TY  - JOUR
AB  - Age and the ε4 variant of the apolipoprotein E gene (APOE ε4) are two major drivers of Alzheimer's disease (AD). APOE is also the major determinant of longevity. How age and APOE interact in the development of AD is largely unknown. In this study we integrate metabolomics (N = 274,259) and proteomics (N = 54,219) data in plasma from the UK Biobank with the metabolomics (N = 514) and proteomics (N = 618) data in brain from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) to understand the interplay of age, APOE ε4 and metabolome in the development of AD. We find that levels of β-hydroxybutyrate (BHBA) and branch-chained amino acids (BCAAs) are dysregulated in plasma and brains of AD patients. APOE ε4 carriers manifest significantly higher plasma concentration of BHBA that is detectable as early as 37 years of age and remains high throughout the studied age range of 37-73 whereas the plasma concentrations of BCAAs decline in APOE ε44 carriers after the age of 58 years. Proteomic signatures of APOE ε4, BHBA and BCAAs suggest downregulation of lysosome, immune and insulin-like growth factor (IGF1) transport/uptake pathways in plasma, and downregulation of the tricarboxylic acid (TCA) cycle, neurexins/neuroligins and clathrin-mediated endocytosis pathways in brain. Our data identifies two major shifts in metabolism occurring decades apart over the age course in AD in APOE ε4 carriers. These include early ketogenesis that manifests around late 30 s and gluconeogenesis, which manifests around the age of 60 years.
AU  - Amin, N.*
AU  - Liu, J.*
AU  - Sproviero, W.*
AU  - Arnold, M.
AU  - Batra, R.*
AU  - Bonnechere, B.*
AU  - Chiou, Y.J.*
AU  - Fernandes, M.*
AU  - Krumsiek, J.*
AU  - Newby, D.*
AU  - Nho, K.*
AU  - Kim, J.P.*
AU  - Saykin, A.J.*
AU  - Shi, L.*
AU  - Winchester, L.M.*
AU  - Yang, Y.*
AU  - Nevado-Holgado, A.J.*
AU  - Kastenmüller, G.
AU  - Kaddurah-Daouk, R.*
AU  - van Duijn, C.M.*
C1  - 75937
C2  - 58207
TI  - Interplay between age, APOE Ɛ4 and the metabolome in plasma and brain in Alzheimer's disease.
JO  - Transl. Psychiatry
VL  - 15
IS  - 1
PY  - 2025
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P < 10-5) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P < 5 × 10-8) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.
AU  - Bentley, A.R.*
AU  - Brown, M.R.*
AU  - Musani, S.K.*
AU  - Schwander, K.L.*
AU  - Winkler, T.W.*
AU  - Sims, M.*
AU  - Kilpeläinen, T.O.*
AU  - Aschard, H.*
AU  - Bartz, T.M.*
AU  - Bielak, L.F.*
AU  - Chai, J.F.*
AU  - Chitrala, K.N.*
AU  - Franceschini, N.*
AU  - Graff, M.*
AU  - Guo, X.*
AU  - Hartwig, F.P.*
AU  - Horimoto, A.R.V.R.*
AU  - Lim, E.*
AU  - Liu, Y.*
AU  - Manning, A.K.*
AU  - Nolte, I.M.*
AU  - Noordam, R.*
AU  - Richard, M.A.*
AU  - Smith, A.V.*
AU  - Sung, Y.J.*
AU  - Vojinovic, D.*
AU  - Wang, R.*
AU  - Wang, Y.*
AU  - Feitosa, M.F.*
AU  - Harris, S.E.*
AU  - Lyytikäinen, L.P.*
AU  - Pistis, G.*
AU  - Rauramaa, R.*
AU  - van der Most, P.J.*
AU  - Ware, E.B.*
AU  - Weiss, S.*
AU  - Wen, W.*
AU  - Yanek, L.R.*
AU  - Arking, D.E.*
AU  - Arnett, D.K.*
AU  - Ballantyne, C.*
AU  - Boerwinkle, E.*
AU  - Chen, Y.I.*
AU  - Daviglus, M.L.*
AU  - de Las Fuentes, L.*
AU  - de Vries, P.S.*
AU  - Delaney, J.A.C.*
AU  - Fretts, A.M.*
AU  - Ekunwe, L.*
AU  - Faul, J.D.*
AU  - Gallo, L.C.*
AU  - Heikkinen, S.*
AU  - Homuth, G.*
AU  - Ikram, M.A.*
AU  - Isasi, C.R.*
AU  - Jonas, J.B.*
AU  - Keltikangas-Järvinen, L.*
AU  - Komulainen, P.*
AU  - Kraja, A.T.*
AU  - Krieger, J.E.*
AU  - Launer, L.*
AU  - Liu, J.*
AU  - Lohman, K.*
AU  - Luik, A.I.*
AU  - Manichaikul, A.W.*
AU  - Marques-Vidal, P.*
AU  - Milaneschi, Y.*
AU  - Mwasongwe, S.E.*
AU  - O'Connell, J.R.*
AU  - Rice, K.*
AU  - Rich, S.S.*
AU  - Schreiner, P.J.*
AU  - Schwettmann, L.
AU  - Shikany, J.M.*
AU  - Shu, X.O.*
AU  - Smith, J.A.*
AU  - Snieder, H.*
AU  - Sotoodehnia, N.*
AU  - Tai, E.S.*
AU  - Taylor, K.D.*
AU  - Tinker, L.E.*
AU  - Tsai, M.Y.*
AU  - Uitterlinden, A.G.*
AU  - van Duijn, C.M.*
AU  - van Heemst, D.*
AU  - Waldenberger, M.
AU  - Wallace, R.B.*
AU  - Wee, H.L.*
AU  - Weir, D.R.*
AU  - Wei, W.B.*
AU  - Willems van Dijk, K.*
AU  - Wilson, G.*
AU  - Yao, J.*
AU  - Young, K.L.*
AU  - Zhang, X.*
AU  - Zhao, W.*
AU  - Zhu, X.*
AU  - Zonderman, A.B.*
AU  - Deary, I.J.*
AU  - Gieger, C.
AU  - Grabe, H.J.*
AU  - Lakka, T.A.*
AU  - Lehtimäki, T.*
AU  - Oldehinkel, A.J.*
AU  - Preisig, M.*
AU  - Wang, Y.X.*
AU  - Zheng, W.*
AU  - Evans, M.K.*
AU  - Province, M.*
AU  - Gauderman, J.*
AU  - Gudnason, V.*
AU  - Hartman, C.A.*
AU  - Horta, B.L.*
AU  - Kardia, S.L.R.*
AU  - Kooperberg, C.*
AU  - Liu, C.T.*
AU  - Mook-Kanamori, D.O.*
AU  - Penninx, B.W.*
AU  - Pereira, A.C.*
AU  - Peyser, P.A.*
AU  - Psaty, B.M.*
AU  - Rotter, J.I.*
AU  - Sim, X.*
AU  - North, K.E.*
AU  - Rao, D.C.*
AU  - Bierut, L.*
AU  - Miller, C.L.*
AU  - Morrison, A.C.*
AU  - Rotimi, C.N.*
AU  - Fornage, M.*
AU  - Fox, E.R.*
C1  - 74990
C2  - 57781
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 12
TI  - Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.
JO  - Transl. Psychiatry
VL  - 15
IS  - 1
PB  - Springernature
PY  - 2025
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Neuropsychiatric disorders show shared and distinct neurobiological correlates. A cross-disorder genome-wide association study (GWAS) identified 23 highly pleiotropic single-nucleotide polymorphisms (SNPs) that were associated with at least four neuropsychiatric disorders, and 22 SNPs that were associated predominantly with schizophrenia. Exploring their link to brain-related traits might advance understanding their distinct neurobiological processes. Using the UK Biobank data (n = 28,952), this study examined the association of both a genetic risk score (GRS) for highly pleiotropic SNPs (PleioPsych-GRS), and a GRS for predominantly schizophrenia-associated SNPs (SCZ-GRS) with 154 measures of subcortical volume, cortical thickness, and surface area as well as 12 outcomes related to mental health. To generate further insights at the individual SNP level, the association between SNPs and brain structure was examined using GWAS summary statistics. The PleioPsych-GRS showed no significant association with brain structure after correction for multiple testing. The SCZ-GRS showed a significant association with an increased surface area of the lateral orbitofrontal region, and an increased volume of the putamen, among others. The PleioPsych-GRS and the SCZ-GRS were associated with eight and four outcomes related to mental health, respectively. Two highly pleiotropic and 10 SCZ-associated SNPs were associated with several structural brain phenotypes. Taken together, these findings indicated that GRSs of highly pleiotropic SNPs and predominantly schizophrenia-associated SNPs have partly distinct associations with brain structure and outcomes related to mental health. Thus, investigating schizophrenia-specific and pleiotropic variants may improve our understanding of the neurobiology of neuropsychiatric disorders.
AU  - Federmann, L.M.*
AU  - Sindermann, L.*
AU  - Primus, S.A.
AU  - Raimondo, F.*
AU  - Oexle, K.
AU  - Goltermann, J.*
AU  - Winkelmann, J.
AU  - Nöthen, M.M.*
AU  - Amunts, K.*
AU  - Mühleisen, T.W.*
AU  - Cichon, S.*
AU  - Eickhoff, S.B.*
AU  - Hoffstaedter, F.*
AU  - Dannlowski, U.*
AU  - Patil, K.R.*
AU  - Forstner, A.J.*
C1  - 75077
C2  - 57742
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Neurobiological correlates of schizophrenia-specific and highly pleiotropic genetic risk scores for neuropsychiatric disorders.
JO  - Transl. Psychiatry
VL  - 15
IS  - 1
PB  - Springernature
PY  - 2025
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Acylcarnitines (ACs) are involved in bioenergetics processes that may play a role in the pathophysiology of depression. Previous genomic evidence identified four ACs potentially linked to depression risk. We carried forward these ACs and tested the association of their circulating levels with Major Depressive Disorder (MDD) diagnosis, overall depression severity and specific symptom profiles. The sample from the Netherlands Study of Depression and Anxiety included participants with current (n = 1035) or remitted (n = 739) MDD and healthy controls (n = 800). Plasma levels of four ACs (short-chain: acetylcarnitine C2 and propionylcarnitine C3; medium-chain: octanoylcarnitine C8 and decanoylcarnitine C10) were measured. Overall depression severity as well as atypical/energy-related (AES), anhedonic and melancholic symptom profiles were derived from the Inventory of Depressive Symptomatology. As compared to healthy controls, subjects with current or remitted MDD presented similarly lower mean C2 levels (Cohen's d = 0.2, p ≤ 1e-4). Higher overall depression severity was significantly associated with higher C3 levels (ß = 0.06, SE = 0.02, p = 1.21e-3). No associations were found for C8 and C10. Focusing on symptom profiles, only higher AES scores were linked to lower C2 (ß = -0.05, SE = 0.02, p = 1.85e-2) and higher C3 (ß = 0.08, SE = 0.02, p = 3.41e-5) levels. Results were confirmed in analyses pooling data with an additional internal replication sample from the same subjects measured at 6-year follow-up (totaling 4141 observations). Small alterations in levels of short-chain acylcarnitine levels were related to the presence and severity of depression, especially for symptoms reflecting altered energy homeostasis. Cellular metabolic dysfunctions may represent a key pathway in depression pathophysiology potentially accessible through AC metabolism.
AU  - Montanari, S.*
AU  - Jansen, R.*
AU  - Schranner, D.
AU  - Kastenmüller, G.
AU  - Arnold, M.
AU  - Janiri, D.*
AU  - Sani, G.*
AU  - Bhattacharyya, S.*
AU  - Mahmoudian Dehkordi, S.*
AU  - Dunlop, B.W.*
AU  - Rush, A.J.*
AU  - Penninx, B.W.H.J.*
AU  - Kaddurah-Daouk, R.*
AU  - Milaneschi, Y.*
C1  - 73451
C2  - 56871
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Acylcarnitines metabolism in depression: Association with diagnostic status, depression severity and symptom profile in the NESDA cohort.
JO  - Transl. Psychiatry
VL  - 15
IS  - 1
PB  - Springernature
PY  - 2025
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach. Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD = 15, MDD = 24, schizophrenia = 68, controls = 62) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR = 0.02), cortisol synthesis and secretion (FDR = 0.026), and dopaminergic synapse (FDR = 0.038). Additional enriched pathways included hormone signaling (FDRs < 0.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR = 0.0028). These pathways highlight shared molecular mechanisms in the three disorders. Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2-6 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction. Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level. This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders.
AU  - Worf, K.
AU  - Matosin, N.*
AU  - Gerstner, N.
AU  - Fröhlich, A.S.*
AU  - Koller, A.C.*
AU  - Degenhardt, F.*
AU  - Thiele, H.*
AU  - Rietschel, M.*
AU  - Udawela, M.*
AU  - Scarr, E.*
AU  - Dean, B.*
AU  - Theis, F.J.
AU  - Müller, N.S.
AU  - Knauer-Arloth, J.
C1  - 74156
C2  - 57349
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons.
JO  - Transl. Psychiatry
VL  - 15
IS  - 1
PB  - Springernature
PY  - 2025
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N = 112) and 24 months (N = 184) in children from the South African Drakenstein Child Health Study. PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. Cord blood DNAm was measured using the EPIC and 450 K BeadChips. Neurodevelopment (cognitive, language, motor, adaptive behavior, socioemotional) was measured using the Bayley Scales of Infant and Toddler Development, Third Edition. We constructed methylation risk scores (MRS) for PTE and PAE and conducted causal mediation analysis (CMA) with these MRS as mediators. Next, we conducted a high-dimensional mediation analysis to identify individual CpG sites as potential mediators, followed by a CMA to estimate the average causal mediation effects (ACME) and total effect (TE). PTE and PAE were associated with neurodevelopment at 6 but not at 24 months. PTE MRS reached a prediction accuracy (R2) of 0.23 but did not significantly mediate the association between PTE and neurodevelopment. PAE MRS was not predictive of PAE (R2 = 0.006). For PTE, 31 CpG sites and eight CpG sites were identified as significant mediators (ACME and TE P < 0.05) for the cognitive and motor domains at 6 months, respectively. For PAE, 16 CpG sites and 1 CpG site were significant mediators for the motor and adaptive behavior domains at 6 months, respectively. Several of the associated genes, including MAD1L1, CAMTA1, and ALDH1A2 have been implicated in neurodevelopmental delay, suggesting that differential DNAm may partly explain the biological mechanisms underlying the relationship between PTE and PAE and child neurodevelopment.
AU  - Abrishamcar, S.*
AU  - Chen, J.*
AU  - Feil, D.*
AU  - Kilanowski, A.
AU  - Koen, N.*
AU  - Vanker, A.*
AU  - Wedderburn, C.J.*
AU  - Donald, K.A.*
AU  - Zar, H.J.*
AU  - Stein, D.J.*
AU  - Hüls, A.*
C1  - 66372
C2  - 53151
TI  - DNA methylation as a potential mediator of the association between prenatal tobacco and alcohol exposure and child neurodevelopment in a South African birth cohort.
JO  - Transl. Psychiatry
VL  - 12
IS  - 1
PY  - 2022
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.
AU  - Price, K.M.*
AU  - Wigg, K.G.*
AU  - Eising, E.*
AU  - Feng, Y.*
AU  - Blokland, K.*
AU  - Wilkinson, M.*
AU  - Kerr, E.N.*
AU  - Guger, S.L.*
AU  - Abbondanza, F.*
AU  - Allegrini, A.G.*
AU  - Andlauer, T.F.M.*
AU  - Bates, T.C.*
AU  - Bernard, M.*
AU  - Bonte, M.*
AU  - Boomsma, D.I.*
AU  - Bourgeron, T.*
AU  - Brandeis, D.*
AU  - Carreiras, M.*
AU  - Ceroni, F.*
AU  - Csépe, V.*
AU  - Dale, P.S.*
AU  - DeFries, J.C.*
AU  - de Jong, P.F.*
AU  - Demonet, J.F.*
AU  - de Zeeuw, E.L.*
AU  - Franken, M.C.J.*
AU  - Francks, C.*
AU  - Gerritse, M.*
AU  - Gialluisi, A.*
AU  - Gordon, S.D.*
AU  - Gruen, J.R.*
AU  - Hayiou-Thomas, M.E.*
AU  - Hernández-Cabrera, J.*
AU  - Hottenga, J.J.*
AU  - Hulme, C.*
AU  - Jansen, P.R.*
AU  - Kere, J.*
AU  - Koomar, T.*
AU  - Landerl, K.*
AU  - Leonard, G.T.*
AU  - Liao, Z.*
AU  - Luciano, M.*
AU  - Lyytinen, H.*
AU  - Martin, N.G.*
AU  - Martinelli, A.*
AU  - Maurer, U.*
AU  - Michaelson, J.J.*
AU  - Mirza-Schreiber, N.
AU  - Moll, K.*
AU  - Monaco, A.P.*
AU  - Morgan, A.T.*
AU  - Müller-Myhsok, B.*
AU  - Newbury, D.F.*
AU  - Nöthen, M.M.*
AU  - Olson, R.K.*
AU  - Paracchini, S.*
AU  - Paus, T.*
AU  - Pausova, Z.*
AU  - Pennell, C.E.*
AU  - Pennington, B.F.*
AU  - Plomin, R.J.*
AU  - Ramus, F.*
AU  - Reilly, S.*
AU  - Richer, L.*
AU  - Rimfeld, K.*
AU  - Schulte-Körne, G.*
AU  - Shapland, C.Y.*
AU  - Simpson, N.H.*
AU  - Smith, S.D.*
AU  - Snowling, M.J.*
AU  - St Pourcain, B.*
AU  - Stein, J.F.*
AU  - Talcott, J.B.*
AU  - Tiemeier, H.*
AU  - Tomblin, J.B.*
AU  - Truong, D.T.*
AU  - van Bergen, E.*
AU  - van der Schroeff, M.P.*
AU  - van Donkelaar, M.M.J.*
AU  - Verhoef, E.*
AU  - Wang, C.A.*
AU  - Watkins, K.E.*
AU  - Whitehouse, A.J.O.*
AU  - Willcutt, E.G.*
AU  - Wright, M.J.*
AU  - Zhu, G.*
AU  - Fisher, S.E.*
AU  - Lovett, M.W.*
AU  - Strug, L.J.*
AU  - Barr, C.L.*
C1  - 66891
C2  - 53347
TI  - Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities.
JO  - Transl. Psychiatry
VL  - 12
IS  - 1
PY  - 2022
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
AU  - Ip, H.F.*
AU  - van der Laan, C.M.*
AU  - Krapohl, E.M.L.*
AU  - Brikell, I.*
AU  - Sánchez-Mora, C.*
AU  - Nolte, I.M.*
AU  - St Pourcain, B.*
AU  - Bolhuis, K.*
AU  - Palviainen, T.*
AU  - Zafarmand, H.*
AU  - Colodro-Conde, L.*
AU  - Gordon, S.*
AU  - Zayats, T.*
AU  - Aliev, F.*
AU  - Jiang, C.*
AU  - Wang, C.A.*
AU  - Saunders, G.*
AU  - Karhunen, V.*
AU  - Hammerschlag, A.R.*
AU  - Adkins, D.E.*
AU  - Border, R.*
AU  - Peterson, R.E.*
AU  - Prinz, J.A.*
AU  - Thiering, E.
AU  - Seppälä, I.*
AU  - Ahluwalia, T.S.*
AU  - Day, F.R.*
AU  - Hottenga, J.J.*
AU  - Allegrini, A.G.*
AU  - Rimfeld, K.*
AU  - Chen, Q.*
AU  - Lu, Y.*
AU  - Martin, J.*
AU  - Soler Artigas, M.*
AU  - Rovira, P.*
AU  - Bosch, R.*
AU  - Español, G.*
AU  - Ramos Quiroga, J.A.*
AU  - Neumann, A.*
AU  - Ensink, J.*
AU  - Grasby, K.*
AU  - Morosoli, J.J.*
AU  - Tong, X.*
AU  - Marrington, S.*
AU  - Middeldorp, C.*
AU  - Scott, J.G.*
AU  - Vinkhuyzen, A.A.*
AU  - Shabalin, A.A.*
AU  - Corley, R.*
AU  - Evans, L.M.*
AU  - Sugden, K.*
AU  - Alemany, S.*
AU  - Sass, L.*
AU  - Vinding, R.*
AU  - Ruth, K.*
AU  - Tyrrell, J.*
AU  - Davies, G.E.*
AU  - Ehli, E.A.*
AU  - Hagenbeek, F.A.*
AU  - De Zeeuw, E.*
AU  - Van Beijsterveldt, T.C.E.M.*
AU  - Larsson, H.*
AU  - Snieder, H.*
AU  - Verhulst, F.C.*
AU  - Amin, N.*
AU  - Whipp, A.M.*
AU  - Korhonen, T.*
AU  - Vuoksimaa, E.*
AU  - Rose, R.J.*
AU  - Uitterlinden, A.G.*
AU  - Heath, A.C.*
AU  - Madden, P.*
AU  - Haavik, J.*
AU  - Harris, J.R.*
AU  - Helgeland, Ø.*
AU  - Johansson, S.*
AU  - Knudsen, G.P.S.*
AU  - Njolstad, P.R.*
AU  - Lu, Q.*
AU  - Rodriguez, A.*
AU  - Henders, A.K.*
AU  - Mamun, A.*
AU  - Najman, J.M.*
AU  - Brown, S.*
AU  - Hopfer, C.J.*
AU  - Krauter, K.*
AU  - Reynolds, C.*
AU  - Smolen, A.*
AU  - Stallings, M.C.*
AU  - Wadsworth, S.*
AU  - Wall, T.L.*
AU  - Silberg, J.L.*
AU  - Miller, A.*
AU  - Keltikangas-Järvinen, L.*
AU  - Hakulinen, C.*
AU  - Pulkki-Råback, L.*
AU  - Havdahl, A.*
AU  - Magnus, P.*
AU  - Raitakari, O.T.*
AU  - Perry, J.R.B.*
AU  - Llop, S.*
AU  - Lopez-Espinosa, M.J.*
AU  - Bønnelykke, K.*
AU  - Bisgaard, H.*
AU  - Sunyer, J.*
AU  - Lehtimäki, T.*
AU  - Arseneault, L.*
AU  - Standl, M.
AU  - Heinrich, J.
AU  - Boden, J.M.*
AU  - Pearson, J.F.*
AU  - Horwood, L.J.*
AU  - Kennedy, M.*
AU  - Poulton, R.*
AU  - Eaves, L.J.*
AU  - Maes, H.H.*
AU  - Hewitt, J.K.*
AU  - Copeland, W.E.*
AU  - Costello, E.J.*
AU  - Williams, G.M.*
AU  - Wray, N.R.*
AU  - Jarvelin, M.R.*
AU  - McGue, M.*
AU  - Iacono, W.G.*
AU  - Caspi, A.*
AU  - Moffitt, T.E.*
AU  - Whitehouse, A.J.*
AU  - Pennell, C.E.*
AU  - Klump, K.L.*
AU  - Burt, S.A.*
AU  - Dick, D.M.*
AU  - Reichborn-Kjennerud, T.*
AU  - Martin, N.G.*
AU  - Medland, S.E.*
AU  - Vrijkotte, T.*
AU  - Kaprio, J.*
AU  - Tiemeier, H.*
AU  - Davey Smith, G.*
AU  - Hartman, C.A.*
AU  - Oldehinkel, A.J.*
AU  - Casas, M.*
AU  - Ribasés, M.*
AU  - Lichtenstein, P.*
AU  - Lundstrom, S.*
AU  - Plomin, R.*
AU  - Bartels, M.*
AU  - Nivard, M.G.*
AU  - Boomsma, D.I.*
C1  - 62773
C2  - 51064
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Genetic association study of childhood aggression across raters, instruments, and age.
JO  - Transl. Psychiatry
VL  - 11
IS  - 1
PB  - Springernature
PY  - 2021
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.
AU  - MahmoudianDehkordi, S.*
AU  - Ahmed, A.T.*
AU  - Bhattacharyya, S.*
AU  - Han, X.*
AU  - Baillie, R.A.*
AU  - Arnold, M.
AU  - Skime, M.K.*
AU  - John-Williams, L.S.*
AU  - Moseley, M.A.*
AU  - Thompson, K.*
AU  - Louie, G.*
AU  - Riva-Posse, P.*
AU  - Craighead, W.E.*
AU  - McDonald, W.*
AU  - Krishnan, R.*
AU  - Rush, A.J.*
AU  - Frye, M.A.*
AU  - Dunlop, B.W.*
AU  - Weinshilboum, R.M.*
AU  - Kaddurah-Daouk, R.*
C1  - 61457
C2  - 50267
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression.
JO  - Transl. Psychiatry
VL  - 11
IS  - 1
PB  - Springernature
PY  - 2021
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.
AU  - Moore, S.R.*
AU  - Halldorsdottir, T.*
AU  - Martins, J.*
AU  - Lucae, S.*
AU  - Müller-Myhsok, B.*
AU  - Müller, N.S.
AU  - Piechaczek, C.*
AU  - Feldmann, L.*
AU  - Freisleder, F.J.*
AU  - Greimel, E.*
AU  - Schulte-Körne, G.*
AU  - Binder, E.B.*
AU  - Knauer-Arloth, J.
C1  - 63839
C2  - 51770
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Sex differences in the genetic regulation of the blood transcriptome response to glucocorticoid receptor activation.
JO  - Transl. Psychiatry
VL  - 11
IS  - 1
PB  - Springernature
PY  - 2021
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Neurodevelopmental disorders are heterogeneous and identifying shared genetic aetiologies and converging signalling pathways affected could improve disease diagnosis and treatment. Truncating mutations of the abnormal spindle-like microcephaly associated (ASPM) gene cause autosomal recessive primary microcephaly (MCPH) in humans. ASPM is a positive regulator of Wnt/beta-Catenin signalling and controls symmetric to asymmetric cell division. This process balances neural progenitor proliferation with differentiation during embryogenesis, the malfunction of which could interfere with normal brain development. ASPM mutations may play a role also in other neurodevelopmental disorders, nevertheless, we lack the details of how or to what extent. We therefore assessed neurodevelopmental disease and circuit endophenotypes in mice with a truncating Aspm(1-7) mutation. Aspm(1-7) mice exhibited impaired short- and long-term object recognition memory and markedly enhanced place learning in the IntelliCage (R). This behaviour pattern is reminiscent of a cognitive phenotype seen in mouse models and patients with a rare form of autism spectrum disorder (ASD) as well as in mouse models of altered Wnt signalling. These alterations were accompanied by ventriculomegaly, corpus callosum dysgenesis and decreased parvalbumin (PV)+ interneuron numbers in the hippocampal Cornu Ammonis (CA) region and thalamic reticular nucleus (TRN). PV+ cell number correlated to object recognition (CA and TRN) and place learning (TRN). This opens the possibility that, as well as causing MCPH, mutant ASPM potentially contributes to other neurodevelopmental disorders such as ASD through altered parvalbuminergic interneuron development affecting cognitive behaviour. These findings provide important information for understanding the genetic overlap and improved treatment of neurodevelopmental disorders associated with ASPM.
AU  - Garrett, L.
AU  - Chang, Y.J.*
AU  - Niedermeier, K.M.
AU  - Heermann, T.
AU  - Enard, W.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Huttner, W.B.*
AU  - Wurst, W.
AU  - Hölter, S.M.
C1  - 58273
C2  - 48192
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
TI  - A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons.
JO  - Transl. Psychiatry
VL  - 10
IS  - 1
PB  - Nature Publishing Group
PY  - 2020
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - beta B2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens before it was detected in various brain regions of the mouse, including the hippocampus and the cerebral cortex. Mutations in the mouse Crybb2 gene lead to alterations of sensorimotor gating measured as prepulse inhibition (PPI) and reduced hippocampal size, combined with an altered number of parvalbumin-positive GABAergic interneurons. Decreased PPI and alterations of parvalbumin-positive interneurons are also endophenotypes that typically occur in schizophrenia. To verify the results found in mice, we genotyped 27 single nucleotide polymorphisms (SNPs) within the CRYBB2 gene and its flanking regions and investigated different schizophrenia typical endophenotypes in a sample of 510 schizophrenia patients and 1322 healthy controls. In the case-control study, no association with schizophrenia was found. However, 3 of the 4 investigated haplotype blocks indicated a decreased CRYBB2 mRNA expression. Two of these blocks were associated with poorer antisaccade task performance and altered working memory-linked functional magnetic resonance imaging signals. For the two haplotypes associated with antisaccade performance, suggestive evidence was found with visual memory and in addition, haplotype block 4 showed a nominally significant association with reduced sensorimotor gating, measured as P50 ratio. These results were not schizophrenia-specific, but could be detected in a combined sample of patients and healthy controls. This is the first study to demonstrate the importance of beta B2-crystallin for antisaccade performance and memory function in humans and therefore provides implications for beta B2-crystallin function in the human brain.
AU  - Giegling, I.*
AU  - Hartmann, A.M.*
AU  - Genius, J.*
AU  - Konte, B.*
AU  - Maul, S.*
AU  - Straube, A.*
AU  - Eggert, T.*
AU  - Mulert, C.*
AU  - Leicht, G.*
AU  - Karch, S.*
AU  - Hegerl, U.*
AU  - Pogarell, O.*
AU  - Hölter, S.M.
AU  - Möller, H.J.*
AU  - Graw, J.
AU  - Rujescu, D.*
C1  - 58996
C2  - 48562
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
TI  - Polymorphisms in CRYBB2 encoding βB2-crystallin are associated with antisaccade performance and memory function.
JO  - Transl. Psychiatry
VL  - 10
IS  - 1
PB  - Nature Publishing Group
PY  - 2020
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - The role of self-perceived general health in predicting morbidity and mortality among older people is established. The predictive value of self-perceived mental health and of its possible biological underpinnings for future depressive symptoms is unexplored. This study aimed to assess the role of mental health-related quality of life (HRQOL) and of its epigenetic markers in predicting depressive symptoms among older people without lifetime history of depression. Data were based on a subgroup (n = 1 492) of participants of the longitudinal ESTHER study. An epigenome-wide association study (EWAS) of mental HRQOL was conducted using DNA from baseline whole blood samples and logistic regression analyses were performed to assess the predictive value of methylation beta values of EWAS identified CpGs for incidence of depressive symptoms in later life. The methylation analyses were replicated in the independent KORA cohort (n = 890) and a meta-analysis of the two studies was conducted. Results of the meta-analysis showed that participants with beta values of cg27115863 within quartile 1 (Q(1)) had nearly a two-fold increased risk of developing depressive symptoms compared to participants with beta values within Q(4) (ORQ1vsQ4 = 1.80; CI 1.25-2.61). In the ESTHER study the predictive value of subjective mental health for future depressive symptoms was also assessed and for 10-unit increase in mental HRQOL scores the odds for incident depressive symptoms were reduced by 54% (OR 0.46; CI 0.40-0.54). These findings suggest that subjective mental health and hypomethylation at cg27115863 are predictive of depressive symptoms, possibly through the activation of inflammatory signaling pathway.
AU  - Perna, L.*
AU  - Zhang, Y.*
AU  - Matias-Garcia, P.R.
AU  - Ladwig, K.-H.
AU  - Wiechmann, T.*
AU  - Wild, B.*
AU  - Waldenberger, M.
AU  - Schöttker, B.*
AU  - Mons, U.*
AU  - Ihle, A.*
AU  - Kliegel, M.*
AU  - Schwettmann, L.
AU  - Peters, A.
AU  - Brenner, H.*
C1  - 60150
C2  - 49110
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Subjective mental health, incidence of depressive symptoms in later life, and the role of epigenetics: Results from two longitudinal cohort studies.
JO  - Transl. Psychiatry
VL  - 10
IS  - 1
PB  - Springernature
PY  - 2020
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine-homogentisic acid and methionine-tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.
AU  - Bhattacharyya, S.*
AU  - Ahmed, A.T.*
AU  - Arnold, M.
AU  - Liu, D.*
AU  - Luo, C.*
AU  - Zhu, H.*
AU  - MahmoudianDehkordi, S.*
AU  - Neavin, D.*
AU  - Louie, G.*
AU  - Dunlop, B.W.*
AU  - Frye, M.A.*
AU  - Wang, L.*
AU  - Weinshilboum, R.M.*
AU  - Krishnan, R.R.*
AU  - Rush, A.J.*
AU  - Kaddurah-Daouk, R.*
C1  - 56553
C2  - 47113
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
TI  - Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.
JO  - Transl. Psychiatry
VL  - 9
IS  - 1
PB  - Nature Publishing Group
PY  - 2019
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - In humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are unknown. To assess the contribution of SAPAP4 to these disorders, we characterized SAPAP4-deficient mice. Our study reveals that the loss of SAPAP4 triggers profound behavioural abnormalities, including cognitive deficits combined with impaired vocal communication and social interaction, phenotypes reminiscent of ASD in humans. These behavioural alterations of SAPAP4-deficient mice are associated with dramatic changes in synapse morphology, function and plasticity, indicating that SAPAP4 is critical for the development of functional neuronal networks and that mutations in the corresponding human gene, DLGAP4, may cause deficits in social and cognitive functioning relevant to ASD-like neurodevelopmental disorders.
AU  - Schob, C.*
AU  - Morellini, F.*
AU  - Ohana, O.*
AU  - Bakota, L.*
AU  - Hrynchak, M.V.*
AU  - Brandt, R.*
AU  - Brockmann, M.D.*
AU  - Cichon, N.*
AU  - Hartung, H.*
AU  - Hanganu-Opatz, I.L.*
AU  - Kraus, V.*
AU  - Scharf, S.*
AU  - Herrmans-Borgmeyer, I.*
AU  - Schweizer, M.*
AU  - Kuhl, D.*
AU  - Wöhr, M.*
AU  - Vörckel, K.J.*
AU  - Calzada-Wack, J.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Garner, C.C.*
AU  - Kreienkamp, H.J.*
AU  - Kindler, S.*
C1  - 55302
C2  - 46282
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
TI  - Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice.
JO  - Transl. Psychiatry
VL  - 9
IS  - 1
PB  - Nature Publishing Group
PY  - 2019
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - The epidemiologic link between schizophrenia (SCZ) and type 2 diabetes (T2D) remains poorly understood. Here, we investigate the presence and extent of a shared genetic background between SCZ and T2D using genome-wide approaches. We performed a genome-wide association study (GWAS) and polygenic risk score analysis in a Greek sample collection (GOMAP) comprising three patient groups: SCZ only (n = 924), T2D only (n = 822), comorbid SCZ and T2D (n = 505); samples from two separate Greek cohorts were used as population-based controls (n = 1,125). We used genome-wide summary statistics from two large-scale GWAS of SCZ and T2D from the PGC and DIAGRAM consortia, respectively, to perform genetic overlap analyses, including a regional colocalisation test. We show for the first time that patients with comorbid SCZ and T2D have a higher genetic predisposition to both disorders compared to controls. We identify five genomic regions with evidence of colocalising SCZ and T2D signals, three of which contain known loci for both diseases. We also observe a significant excess of shared association signals between SCZ and T2D at nine out of ten investigated p value thresholds. Finally, we identify 29 genes associated with both T2D and SCZ, several of which have been implicated in biological processes relevant to these disorders. Together our results demonstrate that the observed comorbidity between SCZ and T2D is at least in part due to shared genetic mechanisms.
AU  - Hackinger, S.*
AU  - Prins, B.*
AU  - Mamakou, V.*
AU  - Zengini, E.*
AU  - Marouli, E.*
AU  - Brčić, L.*
AU  - Serafetinidis, I.*
AU  - Lamnissou, K.*
AU  - Kontaxakis, V.*
AU  - Dedoussis, G.*
AU  - Gonidakis, F.*
AU  - Thanopoulou, A.*
AU  - Tentolouris, N.*
AU  - Tsezou, A.*
AU  - Zeggini, E.
C1  - 54860
C2  - 45901
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
TI  - Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia.
JO  - Transl. Psychiatry
VL  - 8
IS  - 1
PB  - Nature Publishing Group
PY  - 2018
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Despite the fact that mitochondrial dysfunctions are increasingly recognized as key components in stress-related mental disorders, very little is known about the association between posttraumatic stress disorder (PTSD) and mitochondrial variants. To identify susceptibility mitochondrial genes for PTSD, we analyzed a total number of 978 mitochondrial single-nucleotide polymorphisms (mtSNPs) in a sample of 1238 individuals participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Participants were classified with 'no PTSD', 'partial PTSD' or 'full PTSD' by applying the Posttraumatic Diagnostic Scale and the Impact of Event Scale. To assess PTSD-mtSNP association while taking heteroplasmy into account, we used the raw signal intensity values measured on the microarray and applied linear regression. Significant associations were obtained between full versus no PTSD and two mtSNPs; mt8414CT (β=-0.954±0.06, Padjusted=0.037) located in adenosine triphosphate (ATP) synthase subunit 8 (MT-ATP8) and mt12501GA (β=-1.782±0.40, Padjusted=0.015) located in the NADH dehydrogenase subunits 5 (MT-ND5). Heteroplasmy for the two variants towards a larger number of the respective minor alleles increases the risk of having PTSD. NADH dehydrogenase and ATP synthase are both linked to the regulation of reactive oxygen species. Our results highlight the important role of the mitochondrial genome among the factors that contribute to the risk of PTSD. Mitochondrial genetic variants may be more important than has previously been assumed, leading to further insights regarding effects of existing medications, or even to the development of innovative treatments. As this is the first mitochondrial genome-wide association study for PTSDs, further analyses are needed to follow up on the present findings.
AU  - Flaquer, A.
AU  - Baumbach, C.
AU  - Ladwig, K.-H.
AU  - Kriebel, J.
AU  - Waldenberger, M.
AU  - Grallert, H.
AU  - Baumert, J.J.
AU  - Meitinger, T.
AU  - Kruse, J.*
AU  - Peters, A.
AU  - Emeny, R.T.
AU  - Strauch, K.
C1  - 43760
C2  - 36693
TI  - Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder.
JO  - Transl. Psychiatry
VL  - 5
PY  - 2015
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10 -9 across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10 -4). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.
AU  - Hancock, D.B.*
AU  - Reginsson, G.W.*
AU  - Gaddis, N.C.*
AU  - Chen, X.*
AU  - Saccone, N.L.*
AU  - Lutz, S.M.*
AU  - Qaiser, B.*
AU  - Sherva, R.*
AU  - Steinberg, S.*
AU  - Zink, F.*
AU  - Stacey, S.N.*
AU  - Glasheen, C.*
AU  - Chen, J.*
AU  - Gu, F.*
AU  - Frederiksen, B.N.*
AU  - Loukola, A.*
AU  - Gudbjartsson, D.F.*
AU  - Brüske, I.
AU  - Landi, M.T.*
AU  - Bickeböller, H.*
AU  - Madden, P.*
AU  - Farrer, L.A.*
AU  - Kaprio, J.*
AU  - Kranzler, H.R.*
AU  - Gelernter, J.*
AU  - Baker, T.B.*
AU  - Kraft, P.*
AU  - Amos, C.I.*
AU  - Caporaso, N.E.*
AU  - Hokanson, J.E.*
AU  - Bierut, L.J.*
AU  - Thorgeirsson, T.E.*
AU  - Johnson, E.O.*
AU  - Stefansson, K.*
C1  - 47097
C2  - 39110
TI  - Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.
JO  - Transl. Psychiatry
VL  - 5
PY  - 2015
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Alcohol consumption is one of the world's major risk factors for disease development. But underlying mechanisms by which moderate-to-heavy alcohol intake causes damage are poorly understood and biomarkers are sub-optimal. Here, we investigated metabolite concentration differences in relation to alcohol intake in 2090 individuals of the KORA F4 and replicated results in 261 KORA F3 and up to 629 females of the TwinsUK adult bioresource. Using logistic regression analysis adjusted for age, body mass index, smoking, high-density lipoproteins and triglycerides, we identified 40/18 significant metabolites in males/females with P-values <3.8E-04 (Bonferroni corrected) that differed in concentrations between moderate-to-heavy drinkers (MHD) and light drinkers (LD) in the KORA F4 study. We further identified specific profiles of the 10/5 metabolites in males/females that clearly separated LD from MHD in the KORA F4 cohort. For those metabolites, the respective area under the receiver operating characteristic curves were 0.812/0.679, respectively, thus providing moderate-to-high sensitivity and specificity for the discrimination of LD to MHD. A number of alcohol-related metabolites could be replicated in the KORA F3 and TwinsUK studies. Our data suggests that metabolomic profiles based on diacylphosphatidylcholines, lysophosphatidylcholines, ether lipids and sphingolipids form a new class of biomarkers for excess alcohol intake and have potential for future epidemiological and clinical studies.
AU  - Jaremek, M.
AU  - Yu, Z.
AU  - Mangino, M.*
AU  - Mittelstraß, K.
AU  - Prehn, C.
AU  - Singmann, P.
AU  - Xu, T.
AU  - Dahmen, N.*
AU  - Weinberger, K.M.*
AU  - Suhre, K.
AU  - Peters, A.
AU  - Döring, A.
AU  - Hauner, H.*
AU  - Adamski, J.
AU  - Illig, T.
AU  - Spector, T.D.*
AU  - Wang-Sattler, R.
C1  - 25488
C2  - 31860
TI  - Alcohol-induced metabolomic differences in humans.
JO  - Transl. Psychiatry
VL  - 3
PB  - Nature Publishing
PY  - 2013
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities(P-comb=7.71 x 10(-10), n=699), with an effect size of 4.87%. This association was also found in a sample from the general population (P=0.048, n=1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.
AU  - Ludwig, K.U.*
AU  - Samann, P.*
AU  - Alexander, M.*
AU  - Beckers, J.*
AU  - Bruder, J.*
AU  - Moll, K.*
AU  - Spieler, D.
AU  - Czisch, M.*
AU  - Warnke, A.*
AU  - Docherty, S.J.*
AU  - Davis, O.S.P.*
AU  - Plomin, R.*
AU  - Nöthen, M.M.*
AU  - Landerl, K.*
AU  - Müller-Myhsok, B.*
AU  - Hoffmann, P.*
AU  - Schumacher, J.*
AU  - Schulte-Körne, G.*
AU  - Czamara, D.*
C1  - 23656
C2  - 31242
TI  - A common variant in Myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults.
JO  - Transl. Psychiatry
VL  - 3
PB  - Nature Publishing
PY  - 2013
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - There is evidence that naturally occurring antibodies directed against Aβ (nAbs-Aβ) have a role in Aβ-metabolism and Aβ-clearance. The presence of nAbs-Aβ leads to a reduction in amyloid fibrillation and thus a reduction in their toxicity. We investigated the effects of nAbs-Aβ in respect to oligomerization and used the Tg2576 transgenic mouse model in order to investigate the rapid effect with a single-dose (24 h) on oligomer breakdown and cytokine secretion along with immunohistochemical characterization of synaptic plasticity. nAbs-Aβ were able to reduce toxic oligomer concentration with an increase in Aβ-monomers. Cytokine secretion was significantly reduced. Synaptic plasticity was also improved after administration of nAbs. Finally, single treatment lead to a significant improvement in cognition. This study demonstrates the efficacy of nAbs-Aβ and presents evidence that several hallmarks of the disease are targeted by nAbs-Aβ.
AU  - Mengel, D.*
AU  - Röskam, S.*
AU  - Neff, F.
AU  - Balakrishnan, K.*
AU  - Deuster, O.*
AU  - Gold, M.*
AU  - Oertel, W.H.*
AU  - Bacher, M.*
AU  - Bach, J.P.*
AU  - Dodel, R.*
C1  - 30558
C2  - 33689
TI  - Naturally occurring autoantibodies interfere with β-amyloid metabolism and improve cognition in a transgenic mouse model of Alzheimer's disease 24 h after single treatment.
JO  - Transl. Psychiatry
VL  - 3
PY  - 2013
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
AU  - Thorgeirsson, T.E.*
AU  - Gudbjartsson, D.F.*
AU  - Sulem, P.*
AU  - Besenbacher, S.*
AU  - Styrkarsdottir, U.*
AU  - Thorleifsson, G.*
AU  - Walters, G.B.*
AU  - TAG Consortium (*)
AU  - Oxford-GSK Consortium (Heinrich, J.
AU  - Lamina, C.)
AU  - ENGAGE Consortium (Wichmann, H.-E.
AU  - Döring, A.
AU  - Rawal, R.
AU  - Nitz, B.
AU  - Gieger, C.)
AU  - Furberg, H.*
AU  - Sullivan, P.F.*
AU  - Marchini, J.*
AU  - McCarthy, M.I.*
AU  - Steinthorsdottir, V.*
AU  - Thorsteinsdottir, U.*
AU  - Stefansson, K.*
C1  - 28174
C2  - 32987
TI  - A common biological basis of obesity and nicotine addiction.
JO  - Transl. Psychiatry
VL  - 3
PB  - Nature Publishing
PY  - 2013
SN  - 2158-3188
ER  - 

TY  - JOUR
AB  - Schizophrenia is a severe complex mental disorder affecting 0.5-1% of the world population. To date, diagnosis of the disease is mainly based on personal and thus subjective interviews. The underlying molecular mechanism of schizophrenia is poorly understood. Using targeted metabolomics we quantified and compared 103 metabolites in plasma samples from 216 healthy controls and 265 schizophrenic patients, including 52 cases that do not take antipsychotic medication. Compared with healthy controls, levels of five metabolites were found significantly altered in schizophrenic patients (P-values ranged from 2.9 × 10(-8) to 2.5 × 10(-4)) and in neuroleptics-free probands (P-values ranging between 0.006 and 0.03), respectively. These metabolites include four amino acids (arginine, glutamine, histidine and ornithine) and one lipid (PC ae C38:6) and are suggested as candidate biomarkers for schizophrenia. To explore the genetic susceptibility on the associated metabolic pathways, we constructed a molecular network connecting these five aberrant metabolites with 13 schizophrenia risk genes. Our result implicated aberrations in biosynthetic pathways linked to glutamine and arginine metabolism and associated signaling pathways as genetic risk factors, which may contribute to patho-mechanisms and memory deficits associated with schizophrenia. This study illustrated that the metabolic deviations detected in plasma may serve as potential biomarkers to aid diagnosis of schizophrenia.
AU  - He, Y.
AU  - Yu, Z.
AU  - Giegling, I.*
AU  - Xie, L.*
AU  - Hartmann, A.M.*
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Kahn, R.*
AU  - Li, Y.*
AU  - Illig, T.
AU  - Wang-Sattler, R.
AU  - Rujescu, D.*
C1  - 10421
C2  - 30239
TI  - Schizophrenia shows a unique metabolomics signature in plasma.
JO  - Transl. Psychiatry
VL  - 2
PB  - Nature Publishing Group
PY  - 2012
SN  - 2158-3188
ER  -