Psychiatry - Research Publications

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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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    Genome-wide interaction study with major depression identifies novel variants associated with cognitive function
    Thalamuthu, A ; Mills, NT ; Berger, K ; Minnerup, H ; Grotegerd, D ; Dannlowski, U ; Meinert, S ; Opel, N ; Repple, J ; Gruber, M ; Stein, F ; Brosch, K ; Meller, T ; Pfarr, J-K ; Forstner, AJ ; Hoffmann, P ; Nothen, MM ; Witt, S ; Rietschel, M ; Kircher, T ; Adams, M ; McIntosh, AM ; Porteous, DJ ; Deary, IJ ; Hayward, C ; Campbell, A ; Grabe, HJ ; Teumer, A ; Homuth, G ; Van der Auwera-Palitschka, S ; Schubert, KO ; Baune, BT (SPRINGERNATURE, 2021-11-15)
    Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from four large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA®). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development (REST), oligodendrocyte maturation (TNFRSF21), and myelination (ARFGEF1). IPA® identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions (MPO, FOXO1, PDE3A, TSLP, NLRP9, ADAMTS5, ROBO1, REST). Furthermore, IPA® identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.
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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, 2021-09-29)
    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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    Identifying the Common Genetic Basis of Antidepressant Response.
    Pain, O ; Hodgson, K ; Trubetskoy, V ; Ripke, S ; Marshe, VS ; Adams, MJ ; Byrne, EM ; Campos, AI ; Carrillo-Roa, T ; Cattaneo, A ; Als, TD ; Souery, D ; Dernovsek, MZ ; Fabbri, C ; Hayward, C ; Henigsberg, N ; Hauser, J ; Kennedy, JL ; Lenze, EJ ; Lewis, G ; Müller, DJ ; Martin, NG ; Mulsant, BH ; Mors, O ; Perroud, N ; Porteous, DJ ; Rentería, ME ; Reynolds, CF ; Rietschel, M ; Uher, R ; Wigmore, EM ; Maier, W ; Wray, NR ; Aitchison, KJ ; Arolt, V ; Baune, BT ; Biernacka, JM ; Bondolfi, G ; Domschke, K ; Kato, M ; Li, QS ; Liu, Y-L ; Serretti, A ; Tsai, S-J ; Turecki, G ; Weinshilboum, R ; GSRD Consortium, ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, ; McIntosh, AM ; Lewis, CM (Elsevier BV, 2022-04)
    Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.
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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, 2021-05-17)
    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, 2021-07-26)
    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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    Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder.
    Repple, J ; König, A ; de Lange, SC ; Opel, N ; Redlich, R ; Meinert, S ; Grotegerd, D ; Mauritz, M ; Hahn, T ; Borgers, T ; Leehr, EJ ; Winter, N ; Goltermann, J ; Enneking, V ; Fingas, SM ; Lemke, H ; Waltemate, L ; Dohm, K ; Richter, M ; Mehler, DMA ; Holstein, V ; Gruber, M ; Nenadic, I ; Krug, A ; Brosch, K ; Schmitt, S ; Stein, F ; Meller, T ; Jansen, A ; Steinsträter, O ; Amare, AT ; Kircher, T ; Baune, BT ; van den Heuvel, MP ; Dannlowski, U (Elsevier BV, 2022-03)
    BACKGROUND: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD. METHODS: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects. RESULTS: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance. CONCLUSIONS: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.
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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, 2021-03-13)
    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.