedos, R ; Tabuchi, T ; Tadakamadla, SK ; Taherkhani, A ; Tamiru, AT ; Tareque, MI ; Thankappan, KR ; Thapar, R ; Thomas, N ; Titova, MV ; Tonelli, M ; Tovani-Palone, MR ; Bach, XT ; Travillian, RS ; Tsai, AC ; Tsatsakis, A ; Car, LT ; Uddin, R ; Unim, B ; Unnikrishnan, B ; Upadhyay, E ; Vacante, M ; Tahbaz, SV ; Valdez, PR ; Varughese, S ; Vasankari, TJ ; Venketasubramanian, N ; Villeneuve, PJ ; Violante, FS ; Vlassov, V ; Vos, T ; Giang, TV ; Waheed, Y ; Wamai, RG ; Wang, Y ; Wang, Y ; Wang, Y-P ; Westerman, R ; Wickramasinghe, ND ; Wu, A-M ; Wu, C ; Jabbari, SHY ; Yamagishi, K ; Yano, Y ; Yaya, S ; Yazdi-Feyzabadi, V ; Yeshitila, YG ; Yip, P ; Yonemoto, N ; Yoon, S-J ; Younis, MZ ; Yousefinezhadi, T ; Yu, C ; Yu, Y ; Yuce, D ; Zaidi, SS ; Bin Zaman, S ; Zamani, M ; Zamanian, M ; Zarafshan, H ; Zarei, A ; Zastrozhin, MS ; Zhang, Y ; Zhang, Z-J ; Zhao, X-JG ; Zhu, C ; Patton, GC ; Viner, RM (ELSEVIER SCIENCE INC, 2021-10-30)
    BACKGROUND: Documentation of patterns and long-term trends in mortality in young people, which reflect huge changes in demographic and social determinants of adolescent health, enables identification of global investment priorities for this age group. We aimed to analyse data on the number of deaths, years of life lost, and mortality rates by sex and age group in people aged 10-24 years in 204 countries and territories from 1950 to 2019 by use of estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. METHODS: We report trends in estimated total numbers of deaths and mortality rate per 100 000 population in young people aged 10-24 years by age group (10-14 years, 15-19 years, and 20-24 years) and sex in 204 countries and territories between 1950 and 2019 for all causes, and between 1980 and 2019 by cause of death. We analyse variation in outcomes by region, age group, and sex, and compare annual rate of change in mortality in young people aged 10-24 years with that in children aged 0-9 years from 1990 to 2019. We then analyse the association between mortality in people aged 10-24 years and socioeconomic development using the GBD Socio-demographic Index (SDI), a composite measure based on average national educational attainment in people older than 15 years, total fertility rate in people younger than 25 years, and income per capita. We assess the association between SDI and all-cause mortality in 2019, and analyse the ratio of observed to expected mortality by SDI using the most recent available data release (2017). FINDINGS: In 2019 there were 1·49 million deaths (95% uncertainty interval 1·39-1·59) worldwide in people aged 10-24 years, of which 61% occurred in males. 32·7% of all adolescent deaths were due to transport injuries, unintentional injuries, or interpersonal violence and conflict; 32·1% were due to communicable, nutritional, or maternal causes; 27·0% were due to non-communicable diseases; and 8·2% were due to self-harm. Since 1950, deaths in this age group decreased by 30·0% in females and 15·3% in males, and sex-based differences in mortality rate have widened in most regions of the world. Geographical variation has also increased, particularly in people aged 10-14 years. Since 1980, communicable and maternal causes of death have decreased sharply as a proportion of total deaths in most GBD super-regions, but remain some of the most common causes in sub-Saharan Africa and south Asia, where more than half of all adolescent deaths occur. Annual percentage decrease in all-cause mortality rate since 1990 in adolescents aged 15-19 years was 1·3% in males and 1·6% in females, almost half that of males aged 1-4 years (2·4%), and around a third less than in females aged 1-4 years (2·5%). The proportion of global deaths in people aged 0-24 years that occurred in people aged 10-24 years more than doubled between 1950 and 2019, from 9·5% to 21·6%. INTERPRETATION: Variation in adolescent mortality between countries and by sex is widening, driven by poor progress in reducing deaths in males and older adolescents. Improving global adolescent mortality will require action to address the specific vulnerabilities of this age group, which are being overlooked. Furthermore, indirect effects of the COVID-19 pandemic are likely to jeopardise efforts to improve health outcomes including mortality in young people aged 10-24 years. There is an urgent need to respond to the changing global burden of adolescent mortality, address inequities where they occur, and improve the availability and quality of primary mortality data in this age group. FUNDING: Bill & Melinda Gates Foundation.
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    Potential Genetic Overlap Between Insomnia and Sleep Symptoms in Major Depressive Disorder: A Polygenic Risk Score Analysis
    Melhuish Beaupre, LM ; Tiwari, AK ; Goncalves, VF ; Zai, CC ; Marshe, VS ; Lewis, CM ; Martin, NG ; McIntosh, AM ; Adams, MJ ; Baune, BT ; Levinson, DF ; Boomsma, DI ; Penninx, BWJH ; Breen, G ; Hamilton, S ; Awasthi, S ; Ripke, S ; Jones, L ; Jones, I ; Byrne, EM ; Hickie, IB ; Potash, JP ; Shi, J ; Weissman, MM ; Milaneschi, Y ; Shyn, SI ; de Geus, EJC ; Willemsen, G ; Brown, GM ; Kennedy, JL (FRONTIERS MEDIA SA, 2021-12-03)
    Background: The prevalence of insomnia and hypersomnia in depressed individuals is substantially higher than that found in the general population. Unfortunately, these concurrent sleep problems can have profound effects on the disease course. Although the full biology of sleep remains to be elucidated, a recent genome-wide association (GWAS) of insomnia, and other sleep traits in over 1 million individuals was recently published and provides many promising hits for genetics of insomnia in a population-based sample. Methods: Using data from the largest available GWAS of insomnia and other sleep traits, we sought to test if sleep variable PRS scores derived from population-based studies predicted sleep variables in samples of depressed cases [Psychiatric Genomics Consortium - Major Depressive Disorder subjects (PGC MDD)]. A leave-one-out analysis was performed to determine the effects that each individual study had on our results. Results: The only significant finding was for insomnia, where p-value threshold, p = 0.05 was associated with insomnia in our PGC MDD sample (R 2 = 1.75-3, p = 0.006). Conclusion: Our results reveal that <1% of variance is explained by the variants that cover the two significant p-value thresholds, which is in line with the fact that depression and insomnia are both polygenic disorders. To the best of our knowledge, this is the first study to investigate genetic overlap between the general population and a depression sample for insomnia, which has important treatment implications, such as leading to novel drug targets in future research efforts.
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    A genome-wide association study of the longitudinal course of executive functions
    Wendel, B ; Papiol, S ; Andlauer, TFM ; Zimmermann, J ; Wiltfang, J ; Spitzer, C ; Senner, F ; Schulte, EC ; Schmauss, M ; Schaupp, SK ; Repple, J ; Reininghaus, E ; Reimer, J ; Reich-Erkelenz, D ; Opel, N ; Meinert, S ; Konrad, C ; Kloehn-Saghatolislam, F ; Kircher, T ; Kalman, JL ; Juckel, G ; Jansen, A ; Jaeger, M ; Heilbronner, M ; von Hagen, M ; Gade, K ; Figge, C ; Fallgatter, AJ ; Dietrich, DE ; Dannlowski, U ; Comes, AL ; Budde, M ; Baune, BT ; Arolt, V ; Anghelescu, I-G ; Anderson-Schmidt, H ; Adorjan, K ; Falkai, P ; Schulze, TG ; Bickeboeller, H ; Heilbronner, U (SPRINGERNATURE, 2021-07-10)
    Executive functions are metacognitive capabilities that control and coordinate mental processes. In the transdiagnostic PsyCourse Study, comprising patients of the affective-to-psychotic spectrum and controls, we investigated the genetic basis of the time course of two core executive subfunctions: set-shifting (Trail Making Test, part B (TMT-B)) and updating (Verbal Digit Span backwards) in 1338 genotyped individuals. Time course was assessed with four measurement points, each 6 months apart. Compared to the initial assessment, executive performance improved across diagnostic groups. We performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with performance change over time by testing for SNP-by-time interactions using linear mixed models. We identified nine genome-wide significant SNPs for TMT-B in strong linkage disequilibrium with each other on chromosome 5. These were associated with decreased performance on the continuous TMT-B score across time. Variant rs150547358 had the lowest P value = 7.2 × 10-10 with effect estimate beta = 1.16 (95% c.i.: 1.11, 1.22). Implementing data of the FOR2107 consortium (1795 individuals), we replicated these findings for the SNP rs150547358 (P value = 0.015), analyzing the difference of the two available measurement points two years apart. In the replication study, rs150547358 exhibited a similar effect estimate beta = 0.85 (95% c.i.: 0.74, 0.97). Our study demonstrates that longitudinally measured phenotypes have the potential to unmask novel associations, adding time as a dimension to the effects of genomics.