Molecular Psychiatry (2015) 20, 56–71 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp

EXPERT REVIEW An overview of the neurobiology of suicidal behaviors as one meta-system

M Sokolowski1, J Wasserman1 and D Wasserman1,2

Suicidal behaviors (SB) may be regarded as the outmost consequence of mental illnesses, or as a distinct entity per se. Regardless, the consequences of SB are very large to both society and affected individuals. The path leading to SB is clearly a complex one involving interactions between the subject’s biology and environmental influences throughout life. With the aim to generate a representative and diversified overview of the different neurobiological components hypothesized or shown implicated across the entire SB field up to date by any approach, we selected and compiled a list of 212 gene symbols from the literature. An increasing number of novel gene (products) have been introduced as candidates, with half being implicated in SB in only the last 4 years. These candidates represent different neurosystems and functions and might therefore be regarded as competing or redundant explanations. We then adopted a unifying approach by treating them all as parts of the same meta-system, using bioinformatic tools. We present a network of all components connected by physical protein–protein interactions (the SB interactome). We proceeded by exploring the differences between the highly connected core (~30% of the candidate genes) and its peripheral parts, observing more functional homogeneity at the core, with multiple signal transduction pathways and actin- interacting proteins connecting a subset of receptors in nerve cell compartments as well as development/morphology phenotypes and the stress-sensitive synaptic plasticity processes of long term potentiation/depression. We suggest that SB neurobiology might also be viewed as one meta-system and perhaps be explained as intrinsic unbalances acting within the core or as imbalances arising between core and specific peripheral components.

Molecular Psychiatry (2015) 20, 56–71; doi:10.1038/mp.2014.101; published online 2 September 2014

Suicide is the act of dying by one’s own efforts. Suicides may often necessary precondition for SB, as seemingly healthy subjects can be preceded by non-letal suicidal events, that is, suicide attempts engage in SB. As an alternative, SB can also be characterized by (SA), representing an important clinical predictor of increased certain transdiagnostic properties not restricted to any one diagnosis, suicide risk.1–3 A previous SA performed with high intent to die but being present among many of them.10 Poor impulse control (for example, by using a violent method) or resulting in a high (usually coupled with anger/aggresssion)11,12 and certain types of – lethality is also an important sign of the suicide propensity.4,5 The comorbid anxiety and depression appear important overall.13 15 In focus here is on completed suicides and serious SA, termed parallel, there is an increasing focus on certain endophenotypes, suicidal behaviors (SB). Studies focusing on suicide ideation as which prevail relating to stress regulation and neurocognitive outcomes are not primarily covered here, although ideation and changes.14,16,17 Recent studies, for example, confirm certain cognitive desire for death are in turn a major risk factor for SB.6 deficits in decision making, category verbal fluency and the Stroop One can however delineate SB further by using different risk interference test (for example, altered working memory and factors and assessments, which unravels both a substantial hetero- attention),18 in addition to reduced impulse control.19 One may also geneity as well as certain common denominators. These aspects delineate SB by biochemical11,20 or genetic21 correlates as summar- have been fully reviewed elsewhere and are only briefly mentioned ized herein. The integrative study of those correlates with various here.3,5,7,8 Different risk factors have been observed, for example, to endophenotypic delineations of SB appears as a particularly be a male, living alone, exposure to stressful life events/trauma, to promising way forward,14,16 forexample,inthecontextofaneuro- own a handgun or being under chronic pain, while protective factors genetic approach.22 The stress-diathesis model initially introduced for can be, for example, religiousness, spirituality, healthy lifestyles and SB by Mann and Arango23 has also evolved into a developmental social support. It has since long also been known that mental framework of neurogenetic interactions with lifetime stress 24–27 illnesses, for example, as assessed by psychiatric diagnoses, have a exposures. majorroleroleinSB;9 the risk of suicide appears to be elevated in particular among persons with mood disorders, schizophrenia and alcohol/substance use disorders, often during a state of clinical HERITABILITY OF SB worsening of symptoms.3 However, psychiatric disorders are not a A family history of SB is a major risk factor. Indeed, SB aggregates sufficient explanation, as the majority of psychiatrically ill do not in families and involves a substantial genetic component.28,29 A engage in SB. Furthermore, psychiatric disorders are not always a heritability has been observed in the range of 30–55%. This

1National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institute (KI), Stockholm, Sweden and 2WHO Collaborating Centre for Research, Methods Development and Training in Suicide Prevention, Stockholm, Sweden. Correspondence: Dr M Sokolowski, National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institute, S-171 77 Stockholm, Sweden. E-mail: [email protected] Received 14 March 2014; revised 19 June 2014; accepted 22 July 2014; published online 2 September 2014 The neurosystem of suicidal behaviors M Sokolowski et al 57 heritability is however a completely relative and fluent measure, to the increasing sets of candidate genes of psychiatric depending on, for example, the environmental risk burden.30,31 disorders.52–56 The aim here was to explore further the proposition Regardless, it is clear from a qualitative standpoint that the of thinking about SB neurobiology (as approximated by Table 1) genetic diathesis can often have a probabilistic influence on SB, by using a polygenetic ‘meta-’system perspective, with the help of which has led to a hunt for the genes that may be involved. bioinformatic tools. In the biochemical paradigm, all biological functions mediated by proteins (for example, metabolic, structural, regulatory) depend on the physical binding between molecules.57 THE SB GENOME-CANDIDATE GENES Physical PPIs may thus be regarded as a stable generic The gene (products) and neurosystems most frequently studied ‘endophenotype’ or ‘trait’ of any protein. Proteins that interact in have been reviewed in detail elsewhere and represent a highly larger groups may represent the mediating of different functions recommended reading list.7,24,25,32–38 With the aim to generate a by, for example, larger complexes, chain reactions or signal representative and diversified overview of the different neurobio- propagation, involving molecular, cellular or even systemic levels. logical components hypothesized and/or shown implicated across Therefore, certain PPI networks might even depict a simultaneous the entire SB field up to date by any approach, we selected and transversal of the four scenarios recently suggested to be of compiled a list of 212 gene symbols (Table 1). The evidence base interest in psychiatric disorders (that is, the ‘biochemical, cellular, for each gene (product) was not a primary selection criterion, neural network and brain circuit’ levels).58 A PPI network may thus albeit it was used if selecting a subset from many more genes show both vertical (within one level/pathway/neurosystem) and hypothesized or implicated in the one and same neurosystem/ horizontal (between levels/pathways/neurosystems) integration, pathway (aiming at, for example, maximum 5–10 receptor the latter being similar in spirit to functional gene ‘groups’.59 subtypes and transporters from each). We excluded all studies Interestingly, networks of PPIs have been used to identify new, that had not used SB as an outcome. The starting point was the common biology among genes of several complex disorders.60,61 previous review articles.7,24,25,32–38 As ambiguous names of PPI contacts are themselves also important targets for drug proteins cannot be used in, for example, the protein–protein development.62 interaction (PPI) or enrichment analyses performed here, we also We therefore submitted all genes in Table 1 to the online translated all biological findings into official Human Genome Disease Association Protein-Protein Link Evaluator (DAPPLE),60 to Organisation gene symbols. We used PubMed to gain more investigate the PPIs among the genes in Table 1. Figure 2 (upper) insight about all studies up to date for each such gene (product), depicts the large PPI network of proteins encoded by the SB by combining with the ‘suicid*’ search item as well as by browsing candidate genes, as well as other common interacting proteins for novel articles, which had cited older articles on this topic. among them (the ‘indirect’ interactions of the first degree, that is, Because of space concerns, we often did not cite all the their nearest neighbors), with 1793 genes in total. We can call this publications found about each gene (product), providing instead the candidate ‘SB interactome’. DAPPLE also performs a rigorous relevant reviews for further exploration (Table 1). We additionally significance test of the generated network, determining if the also extracted the gene symbols implicated by mRNA expression connectivity of the network exceeds that expected by chance. The array39–46 or proteomic47 studies, and included those genes that SB interactome has an average of 297 direct PPIs (91 expected by were highlighted as major study findings in the abstract or chance) between the gene products of Table 1, with an average of subsequent reviews and/or showed significant results in at least 4.5 PPIs per protein (2.3 expected by chance), both being highly two of the mRNA expression studies. Finally, we also included all significant (Po0.0001). Furthermore, the indirect connectivity was the genes in four previous genome-wide association study on SB highly significant as well. The observed high connectivity of the SB suggested by the authors to be of interest for follow-up,48–51 even interactome suggests that many of the proteins in Table 1 though few were genome-wide significant. During this literature cooperate in a common pathological process.61 We next zoomed research and gene (product) selection process, we also concur- in on the center of this SB interactome, that is, the most rently estimated an overall evidence base across the different connected, inner parts of the PPI network, containing 76 proteins studies found and graded it, respectively, as shown and described from Table 1 suggested by DAPPLE to be prioritized. This ‘core’ SB in Table 1. interactome (Figure 2, bottom left) showed 225 direct PPIs (38 Among the 212 gene (products), ~ 80 were originally implicated expected by chance), with an average of 5.9 PPIs per protein (2.1 in SB by hypothesis-free screens (genome-wide association study, expected by chance), as well as significant indirect connectivity. In mRNA expression arrays or proteomic), whereas the others were comparison, the genes not being part of the core SB interactome tested by using hypothesis-driven studies. But all 212 gene (that is, the ‘peripheral’ SB interactome; Figure 2, bottom right) (products) are here now referred to as ‘candidate genes’. The SB showed less PPI connectivity, with 23 direct PPIs (11 expected by candidate genes (Table 1) are evenly dispersed across the genome chance), an average of 1.3 PPIs per protein (1.2 expected by (Figure 1a), have a median size of 35 kb (interquartile range chance) and no significant indirect connectivity. 8.4–140) and a range from 1 (OXT) to 2000 kb (MACROD2). We can Thus, a subset of proteins encoded by the SB candidate genes see how increasing amounts of genes have been implicated as SB form a core SB interactome (Figure 3), which may motivate their candidates by each year, accelerating notably during last decade co-investigation in future studies. A majority of these genes have (see Figure 1b). Half of the genes have been implicated as of year been shown to be either up- or downregulated in, for example, 2010 onward, and 75% of them in the last decade since the year the prefrontal cortex of suicides (depicted by node colors, 2004. It seems we are thus indeed ‘Broadening our horizons’32 Figure 3). Interestingly, the ‘core SB interactome’ contains genes concerning the neurobiology of SB and we next continued by from different neurosystems, suggesting a merit of adopting an using bioinformatics tools to explore any general patterns that intersystem study approach. This would be in line with the refined might emerge. stress-vulnerability model for SB24–27 as well as our generally evolving understanding of crosstalk between neurosystems in relation to, for example, stress, for both prefrontal and limbic AN SB INTERACTOME AS VIEWED THROUGH PPIS regions.63–65 There are both old classics as well as new players in The focus in other reviews on this topic was usually on a subset of the core SB interactome; 75% of the genes were first ever molecular components in a subset of neurosystems. Integrative implicated in SB during the last 10 years and 50% of them during approaches recently used in SB research are combined pathway/ the last 4 years (depicted by node border thickness, Figure 3). In functional networks39 as well as convergent functional geno- all, PPIs suggest that many of SB candidate genes can be unified mics,46 with similar systems biology approaches being applied on a common biological framework.

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 56 – 71 The neurosystem of suicidal behaviors M Sokolowski et al 58

Table 1. 212 Selected gene (products) implicated in SB with varying levels of evidence

Gene symbol Protein name Genetic Functional Cumulative associationa evidence

Candidate GWAS mRNAb Proteinc Range of Repeated alterations independent implicatedd observationse

ABCB1 ATP-binding cassette, subfamily B (MDR/TAP), member 1 i79 CNA ABCG1 ATP-binding cassette, subfamily G (WHITE), member 1 ii, n80,81 CC ABI3BP ABI family, member 3 (NESH) binding protein i,n48 CNA ACE Angiotensin I-converting enzyme ii82–84 CC ACP1 Acid phosphatase 1, soluble i50 CNA ACTB Actin, beta i47,f CNA ACTN2 Actinin, alpha 2 i85 CNA ADH1B Alcohol dehydrogenase 1B (class I), beta polypeptide i86 CNA ADRA2A Adrenoceptor alpha 2A ii, n87–89 ii90,40 ii90–92 AB ADRA2B Adrenoceptor alpha 2B i93 i92 BNA ADRB2 Adrenoceptor beta 2, surface i94 CNA ADRBK1 Adrenergic, beta, receptor kinase 1 i91 CNA ADRBK2 Adrenergic, beta, receptor kinase 2 i91 CNA AGO1 Argonaute RISC catalytic component 1 i95 CNA AKT1 v-akt murine thymoma viral oncogene homolog 1 i96 i97 BNA ALDH2 Aldehyde dehydrogenase 2 family (mitochondrial) i86 i42 BNA ANK3 Ankyrin 3, node of Ranvier (ankyrin G) n98 NA NA APOB Apolipoprotein B i99 CNA APOE Apolipoprotein E i100 i41 BNA ASIC2 Acid-sensing (proton-gated) ion channel 2 i, n51 CNA AUTS2 Autism susceptibility candidate 2 i101 CNA AVP Arginine vasopressin i102,103 CC38 AVPR1B Arginine vasopressin receptor 1B i104 CNA B3GALT5 UDP-Gal:betaGlcNAc beta 1,3-galactosyltransferase, i, n48 CNA polypeptide 5 BDNF Brain-derived neurotrophic factor iii, n105,106 iii107 iii107 AA108,109 CACNA1C Calcium channel, voltage-dependent, L-type, n98 NA NA alpha 1C subunit CBR1 Carbonyl reductase 1 i47,f CNA CCK Cholecystokinin i, n49,110 i111 i112 AB38 CCKBR Cholecystokinin B receptor ii110,113 i114 ii115 AB38 CD300LB CD300 molecule-like family member b i, n51 i51,g BNA CD44 CD44 molecule (Indian blood group) i, n51 i51,g BNA CDCA7L Cell division cycle associated 7-like i42,g CNA CDH10 Cadherin 10, type 2 (T2-cadherin) i116 CNA CDH12 Cadherin 12, type 2 (N-cadherin 2) i42,g CNA CDH13 Cadherin 13 i, n51 CNA CDH9 Cadherin 9, type 2 (T1-cadherin) i116 CNA CKB Creatine kinase, brain i43,g i47,f BB CNR1 Cannabinoid receptor 1 (brain) ii117,118 CC119 COL14A1 Collagen, type XIV, alpha 1 i, n51 CNA COMT Catechol-O-methyltransferase iii, n120,121 ii122,123 BC124–126 CREB1 cAMP responsive element-binding protein 1 ii127 ii127,128 BB CRH Corticotropin-releasing hormone i41 ii, n129 BB38 CRHBP Corticotropin-releasing hormone-binding protein ii130,131 n132 CC CRHR1 Corticotropin-releasing hormone receptor 1 ii, n133,134 ii, n132,135 i136 AB137 CRHR2 Corticotropin-releasing hormone receptor 2 ii, n138 ii, n132,135 i136 AB137 CRP C-reactive protein, pentraxin related i139 CNA CTSD Cathepsin D i47,f CNA CYP19A1 Cytochrome P450, family 19, subfamily A, polypeptide 1 i, n51 i51,g BNA CYP2D6 Cytochrome P450, family 2, subfamily D, polypeptide 6 ii, n140–142 CC DBH Dopamine beta-hydroxylase (dopamine n143 NA NA beta-monooxygenase) DBI Diazepam-binding inhibitor (GABA receptor i143,144 i145 BNA modulator, acyl-CoA-binding protein) 146 147 DDC Dopa decarboxylase (aromatic L-amino acid decarboxylase) i i BNA DGCR8 DGCR8 microprocessor complex subunit i95 CNA DHCR7 7-Dehydrocholesterol reductase n148 i149 CNA DISC1 Disrupted in schizophrenia 1 i150 i, n51 i46 BNA DLK1 Delta-like 1 homolog (Drosophila)i151 CNA DLK2 Delta-like 2 homolog (Drosophila)n151 NA NA DLL1 Delta-like 1 (Drosophila)i151 CNA DLL4 Delta-like 4 (Drosophila)i151 CNA DNMT3B DNA (cytosine-5-)-methyltransferase 3 beta i152 i153 i152 AB DPYSL2 Dihydropyrimidinase-like 2 i47,f CNA DRD2 Dopamine receptor D2 ii154,155 i156 BC DSC2 Desmocollin 2 i, n51 i51,g BNA EFEMP1 EGF-containing fibulin-like extracellular matrix protein 1 i42,g CNA EFHD2 EF-hand domain family, member D2 i47,f CNA ESR1 ER1 ii, n157,158 i159 CNA ESR2 ER2 (beta) i160 i159 CB EVC Ellis van Creveld syndrome i161 CNA FAAH Fatty acid amide hydrolase i162 i163 BNA

Molecular Psychiatry (2015), 56 – 71 © 2015 Macmillan Publishers Limited The neurosystem of suicidal behaviors M Sokolowski et al 59

Table. 1. (Continued )

Gene symbol Protein name Genetic Functional Cumulative associationa evidence

Candidate GWAS mRNAb Proteinc Range of Repeated alterations independent implicatedd observationse

FADS1 Fatty acid desaturase 1 i164,g CNA FKBP4 FK506-binding protein 4, 59 kDa i47,f CNA FKBP5 FK506-binding protein 5 iii165,166 i167 i167 AB FOXD4 Forkhead box D4 i168 CNA FOXN3 Forkhead box N3 i, n51 ii39,46,51,g BC GABRA1 GABA A receptor, alpha 1 n169 iii45,132,153,170 iii171,172 BB32,173 GABRA2 GABA A receptor, alpha 2 n169 i170 iii171,172 BB32,173 GABRG1 GABA A receptor, gamma 1 n169 ii40,45,170,g iii171,172 BB32,173 GABRG2 GABA A receptor, gamma 2 n169 ii40,45,170,g iii171,172 BB32,173 GABRG3 GABA A receptor, gamma 3 i144 i170 iii171,172 BB32,173 GABRP GABA A receptor, pi i85 iii171,172 C32,173 GFAP Glial fibrillary acidic protein i47,f CNA GFRA1 GDNF family receptor alpha 1 i, n49 CNA GLUL Glutamate-ammonia ligase n169 ii39–41,45,g i47,f BB32 GNAI1 Guanine nucleotide-binding protein (G protein), i91 CNA alpha inhibiting activity polypeptide 1 GNAI2 G protein, alpha inhibiting activity polypeptide 2 i91 CNA GRIA1 Glutamate receptor, ionotropic, AMPA 1 n169 i45,g CNA GRIA3 Glutamate receptor, ionotropic, AMPA 3 i, n169,174 ii40,45,g BC GRIK2 Glutamate receptor, ionotropic, kainate 2 n169 i175 CNA 40,45,g GRIN2A Glutamate receptor, ionotropic, N-methyl D-aspartate 2A ii CC 169 GRIN2B Glutamate receptor, ionotropic, N-methyl D-aspartate 2B i CNA GSK3B Glycogen synthase kinase 3 beta i, n176,177 i178 i97 AB HES1 Hes family bHLH transcription factor 1 i151 CNA HOMER1 Homer homolog 1 (Drosophila)i179 CNA HSPA8 Heat–shock 70 kDa protein 8 i47,f CNA HTR1A 5-Hydroxytryptamine (serotonin) receptor 1A, iii, n180,181 i90 iii, n182 AB35,137,183 G protein coupled HTR1B Serotonin receptor 1B, G protein coupled ii, n184–187 ii188,189 AC35,137,190 HTR1E Serotonin receptor 1E, G protein coupled i, n85,187 n191 BC35,137 HTR2A Serotonin receptor 2A, G protein coupled iii, n192 ii193,194 iii, n94,194 BB35,137,190 HTR2B Serotonin receptor 2B, G protein coupled i195 CNA HTR2C Serotonin receptor 2C, G protein coupled i, n187,196 i197 BC35,137 HTR4 Serotonin receptor 4, G protein coupled n198 NA NA HTR6 Serotonin receptor 6, G protein coupled i, n187,199 CC IFNG Interferon, gamma i200 ii, n37 BC37 IL10 Interleukin 10 i200 n37 CNA37 IL2 Interleukin 2 ii, n37 CC IL6 Interleukin 6 (interferon, beta 2) i201 ii, n37 BB37 IL8 Interleukin 8 ii, n37 CC37 IMPA2 Inositol(myo)-1(or 4)-monophosphatase 2 i176 CNA INA Internexin neuronal intermediate filament protein, alpha i47,f CNA INPP1 Inositol polyphosphate-1-phosphatase i176 CNA JAG1 Jagged 1 i151 CNA JAG2 Jagged 2 i151 CNA KBTBD2 Kelch repeat and BTB (POZ)-domain containing 2 i, n51 i51,g BNA KIAA1244 KIAA1244 i, n49 CNA KIAA1549L KIAA1549 like i, n50 CNA LEPR Leptin receptor ii39,40,44,164,g CC LIPA Lipase A, lysosomal acid, cholesterol esterase ii46,202 CC LRRTM4 Leucine-rich repeat transmembrane neuronal 4 i, n50 CNA LSAMP Limbic system-associated membrane protein i203 i, n51 CNA MACROD2 MACRO domain containing 2 i, n204 CNA MAOA Monoamine oxidase A ii, n205,206 ii, n207,208 BC35,137,206 MAOB Monoamine oxidase B i209 ii, n207,208 BC35,137 MAP3K3 Mitogen-activated protein kinase kinase kinase 3 i46 CNA MARCKS Myristoylated alanine-rich protein kinase C substrate i46 i210 BB MBNL2 Muscleblind-like splicing regulator 2 i, n51 i51,g BNA MLC1 Megalencephalic leukoencephalopathy with i42,g CNA subcortical cysts 1 MTHFR Methylenetetrahydrofolate reductase (NAD(P)H) n211 NA NA MYO3A Myosin IIIA i, n51 CNA NCAM1 Neural cell adhesion molecule 1 i, n212,213 i214 BNA NEFL Neurofilament, light polypeptide i47,f CNA NEFM Neurofilament, medium polypeptide i47,f CNA NGF Nerve growth factor (beta polypeptide) ii215,216 ii215,216 BB NGFR Nerve growth factor receptor i, n48,217 i215 i215 AB NOS1 Nitric oxide synthase 1 (neuronal) ii, n212,218,219 CC NOTCH1 Notch 1 ii151,164 CC NOTCH2 Notch 2 i41,151 CC NOTCH3 Notch 3 i151 CNA NOTCH4 Notch 4 i151 CNA NPR351 Natriuretic peptide receptor C/guanylate cyclase C i, n51 CNA (atrionatriuretic peptide receptor C)

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 56 – 71 The neurosystem of suicidal behaviors M Sokolowski et al 60

Table. 1. (Continued )

Gene symbol Protein name Genetic Functional Cumulative associationa evidence

Candidate GWAS mRNAb Proteinc Range of Repeated alterations independent implicatedd observationse

NPTX2 Neuronal pentraxin II i179 i45,g BNA NPY Neuropeptide Y n220 i41,45 ii, n221,222 CC38 NPY2R Neuropeptide Y receptor Y2 i 223 CNA NR3C1 Nuclear receptor subfamily 3, group C, member 1 ii224–226 iii, n226–229 BB (glucocorticoid receptor) NTF3 Neurotrophin 3 i215 i215 BB NTF4 Neurotrophin 4 i215 i215 BB NTRK2 Neurotrophic tyrosine kinase, receptor, type 2 ii230 ii41,45,107 ii107 AB108 ODC1 Ornithine decarboxylase 1 i169 ii43,231,232 BC233 OPRM1 Opioid receptor, mu 1 i, n234,235 i90 i236 AB OXT Oxytocin/neurophysin I prepropeptide i, n237,238 CNA PAH Phenylalanine hydroxylase i144 CNA PCDHB5 Protocadherin beta 5 i42,g CNA PGAM1 Phosphoglycerate mutase 1 (brain) i47,f CNA PIK3C2A Phosphatidylinositol-4-phosphate 3-kinase, catalytic i164 i239 BB subunit type 2 alpha PLCB1 Phospholipase C, beta 1 (phosphoinositide specific) i240 CNA POMC Proopiomelanocortin i224 CNA PPP1R1B Protein phosphatase 1, regulatory (inhibitor) i241 CNA subunit 1B (DARPP-32) PRDX6 Peroxiredoxin 6 i47,f CNA PRKACA Protein kinase, cAMP-dependent, catalytic, alpha ii242,243 ii242,243 BB PRKCA Protein kinase C, alpha i244 ii244,245 PRKCB Protein kinase C, beta i244 ii244,245 BB PRKCE protein kinase C, epsilon i, n48 i245 BNA PRKCG Protein kinase C, gamma i244 ii244,245 BB PTEN Phosphatase and tensin homolog ii46,97 i97 BB PTPRR Protein tyrosine phosphatase, receptor type, R i42,g CNA QKI QKI, KH domain containing, RNA binding i246,g CNA RGS18 Regulator of G-protein signaling 18 i, n49 CNA RGS2 Regulator of G-protein signaling 2, 24 kDa i247 CNA RGS4 Regulator of G-protein signaling 4 i248 CNA S100A13 S100 calcium-binding protein A13 i42,46,189,g CNA S100A8 S100 calcium-binding protein A8 i42,46,189 CNA SAT1 Spermidine/spermine N1-acetyltransferase 1 ii169,249,250 iii40,43,44,46,250, i231 AB233 251,g SAT2 Spermidine/spermine N1-acetyltransferase family member 2 n169 i44 i231 BB SCD Stearoyl-CoA desaturase (delta-9-desaturase) i164 CNA SCN2B Sodium channel, voltage-gated, type II, beta subunit i42,g CNA SCN8A Sodium channel, voltage-gated, type VIII, alpha subunit i252 CNA253 SELENBP1 Selenium-binding protein 1 i47,f CNA SLC1A2 Solute carrier family 1 (glial high-affinity glutamate i186 ii40,45,g BC32,173 transporter), member 2 SLC6A1 Solute carrier family 6 (GABA transporter), member 1 ii40,45,g n254 CC32,173 SLC6A3 Solute carrier family 6 (dopamine transporter), member 3 n186 i, n255,256 CNA SLC6A4 Solute carrier family 6 (neurotransmitter transporter), iii, n257,258 n259 iii, n182 BC35,137,190,260 member 4: 5-HTT SLIT2 Slit homolog 2 (Drosophila)i261 CNA SMOX Spermine oxidase n169,262 ii44,262,g i231 BB233 SMS Spermine synthase n169,262 ii44,262,g i231 BB233 SNTG2 Syntrophin, gamma 2 i, n204 CNA SORBS1 Sorbin and SH3 domain containing 1 i, n48 CNA SPTLC1 Serine palmitoyltransferase, long chain base subunit 1 i, n51 CNA SRSF11 Serine/arginine-rich splicing factor 11 i, n51 CNA SST Somatostatin ii, n221 CC38 TAC1 Tachykinin, precursor 1 (substance P) i263 CNA38 TACR1 Tachykinin receptor 1 i264 i, n265,266 BNA38 TBC1D1 TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1 n161 NA NA TBC1D25 TBC1 domain family, member 25 (OATL1) i249 i44 BNA233 TBX19 T-box 19 i267 CNA TGFB1 Transforming growth factor, beta 1 i268 n269 CNA37 TGOLN2 Trans-golgi network protein 2 i270 i250,g BNA TH Tyrosine hydroxylase i271 ii, n272–275 BC TMEM132C Transmembrane protein 132C i, n50 CNA TNF Tumor necrosis factor i200 ii, n201,276 ii, n37 AB37 TPH1 Tryptophan hydroxylase 1 iii, n277 i278 ii, n279,280 AB35,137,190,260 TPH2 Tryptophan hydroxylase 2 iii, n281,282 ii283 ii, n279,280 AB35,137 TUBA1A Tubulin, alpha 1a i47,f CNA TUBGCP3 Tubulin, gamma complex-associated protein 3 i, n51 CNA VAMP4 Vesicle-associated membrane protein 4 i252 CNA VEGFA Vascular endothelial growth factor A ii284,285 CC37 WFS1 Wolfram syndrome 1 (wolframin) ii, n161,286,287 CNA VGF Nerve growth factor inducible NA NA38,288

Molecular Psychiatry (2015), 56 – 71 © 2015 Macmillan Publishers Limited The neurosystem of suicidal behaviors M Sokolowski et al 61

Table. 1. (Continued )

Gene symbol Protein name Genetic Functional Cumulative associationa evidence

Candidate GWAS mRNAb Proteinc Range of Repeated alterations independent implicatedd observationse

VIM Vimentin i47,f CNA YWHAE Tyrosine 3-monooxygenase/tryptophan i289 i289 i289 AB 5-monooxygenase (YWHA) activation protein, epsilon YWHAH YWHA activation protein, eta i47,f CNA YWHAZ YWHA activation protein, zeta i40,g i47,f BB ZFP36 ZFP36 ring finger protein i42,g CNA ZNF804A Zinc-finger protein 804A i290 CNA291 Abbreviations: EF-hand, helix-loop-helix motif; EGF, epidermal growth factor; ER, estrogen receptor; GABA, gamma-aminobutyric acid; GWAS, genome-wide association study; RISC, RNA-induced silencing complex. Gene (products) implicated with SB with varying levels of cumulative evidence. Each gene (product) investigated in relation to SB outcomes is grouped into three study categories 1–3. References refer to first studies positively or negatively (‘n’) associating this gene (product) with SB, or a recent meta-analysis/review for that category. i, 1 study with positive result. ii, 2–4 studies with positive result. iii, 5 or more studies with positive result. ‘n’ highlights that either hypothesis-driven replication attempts or original studies reported negative results, that we noted inconsistencies that may need consideration or that the implication in SB was by mainly nonsignificant trends (nominal significances). NA, did not fulfill the grade of at least ‘C’. a‘Genetic association’ for testing single nucleotide polymorphism by any method (including gene-environment interactions) in either candidate gene or genome-wide (GWAS) context. b‘mRNA’ gene expression levels, usually by post-mortem studies of brain tissues from completed suicides. cThe activity/levels/ ligand binding or other functional alterations of the gene product, that is, ‘Protein’ per se, in some cases also by known metabolites, ligands and other functional processes relating directly to the protein activity. d‘Range of alterations implicated’ was graded by C, B or A, corresponding to if one, two or three of the study categories 1–3 have implicated the gene (product) in relation to SB, respectively. e‘Repeated independent observations’ grades the amount reproducibility as follows: ‘A’, one of the study categories 1–3 shows significance in a current meta-analysis; ‘B’, 5 or more studies with positive result in category 1 but with no meta-analysis conducted yet, or that both categories 2 and 3 show positive results; ‘C’, at least two studies with positive results conducted in one of the categories 1–3. For grades B and C, negative replications and meta-analyses may also have been reported, so the results can be inconclusive or the current generalizability be uncertain from a quantitative standpoint. References refer to recent meta-analyses or systematic reviews. fGene originally identified by using large-scale, hypothesis-free proteomic screening of brain tissues of completed suicides. gGene originally identified by using large- scale, hypothesis-free mRNA expression array screening of brain tissues of completed suicides.

THE BIOLOGICAL FUNCTIONS OF THE SB INTERACTOME A slightly more detailed view on differences between the The genes in Table 1 clearly represent a very heterogeneous peripheral vs core SB interactome can be obtained through the assembly of functions. Using the gene ontology (GO)66 and help glasses of KEGG (Kyoto Encyclopedia of Genes and Genomes) 68 from the online tool ToppGene67 to explore functional enrich- pathways. A widespread feature of the core (24%) is the ments, we mainly find the general molecular functions of receptor neuroactive ligand–receptor interactions of many neurosystems: binding (for 31% of the genes), enzyme binding (21%) and serotonergic (HTR2A, HTR2B), adrenergic (ADRA2A, ADRB2), vaso- (transmembrane) signaling receptor activity (20%). The general pressergic (AVPR1B), cannabinoid (CNR1), hypothalamic–pituitary- biological processes of transmission of nerve impulse (42%), –adrenal axis (CRHR1), dopaminergic (DRD2), GABAergic (GABRA1, regulation of transport (35%) and response to endogenous GABRA2, GABRG1, GABRG2), glutamatergic (GRIA3, GRIA1, GRIN2A, stimulus (34%) are prevalent, and so are the major cellular GRIN2B, GRIK2) and opioid (OPRM1). The neuroactive ligand–- compartments are the neuron part/projection (35%) and plasma receptor interactions is also the major pathway among the membrane (25%). peripheral genes, containing a lower but still notable proportion More interesting is perhaps what sets the peripheral and core (11%) of receptors; serotonergic (HTR1A, HTR1B, HTR1E, HTR2C, SB interactome apart, that is, which functional features are found HTR4, HTR6), adrenergic (ADRA2B), cholecystokinin (CCKBR), predominant in one but not the other. General molecular GO hypothalamic–pituitary–adrenal axis (CRHR2, NR3C1), GABAergic functions in the core were enzyme binding (41% of input), (GABRG3, GABRP), leptin (LEPR), neuropeptide Y (NPY2R) and (transmembrane) signaling receptor activity (29%) and kinase substance P (TACR1). The apparent concentration of some but not binding (20%), whereas for peripheral genes it was protein other receptors to the center of the SB interactome is due to the homodimerization activity (13%) and hormone binding/activity stronger PPI coupling with certain intracellular processes impli- (5%). General biological GO functions in the core were neurogen- cated in SB, which sequestered into the core SB interactome. esis/generation of neurons (42%), regulation of cell death (39%) Prototypic components of G-coupled protein receptor signaling and neuron differentiation (37%), whereas for peripheral genes it are apparent in the core SB interactome (7%): G-protein alpha was related to lipids (response/metabolic process; 21%), growth (GNAI1, GNAI2) and regulators (RGS2, RGS4, RGS18). We further find (21%) and organic hydroxy compound metabolic process (19%). partially overlapping signal transduction pathways represented: General cellular GO components for the core were the cytoskeletal neurotropic (14%; BDNF, GSK3B, MAP3K3, NGF, NGFR, NTRK2, NTF3, part (33%), (membrane-bounded or cytoplasmic) vesicles (26– NTF4, YWHAE, YWHAH, YWHAZ), calcium (16%; HTR2A, HTR2B, 32%), cell junction (20%), synaptic membrane (17%), dentritic/ ADRB2, AVPR1B, GRIN2A, CACNA1C, NOS1, PLCB1, PRKCA, PRKCB, neuron spine (16%) and post-synaptic (13%). In contrast, for PRKCG, PRKACA) and Wnt (8%; GSK3B, PLCB1, PRKCA, PRKCB, PRKCG, peripheral genes only, the extracellular (region part/space; 24%) PRKACA), as well as Notch (11%; NOTCH1, NOTCH2, NOTCH3, was predominant. Together, this implies that there are both NOTCH4, DLL1, DLL4, JAG1, JAG2) interacting with Wnt through quantitative and qualitative divergences concerning all GO GSK3B. Stress-sensitive synaptic plasticity processes of importance domains between the peripheral vs core SB interactome, wherein for learning/memory, cognition and emotions63,65,69–71 are also the core appears more enriched and homogenized for certain clearly represented in the core SB interactome: LTP (long-term features of particular interest. potentiation, 12%; GRIA1, GRIN2A, GRIN2B, CACNA1C, PLCB1,

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 56 – 71 The neurosystem of suicidal behaviors M Sokolowski et al 62

Figure 1. (a) An ideogram showíng the locations of the SB candidate genes across the genome. The figure was generated by using the online tool Idiographica.292 (b) Graph showing the accumulation of SB candidate genes (from Table 1) by the year.

PRKCA, PRKCB, PRKCG, PRKACA) and long-term depression (LTD, MAOA, MAOB, TPH2) or drug (ADH1B, CYP2D6, MAOA, MAOB) 14%; CRH, CRHR1, GRIA3, GRIA1, GNAI1, GNAI2, NOS1, PLCB1, PRKCA, metabolism. A large subset of the genes important for the high PRKCB, PRKCG). Interestingly, none of these many signaling connectivity of the core SB interactome was just recently pathways or the LTP/LPD were representative for the peripheral implicated in SB by the only yet conducted proteomic post- SB interactome. Finally, three metabolic enzymes of serotonin (TH, mortem expression study (ACTB, DPYSL2, FKBP4, GFAP, GLUL, TPH1) and glutamate (GLUL) are seen in the core, but else HSPA8, INA, NEFL, NEFM, PGAM1, PRDX6, TUBA1A, VIM, YWHAH, metabolic processes constituted predominant features of the YWHAZ). Several are integral parts of the cytoskeleton (ACTB, peripheral SB interactome; for example, arginine and proline DPYSL2, GFAP, INA, NEFL, NEFM, TUBA1A, VIM) and also imply (ALDH2, CKB, MAOA, MAOB, ODC1, SAT1, SAT2, SMS), tyrosine developmental/plasticity processes: structural plasticity (ACTB), (ADH1B, COMT, DDC, DBH, MAOA, MAOB), tryptophan (ALDH2, DDC, neuron guidance (DPYSL2), astrocyte development marker (GFAP),

Molecular Psychiatry (2015), 56 – 71 © 2015 Macmillan Publishers Limited The neurosystem of suicidal behaviors M Sokolowski et al 63

Figure 2. The SB interactome (upper panel; direct and common indirect interactions involving 1793 proteins) can be divided into a highly connected core (lower left panel; all being connected by direct interactions among 76 proteins) and a loosely connected peripheral part (lower right panel; the much fewer direct interactions are shown among a total of 136 proteins). The networks were generated as outputs by the online tool DAPPLE using default settings.60

neuron morphogenesis (INA), neuronal caliber maintenance (NEFL, changes observed in suicides might therefore be interpreted as a NEFM) and neuronal migration (TUBA1A). Finally, we can also note general imbalance of multiple intracellular signaling pathways and that the most connected components of the core SB interactome LTP/LTD vs the neuroactive ligand–receptors. suggest them to have central importance in the core network, for example, buffering effects of perturbations from the periphery (ACTB, ACTN2, GNAI1, GNAI2, GRIK2, GRIN2A, GRIN2B, HSPA8, PRKCA, CONCLUDING SUMMARY PRKCB, PRKCG, PRKACA, PRKCE, PLCB1, TUBA1A, VIM, YWHAE and Here we have presented a representative and diversified overview YWHAZ; with each encoded protein having 10–22 direct connec- of the different neurobiological components hypothesized and/or tions with the other proteins in the core). shown implicated across the entire SB field up to date by any We can also take into account the information about up- vs approach (Table 1). It might be used as a starting point for, for downregulation observed in suicides among the genes in the core example, application of future polygenetic and/or bioinformatics SB interactome. For putative future SB interventions based on analyses, as was briefly explored here. Although the PPI network neurobiology, down-specific processes might be those that need approach has proven advantages, such as helping in the to be agonized, up-specific processes in need to be antagonized, abstraction of basic science knowledge or for identifying new, whereas common processes might need some more fine-tuned testable biological gene (product) groupings,57,72 it is also intra-modulation. Here we also took into account the changes in important to consider the limitations of PPI networks (Figures 2 the composition among the common interacting proteins, giving and 3). The ‘InWeb’ PPI database73 used by DAPPLE is focused on ~ 300 genes specific for the up- and down-networks, respectively. physical PPIs with good coverage and high confidence (with Main down-specific pathways were calcium-, notch- and Wnt- 169 810 non-self PPIs across 12 793 proteins), but lacks more signaling, as well as LTP/LTD. Up-specific changes involved mainly indirect functional couplings or recently identified PPIs. We neuroactive ligand–receptor interactions. This can basically be therefore also show the connectivity of the core SB interactome inferred also from studying Figure 3. Thus, the overall expression by using the more inclusive STRING74 protein–protein association

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 56 – 71 The neurosystem of suicidal behaviors M Sokolowski et al 64

Figure 3. A more detailed view of the core SB interactome (with only direct interactions) according to DAPPLE. Membrane-bound components are arranged toward the right side. The thickness of the node borders indicate how ‘old’ the candidate gene is, with greatest thickness for genes implicated during the last 4 years and thickness fading off gradually for additional years of history as a SB candidate gene. Node colors represent the reported up- (red), down- (blue) or altered (green) (co)expression of the mRNA and/or proteins in mainly the prefrontal cortex tissues (but in blood for MAP3K3, in locus coeruleus for TH and different regions for GABA receptors170).

data for comparisons (Supplementary Figure S1). There were, for But in line with the meta-system approach herein, the concepts example, qualitative differences in the couplings between nodes of intersystem effects have indeed been suggested for SB; for with the overall high connectivity of the core confirmed, example, in multiple chapters of a recent book on the current but with the differences in connectivity between the core vs topic.7 Therein is discussed, for example, the interplay between peripheral interactome not as pronounced as with DAPPLE CRH–GABA–serotonin, endocannabinoid–hypothalamic–pituitary–- (Supplementary Figure S1). Other aspects of importance are that adrenal–monoamines, effects of epigenetics across neurosystems the PPI data are ‘global’ (that is not cell-type specific) and that the and the potential of using biomarkers from different neuro- more detailed dynamics of local gene expression and homeostatic systems.7 The stress-vulnerability model also naturally invites to a responses are only indirectly and partially captured; the network more systemic thinking, as the role of, for example, stress-interface depicted in, for example, Figure 3 represents an incomplete mix of genes such as CRHR1 spread out across multiple brain regions.64 such spatiotemporal aspects. Finally, although epistasis on the Here we took an even wider approach and incorporated the level of PPIs is more likely among the connected components75,76 majority of implicated SB players across all different neurosystems such as in Figure 3 and should be investigated in the future, it and brain sites into one simultaneous cross-sectional view, would also miss epistasis on other indirect functional couplings organized by robust PPI knowledge. We find that a core SB apparent, for example, in the periphery according to STRING interactome is formed involving ~ 30% of implicated SB players (Supplementary Figure S1). Together, PPI networks are to be being enriched for certain distinct functions, pinpointing the role regarded as a distorted view of the reality, which is subject to of several signal transduction pathways (neurotropic, calcium, Wnt change,77 used here primarily as an abstraction to make clearer and Notch), a subset of receptors from multiple neurosystems and the proposition of thinking about SB neurobiology from a poly- certain actin-interacting proteins. With support in mouse pheno- genetic meta-system perspective. It must also not be interpreted types (not shown), we also find that development/morphology as a call against neurosystem-focused studies, as they underlie and the stress-sensitive synaptic plasticity processes of LTP/LTD most of the data compiled here (Table 1) and will always remain appear to have a specific role therein. The core was also mainly important for generating high-quality results and more detailed related to nerve cell compartments, in contrast to many mechanistic understandings. extracellular components in the peripheral SB interactome.

Molecular Psychiatry (2015), 56 – 71 © 2015 Macmillan Publishers Limited The neurosystem of suicidal behaviors M Sokolowski et al 65 Approximate meta-networks like this might be used as testable 11 Asberg M, Traskman L, Thoren P. 5-HIAA in the cerebrospinal fluid. A bio- models of our systemic understanding in future studies, simulta- chemical suicide predictor? Arch Gen Psychiatry 1976; 33:1193–1197. neously traversing the many neurosystems and levels of functions 12 Goldston DB, Daniel S, Reboussin DM, Kelley A, Ievers C, Brunstetter R. First-time implicated in SB neurobiology; it may also help us to face the suicide attempters, repeat attempters, and previous attempters on an adoles- 35 troubling complexities of biological pleiotrophy, epistasis, redun- cent inpatient psychiatry unit. J Am Acad Child Adolesc Psychiatry 1996; : 631–639. dancies and overlaps. For example, the peripheral components may ‘ fi ’ 13 Nock MK, Hwang I, Sampson N, Kessler RC, Angermeyer M, Beautrais A et al. contain less promiscuous disease speci ers that act crucially on the Cross-national analysis of the associations among mental disorders and suicidal core as a whole through the propagating (epistatic) effects within. behavior: findings from the WHO World Mental Health Surveys. PLoS Med 2009; The central players in the highly connected core may then instead 6: e1000123. be regarded as ‘disease modifiers’, creating the functional 14 Mann JJ, Arango VA, Avenevoli S, Brent DA, Champagne FA, Clayton P et al. redundancies needed for, for example, buffering out the effects Candidate endophenotypes for genetic studies of suicidal behavior. Biol Psy- of pathological interferences by the periphery. Testing for either chiatry 2009; 65:556–563. specific changes or perhaps overall imbalances between the core 15 Brent D. What family studies teach us about suicidal behavior: implications for 25 – and the periphery may be a fruitful way forward. On the other research, treatment, and prevention. Eur Psychiatry 2010; : 260 263. 16 Courtet P, Gottesman II, Jollant F, Gould TD. The neuroscience of suicidal hand, excess pathologies in the core could also bring about behaviors: what can we expect from endophenotype strategies? Transl Psy- vulnerability toward a normal range of perturbations by the chiatry 2011; 1: e7. periphery. The polygenetic framework discussed here thus do not 17 Schumann G, Binder EB, Holte A, de Kloet ER, Oedegaard KJ, Robbins TW et al. rule out the action of strong single-gene mediators, for example, Stratified medicine for mental disorders. Eur Neuropsychopharmacol 2014; 24: as recently shown for calcium/calmodulin-dependent protein 5–50. kinase type II (CAMK2B) and core depressive symptoms of animal 18 Richard-Devantoy S, Berlim MT, Jollant F. A meta-analysis of neuropsychological models.78 CAMK2B encodes a protein with high PPI connectivity, markers of vulnerability to suicidal behavior in mood disorders. Psychol Med – which is interestingly also one of the common interacting partners 2013; 1 11. 19 Keilp JG, Gorlyn M, Russell M, Oquendo MA, Burke AK, Harkavy-Friedman J et al. of the core SB interactome (interacting directly with GRIN2A, Neuropsychological function and suicidal behavior: attention control, memory GRIN2B, CACNA1C and PLCB1). Although it can be expected that and executive dysfunction in suicide attempt. Psychol Med 2013; 43:539–551. big challenges remain in an endeavor such as finding and defining 20 Bunney WE Jr, Fawcett JA. Possibility of a biochemical test for suicidal potential: links between genes, biology and SB, we feel optimistic about the an analysis of endocrine findings prior to three suicides. Arch Gen Psychiatry future being able to define a critical mass of inter-system 1965; 13:232–239. components and alterations, which could be used (by assaying 21 Brezo J, Klempan T, Turecki G. The genetics of suicide: a critical review of their genes and concordant biomarkers) to more reliably capture molecular studies. Psychiatr Clin North Am 2008; 31: 179–203. the risk of SB in prevention, intervention and clinical applications. 22 Bogdan R, Hyde LW, Hariri AR. A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology. Mol Psychiatry 2013; 18:288–299. CONFLICT OF INTEREST 23 Mann JJ, Arango V. Integration of neurobiology and psychopathology in a uni- fied model of suicidal behavior. J Clin Psychopharmacol 1992; 12(Suppl 2): 2S–7S. fl The authors declare no con ict of interest. 24 Carballo JJ, Akamnonu CP, Oquendo MA. Neurobiology of suicidal behavior. An integration of biological and clinical findings. Arch Suicide Res 2008; 12:93–110. ACKNOWLEDGMENTS 25 Turecki G, Ernst C, Jollant F, Labonte B, Mechawar N. The neurodevelopmental origins of suicidal behavior. Trends Neurosci 2012; 35:14–23. The study was funded by the Marianne and Marcus Wallenberg Foundation, the 26 Wasserman D, Wasserman J, Sokolowski M. Genetics of HPA-axis, depression and American Foundation for Suicide Prevention, and Knut and Alice Wallenberg suicidality. Eur Psychiatry 2010; 25:278–280. Foundation. 27 Mann JJ, Currier DM. Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression. Eur Psychiatry 2010; 25:268–271. 28 Brent DA, Melhem N. Familial transmission of suicidal behavior. Psychiat Clin REFERENCES North Am 2008; 31:157–177. 1 Isometsa ET, Lonnqvist JK. Suicide attempts preceding completed suicide. Br J 29 Voracek M, Loibl LM. Genetics of suicide: a systematic review of twin studies. 119 – Psychiatry 1998; 173: 531–535. Wien Klin Wochenschr 2007; :463 475. 2 Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 30 Vineis P, Pearce NE. Genome-wide association studies may be misinterpreted: Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the genes versus heritability. Carcinogenesis 2011; 32: 1295–1298. FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 2007; 31 Kendler KS. Decision making in the pathway from genes to psychiatric and 164: 1035–1043. substance use disorders. Mol Psychiatry 2013; 18: 640–645. 3 Wasserman D, Rihmer Z, Rujescu D, Sarchiapone M, Sokolowski M, Titelman D 32 Fiori LM, Turecki G. Broadening our horizons: gene expression profiling to help et al. The European Psychiatric Association (EPA) guidance on suicide treatment better understand the neurobiology of suicide and depression. Neurobiol Dis and prevention. Eur Psychiatry 2012; 27:129–141. 2012; 45:14–22. 4 Carli V, Mandelli L, Zaninotto L, Iosue M, Hadlaczky G, Wasserman D et al. Serious 33 Rujescu D, Giegling I. The genetics of neurosystems in mental ill-health and suicidal behaviors: socio-demographic and clinical features in a multinational, suicidality: beyond serotonin. Eur Psychiatry 2010; 25:272–274. multicenter sample. Nord J Psychiatry 2014; 68:44–52. 34 Wasserman D, Sokolowski M, Wasserman J, Rujescu D. Neurobiology and 5 Mann JJ. A current perspective of suicide and attempted suicide. Ann Intern Med genetics of suicide. In: Wasserman D, Wasserman C (eds), Oxford Textbook of 2002; 136:302–311. Suicidology – The Five Continents Perspective. Oxford University Press: Oxford, UK, 6 Baca-Garcia E, Perez-Rodriguez MM, Oquendo MA, Keyes KM, Hasin DS, Grant BF 2009, pp 165–182. et al. Estimating risk for suicide attempt: are we asking the right questions? 35 Antypa N, Serretti A, Rujescu D. Serotonergic genes and suicide: a Passive suicidal ideation as a marker for suicidal behavior. J Affect Disord 2011; systematic review. Eur Neuropsychopharmacol 2013; 23: 1125–1142. 134: 327–332. 36 Mann JJ. The serotonergic system in mood disorders and suicidal behaviour. 7 Dwivedi Y (ed) The Neurobiological Basis of Suicide. CRC Press: Boca Raton, FL, Philos Trans R Soc Lond B Biol Sci 2013; 368: 20120537. USA, 2012. 37 Serafini G, Pompili M, Elena Seretti M, Stefani H, Palermo M, Coryell W et al. The 8 Wasserman D, Wasserman C (eds) Oxford Textbook of Suicidology – The Five role of inflammatory cytokines in suicidal behavior: a systematic review. Eur Continents Perspective. Oxford University Press: Oxford, UK, 2009. Neuropsychopharmacol 2013; 23: 1672–1686. 9 Robins E, Murphy GE, Wilkinson RH Jr, Gassner S, Kayes J. Some clinical con- 38 Serafini G, Pompili M, Lindqvist D, Dwivedi Y, Girardi P. The role of neuropeptides siderations in the prevention of suicide based on a study of 134 successful in suicidal behavior: a systematic review. Biomed Res Int 2013; 2013: 687575. suicides. Am J Public Health Nations Health 1959; 49:888–899. 39 Zhurov V, Stead JD, Merali Z, Palkovits M, Faludi G, Schild-Poulter C et al. 10 Harris EC, Barraclough B. Suicide as an outcome for mental disorders. Molecular pathway reconstruction and analysis of disturbed gene expression in A meta-analysis. Br J Psychiatry 1997; 170:205–228. depressed individuals who died by suicide. PLoS One 2012; 7: e47581.

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 56 – 71 The neurosystem of suicidal behaviors M Sokolowski et al 66 40 Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, ffrench-Mullen J et al. 66 Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. Gene Altered expression of genes involved in ATP biosynthesis and GABAergic neuro- ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat transmission in the ventral prefrontal cortex of suicides with and without major Genet 2000; 25:25–29. depression. Mol Psychiatry 2009; 14:175–189. 67 Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrich- 41 Kim S, Choi KH, Baykiz AF, Gershenfeld HK. Suicide candidate genes associated ment analysis and candidate gene prioritization. Nucleic Acids Res 2009; 37, Web with bipolar disorder and schizophrenia: an exploratory gene expression pro- Server issue W305–W311. filing analysis of post-mortem prefrontal cortex. BMC Genomics 2007; 8: 413. 68 Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M. Data, 42 Thalmeier A, Dickmann M, Giegling I, Schneider B, M Hartmann A, Maurer K et al. information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Gene expression profiling of post-mortem orbitofrontal cortex in violent suicide Res 2014; 42: D199–D205. victims. Int J Neuropsychopharmacol 2008; 11:217–228. 69 Levy BH, Tasker JG. Synaptic regulation of the hypothalamic-pituitary-adrenal 43 Fiori LM, Bureau A, Labbe A, Croteau J, Noel S, Merette C et al. Global gene axis and its modulation by glucocorticoids and stress. Front Cell Neurosci 2012; expression profiling of the polyamine system in suicide completers. Int J Neu- 6:24. ropsychopharmacol 2011; 14:595–605. 70 Maras PM, Baram TZ. Sculpting the hippocampus from within: stress, spines, 44 Sequeira A, Klempan T, Canetti L, ffrench-Mullen J, Benkelfat C, Rouleau GA et al. and CRH. Trends Neurosci 2012; 35: 315–324. Patterns of gene expression in the limbic system of suicides with and without 71 Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat major depression. Mol Psychiatry 2007; 12: 640–655. Rev Neurosci 2009; 10:423–433. 45 Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V et al. Global 72 Lage K. Protein-protein interactions and genetic diseases: the interactome. Bio- brain gene expression analysis links glutamatergic and GABAergic alterations to chim Biophys Acta 2014; S0925-4439: 00156–2. suicide and major depression. PLoS One 2009; 4: e6585. 73 Lage K, Hansen NT, Karlberg EO, Eklund AC, Roque FS, Donahoe PK et al. A large- 46 Le-Niculescu H, Levey DF, Ayalew M, Palmer L, Gavrin LM, Jain N et al. Discovery scale analysis of tissue-specific pathology and gene expression of human disease and validation of blood biomarkers for suicidality. Mol Psychiatry 2013; 18: genes and complexes. Proc Natl Acad Sci USA 2008; 105: 20870–20875. 1249–1264. 74 Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A et al. 47 Kekesi KA, Juhasz G, Simor A, Gulyassy P, Szego EM, Hunyadi-Gulyas E et al. STRING v9.1: protein-protein interaction networks, with increased coverage and Altered functional protein networks in the prefrontal cortex and amygdala of integration. Nucleic Acids Res 2013; 41, Database issue D808–D815. victims of suicide. PLoS One 2012; 7: e50532. 75 Lehner B. Molecular mechanisms of epistasis within and between genes. Trends 48 Perlis RH, Huang J, Purcell S, Fava M, Rush AJ, Sullivan PF et al. Genome-wide Genet 2011; 27: 323–331. association study of suicide attempts in mood disorder patients. Am J Psychiatry 76 Pattin KA, Moore JH. Exploiting the proteome to improve the genome-wide 2010; 167: 1499–1507. genetic analysis of epistasis in common human diseases. Hum Genet 2008; 124: 49 Schosser A, Butler AW, Ising M, Perroud N, Uher R, Ng MY et al. Genomewide 19–29. association scan of suicidal thoughts and behaviour in major depression. PLoS 77 Kim YA, Przytycka TM. Bridging the gap between genotype and phenotype via One 2011; 6: e20690. network approaches. Front Genet 2012; 3: 227. 50 Willour VL, Seifuddin F, Mahon PB, Jancic D, Pirooznia M, Steele J et al. 78 Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F et al. betaCaMKII in lateral habenula A genome-wide association study of attempted suicide. Mol Psychiatry 2012; 17: mediates core symptoms of depression. Science 2013; 341: 1016–1020. 433–444. 79 Boiso Moreno S, Zackrisson AL, Jakobsen Falk I, Karlsson L, Carlsson B, Tillmar A 51 Galfalvy H, Zalsman G, Huang YY, Murphy L, Rosoklija G, Dwork AJ et al. A pilot et al. ABCB1 gene polymorphisms are associated with suicide in forensic genome wide association and gene expression array study of suicide with and autopsies. Pharmacogenet Genomics 2013; 23: 463–469. without major depression. World J Biol Psychiatry 2013; 14: 574–582. 80 Gietl A, Giegling I, Hartmann AM, Schneider B, Schnabel A, Maurer K et al. ABCG1 52 Cristino AS, Williams SM, Hawi Z, An JY, Bellgrove MA, Schwartz CE et al. gene variants in suicidal behavior and aggression-related traits. Eur Neu- Neurodevelopmental and neuropsychiatric disorders represent an inter- ropsychopharmacol 2007; 17:410–416. connected molecular system. Mol Psychiatry 2014; 19:294–301. 81 Rujescu D, Giegling I, Dahmen N, Szegedi A, Anghelescu I, Gietl A et al. Asso- 53 Deo AJ, Huang YY, Hodgkinson CA, Xin Y, Oquendo MA, Dwork AJ et al. A large- ciation study of suicidal behavior and affective disorders with a genetic poly- scale candidate gene analysis of mood disorders: evidence of neurotrophic morphism in ABCG1, a positional candidate on chromosome 21q22.3. tyrosine kinase receptor and opioid receptor signaling dysfunction. Psychiatr Neuropsychobiology 2000; 42(Suppl 1): 22–25. Genet 2013; 23:47–55. 82 Fudalej S, Fudalej M, Kostrzewa G, Kuzniar P, Franaszczyk M, Wojnar M et al. 54 Jia P, Kao CF, Kuo PH, Zhao Z. A comprehensive network and pathway analysis of Angiotensin-converting enzyme polymorphism and completed suicide: an candidate genes in major depressive disorder. BMC Syst Biol 2011; 5(Suppl 3): S12. association in Caucasians and evidence for a link with a method of self-injury. 55 Sun J, Jia P, Fanous AH, van den Oord E, Chen X, Riley BP et al. Schizophrenia Neuropsychobiology 2009; 59:151–158. gene networks and pathways and their applications for novel candidate gene 83 Hishimoto A, Shirakawa O, Nishiguchi N, Hashimoto T, Yanagi M, Nushida H et al. selection. PLoS One 2010; 5: e11351. Association between a functional polymorphism in the renin-angiotensin system 56 Wong ML, Dong C, Andreev V, Arcos-Burgos M, Licinio J. Prediction of sus- and completed suicide. J Neural Transm 2006; 113:1915–1920. ceptibility to major depression by a model of interactions of multiple functional 84 Sparks DL, Hunsaker JC 3rd, Amouyel P, Malafosse A, Bellivier F, Leboyer M et al. genetic variants and environmental factors. Mol Psychiatry 2012; 17:624–633. Angiotensin I-converting enzyme I/D polymorphism and suicidal behaviors. Am J 57 Gonzalez MW, Kann MG. Chapter 4: protein interactions and disease. PLoS Med Genet B Neuropsychiatr Genet 2009; 150B: 290–294. Comput Biol 2012; 8: e1002819. 85 Baca-Garcia E, Vaquero-Lorenzo C, Perez-Rodriguez MM, Gratacos M, Bayes M, 58 Kendler KS. What psychiatric genetics has taught us about the nature of psy- Santiago-Mozos R et al. Nucleotide variation in central nervous system genes chiatric illness and what is left to learn. Mol Psychiatry 2013; 18:1058–1066. among male suicide attempters. Am J Med Genet B Neuropsychiatr Genet 2010; 59 Lehner B. Genotype to phenotype: lessons from model organisms for human 153B:208–213. genetics. Nat Rev Genet 2013; 14: 168–178. 86 Hishimoto A, Fukutake M, Mouri K, Nagasaki Y, Asano M, Ueno Y et al. Alcohol 60 Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y et al. Proteins and aldehyde dehydrogenase polymorphisms and risk for suicide: a preliminary encoded in genomic regions associated with immune-mediated disease physi- observation in the Japanese male population. Genes Brain Behav 2010; 9: cally interact and suggest underlying biology. PLoS Genet 2011; 7: e1001273. 498–502. 61 Gandhi TK, Zhong J, Mathivanan S, Karthick L, Chandrika KN, Mohan SS et al. 87 Fukutake M, Hishimoto A, Nishiguchi N, Nushida H, Ueno Y, Shirakawa O et al. Analysis of the human protein interactome and comparison with yeast, worm Association of alpha2A-adrenergic receptor gene polymorphism with suscept- and fly interaction datasets. Nat Genet 2006; 38:285–293. ibility to suicide in Japanese females. Prog Neuropsychopharmacol Biol Psychiatry 62 Smith MC, Gestwicki JE. Features of protein-protein interactions that translate 2008; 32:1428–1433. into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med 88 Sequeira A, Mamdani F, Lalovic A, Anguelova M, Lesage A, Seguin M et al. Alpha 2012; 14: e16. 2A adrenergic receptor gene and suicide. Psychiatry Res 2004; 125:87–93. 63 Chen Y, Andres AL, Frotscher M, Baram TZ. Tuning synaptic transmission in the 89 Martin-Guerrero I, Callado LF, Saitua K, Rivero G, Garcia-Orad A, Meana JJ. The hippocampus by stress: the CRH system. Front Cell Neurosci 2012; 6:13. N251K functional polymorphism in the alpha(2A)-adrenoceptor gene is not 64 Joels M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci 2009; 10: associated with depression: a study in suicide completers. Psychopharmacology 459–466. 2006; 184:82–86. 65 Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of 90 Escriba PV, Ozaita A, Garcia-Sevilla JA. Increased mRNA expression of alpha2A- stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2012; 13: adrenoceptors, serotonin receptors and mu-opioid receptors in the brains of 22–37. suicide victims. Neuropsychopharmacology 2004; 29:1512–1521.

Molecular Psychiatry (2015), 56 – 71 © 2015 Macmillan Publishers Limited The neurosystem of suicidal behaviors M Sokolowski et al 67 91 Garcia-Sevilla JA, Escriba PV, Ozaita A, La Harpe R, Walzer C, Eytan A et al. 115 Harro J, Marcusson J, Oreland L. Alterations in brain cholecystokinin receptors in Up-regulation of immunolabeled alpha2A-adrenoceptors, Gi coupling proteins, suicide victims. Eur Neuropsychopharmacol 1992; 2:57–63. and regulatory receptor kinases in the prefrontal cortex of depressed suicides. 116 Chojnicka I, Strawa K, Fudalej S, Fudalej M, Pawlak A, Kostrzewa G et al. Analysis J Neurochem 1999; 72:282–291. of four genes involved in the neurodevelopment shows association of 92 Meana JJ, Garcia-Sevilla JA. Increased alpha 2-adrenoceptor density in the frontal rs4307059 polymorphism in the cadherin 9/10 region with completed suicide. cortex of depressed suicide victims. J Neural Transm 1987; 70:377–381. Neuropsychobiology 2012; 66: 134–140. 93 Molnar S, Mihanovic M, Grah M, Kezic S, Filakovic P, Degmecic D. Comparative 117 Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB study on gene tags of the neurotransmission system in schizophrenic and sui- et al. Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS cidal subjects. Coll Antropol 2010; 34: 1427–1432. binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry 94 Mann JJ, Stanley M, McBride PA, McEwen BS. Increased serotonin2 and beta- 2004; 9:184–190. adrenergic receptor binding in the frontal cortices of suicide victims. Arch Gen 118 Vinod KY, Arango V, Xie S, Kassir SA, Mann JJ, Cooper TB et al. Elevated levels of Psychiatry 1986; 43: 954–959. endocannabinoids and CB1 receptor-mediated G-protein signaling in the pre- 95 He Y, Zhou Y, Xi Q, Cui H, Luo T, Song H et al. Genetic variations in microRNA frontal cortex of alcoholic suicide victims. Biol Psychiatry 2005; 57:480–486. processing genes are associated with susceptibility in depression. DNA Cell Biol 119 Vinod KY. Role of the endocannabinoid system in the neurobiology of 2012; 31: 1499–1506. suicide. In: Dwivedi Y (ed) The Neurobiological Basis of Suicide. CRC Press: Boca 96 Magno LA, Miranda DM, Neves FS, Pimenta GJ, Mello MP, De Marco LA et al. Raton, FL, USA, 2012. Association between AKT1 but not AKTIP genetic variants and increased risk for 120 Nolan KA, Volavka J, Czobor P, Cseh A, Lachman H, Saito T et al. Suicidal behavior suicidal behavior in bipolar patients. Genes Brain Behav 2010; 9:411–418. in patients with schizophrenia is related to COMT polymorphism. Psychiatr Genet 97 Dwivedi Y, Rizavi HS, Zhang H, Roberts RC, Conley RR, Pandey GN. Modulation in 2000; 10: 117–124. activation and expression of phosphatase and tensin homolog on chromosome 121 Zalsman G, Huang YY, Oquendo MA, Brent DA, Giner L, Haghighi F et al. No ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence association of COMT Val158Met polymorphism with suicidal behavior or CSF demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain monoamine metabolites in mood disorders. Arch Suicide Res 2008; 12:327–335. of suicide subjects. Biol Psychiatry 2010; 67: 1017–1025. 122 Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F et al. 98 Finseth PI, Sonderby IE, Djurovic S, Agartz I, Malt UF, Melle I et al. Association Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia analysis between suicidal behaviour and candidate genes of bipolar disorder and bipolar disorder. Hum Mol Genet 2006; 15: 3132–3145. and schizophrenia. J Affect Disord 2014; 163: 110–114. 123 Du L, Merali Z, Poulter MO, Palkovits M, Faludi G, Anisman H. Catechol-O- 99 Edgar PF, Hooper AJ, Poa NR, Burnett JR. Violent behavior associated with methyltransferase Val158Met polymorphism and altered COMT gene expression hypocholesterolemia due to a novel APOB gene mutation. Mol Psychiatry 2007; in the prefrontal cortex of suicide brains. Prog Neuropsychopharmacol Biol Psy- 123: 221, 258–263. chiatry 2014; 50C:178–183. 100 Hwang JP, Yang CH, Hong CJ, Lirng JF, Yang YM, Tsai SJ. Association of APOE 124 Calati R, Porcelli S, Giegling I, Hartmann AM, Moller HJ, De Ronchi D et al. genetic polymorphism with cognitive function and suicide history in geriatric Catechol-o-methyltransferase gene modulation on suicidal behavior and per- depression. Dement Geriatr Cogn Disord 2006; 22:334–338. sonality traits: review, meta-analysis and association study. J Psychiatr Res 2011; 101 Chojnicka I, Gajos K, Strawa K, Broda G, Fudalej S, Fudalej M et al. Possible 45:309–321. association between suicide committed under influence of ethanol and a variant 125 Kia-Keating BM, Glatt SJ, Tsuang MT. Meta-analyses suggest association between in the AUTS2 gene. PLoS One 2013; 8: e57199. COMT, but not HTR1B, alleles, and suicidal behavior. Am J Med Genet B Neu- 102 Inder WJ, Donald RA, Prickett TC, Frampton CM, Sullivan PF, Mulder RT et al. ropsychiatr Genet 2007; 144B: 1048–1053. Arginine vasopressin is associated with hypercortisolemia and suicide attempts 126 Tovilla-Zarate C, Juarez-Rojop I, Ramon-Frias T, Villar-Soto M, Pool-Garcia S, in depression. Biol Psychiatry 1997; 42: 744–747. Medellin BC et al. No association between COMT val158met polymorphism and 103 Merali Z, Kent P, Du L, Hrdina P, Palkovits M, Faludi G et al. Corticotropin- suicidal behavior: meta-analysis and new data. BMC Psychiatry 2011; 11:151. releasing hormone, arginine vasopressin, gastrin-releasing peptide, and neuro- 127 Dwivedi Y, Rao JS, Rizavi HS, Kotowski J, Conley RR, Roberts RC et al. Abnormal medin B alterations in stress-relevant brain regions of suicides and control expression and functional characteristics of cyclic adenosine monophosphate subjects. Biol Psychiatry 2006; 59: 594–602. response element binding protein in postmortem brain of suicide subjects. Arch 104 Ben-Efraim YJ, Wasserman D, Wasserman J, Sokolowski M. Family-based study of Gen Psychiatry 2003; 60: 273–282. AVPR1B association and interaction with stressful life events on depression and 128 Dowlatshahi D, MacQueen GM, Wang JF, Reiach JS, Young LT. G Protein-coupled anxiety in suicide attempts. Neuropsychopharmacology 2013; 38: 1504–1511. cyclic AMP signaling in postmortem brain of subjects with mood disorders: 105 Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ. Association study of a brain- effects of diagnosis, suicide, and treatment at the time of death. J Neurochem derived neurotrophic-factor genetic polymorphism and mood disorders, age of 1999; 73: 1121–1126. onset and suicidal behavior. Neuropsychobiology 2003; 48: 186–189. 129 Arato M, Banki CM, Bissette G, Nemeroff CB. Elevated CSF CRF in suicide victims. 106 Sarchiapone M, Carli V, Roy A, Iacoviello L, Cuomo C, Latella MC et al. Association Biol Psychiatry 1989; 25: 355–359. of polymorphism (Val66Met) of brain-derived neurotrophic factor with suicide 130 De Luca V, Tharmalingam S, Zai C, Potapova N, Strauss J, Vincent J et al. Asso- attempts in depressed patients. Neuropsychobiology 2008; 57:139–145. ciation of HPA axis genes with suicidal behaviour in schizophrenia. J Psycho- 107 Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN. Altered pharmacol 2010; 24: 677–682. gene expression of brain-derived neurotrophic factor and receptor tyrosine 131 Roy A, Hodgkinson CA, Deluca V, Goldman D, Enoch MA. Two HPA axis genes, kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 2003; 60: CRHBP and FKBP5, interact with childhood trauma to increase the risk for sui- 804–815. cidal behavior. J Psychiatr Res 2012; 46:72–79. 108 Dwivedi Y. Brain-derived neurotrophic factor in suicide pathophysiology. In: 132 Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO et al. Dysregulation in Dwivedi Y (ed) The Neurobiological Basis of Suicide. CRC Press: Boca Raton, FL, the suicide brain: mRNA expression of corticotropin-releasing hormone recep- USA, 2012. tors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 109 Zai CC, Manchia M, De Luca V, Tiwari AK, Chowdhury NI, Zai GC et al. The brain- 2004; 24: 1478–1485. derived neurotrophic factor gene in suicidal behaviour: a meta-analysis. Int J 133 Wasserman D, Sokolowski M, Rozanov V, Wasserman J. The CRHR1 gene: a Neuropsychopharmacol 2012; 15: 1037–1042. marker for suicidality in depressed males exposed to low stress. Genes Brain 110 Shindo S, Yoshioka N. Polymorphisms of the cholecystokinin gene promoter Behav 2008; 7:14–19. region in suicide victims in Japan. Forensic Sci Int 2005; 150:85–90. 134 Wasserman D, Wasserman J, Rozanov V, Sokolowski M. Depression in suicidal 111 Bachus SE, Hyde TM, Herman MM, Egan MF, Kleinman JE. Abnormal cholecys- males: genetic risk variants in the CRHR1 gene. Genes Brain Behav 2009; 8:72–79. tokinin mRNA levels in entorhinal cortex of schizophrenics. J Psychiatr Res 1997; 135 Hiroi N, Wong ML, Licinio J, Park C, Young M, Gold PW et al. Expression of 31:233–256. corticotropin releasing hormone receptors type I and type II mRNA in suicide 112 Lofberg C, Agren H, Harro J, Oreland L. Cholecystokinin in CSF from depressed victims and controls. Mol Psychiatry 2001; 6:540–546. patients: possible relations to severity of depression and suicidal behaviour. Eur 136 Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M. Reduced cortico- Neuropsychopharmacol 1998; 8:153–157. tropin releasing factor binding sites in the frontal cortex of suicide victims. Arch 113 Sears C, Wilson J, Fitches A. Investigating the role of BDNF and CCK system Gen Psychiatry 1988; 45: 577–579. genes in suicidality in a familial bipolar cohort. J Affect Disord 2013; 151: 137 Mandelli L, Serretti A. Gene environment interaction studies in depression and 611–617. suicidal behavior: An update. Neurosci Biobehav Rev 2013; 37: 2375–2397. 114 Sherrin T, Heng KY, Zhu YZ, Tang YM, Lau G, Tan CH. Cholecystokinin-B receptor 138 De Luca V, Tharmalingam S, Kennedy JL. Association study between the gene expression in cerebellum, pre-frontal cortex and cingulate gyrus and its corticotropin-releasing hormone receptor 2 gene and suicidality in bipolar dis- association with suicide. Neurosci Lett 2004; 357: 107–110. order. Eur Psychiatry 2007; 22: 282–287.

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 56 – 71 The neurosystem of suicidal behaviors M Sokolowski et al 68 139 Suchankova P, Holm G, Traskman-Bendz L, Brundin L, Ekman A. The +1444C4T 163 Vinod KY, Kassir SA, Hungund BL, Cooper TB, Mann JJ, Arango V. Selective polymorphism in the CRP gene: a study on personality traits and suicidal alterations of the CB1 receptors and the fatty acid amide hydrolase in the ventral behaviour. Psychiatr Genet 2013; 23:70–76. striatum of alcoholics and suicides. J Psychiatr Res 2010; 44:591–597. 140 Hofer P, Schosser A, Calati R, Serretti A, Massat I, Kocabas NA et al. The impact of 164 Lalovic A, Klempan T, Sequeira A, Luheshi G, Turecki G. Altered expression of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide lipid metabolism and immune response genes in the frontal cortex of suicide attempt and suicide risk-a European multicentre study on treatment-resistant completers. J Affect Disord 2010; 120:24–31. major depressive disorder. Eur Arch Psychiatry Clin Neurosci 2013; 263:385–391. 165 Willour VL, Chen H, Toolan J, Belmonte P, Cutler DJ, Goes FS et al. Family-based 141 Penas-Lledo EM, Blasco-Fontecilla H, Dorado P, Vaquero-Lorenzo C, Baca-Garcia association of FKBP5 in bipolar disorder. Mol Psychiatry 2009; 14:261–268. E, Llerena A. CYP2D6 and the severity of suicide attempts. Pharmacogenomics 166 Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch MA. Interaction of FKBP5, a 2012; 13: 179–184. stress-related gene, with childhood trauma increases the risk for attempting 142 Zackrisson AL, Lindblom B, Ahlner J. High frequency of occurrence of CYP2D6 suicide. Neuropsychopharmacology 2010; 35: 1674–1683. gene duplication/multiduplication indicating ultrarapid metabolism among 167 Perez-Ortiz JM, Garcia-Gutierrez MS, Navarrete F, Giner S, Manzanares J. Gene suicide cases. Clin Pharmacol Ther 2010; 88: 354–359. and protein alterations of FKBP5 and glucocorticoid receptor in the amygdala of 143 Preuss UW, Wurst FM, Ridinger M, Rujescu D, Fehr C, Koller G et al. Association of suicide victims. Psychoneuroendocrinology 2013; 38:1251–1258. functional DBH genetic variants with alcohol dependence risk and related 168 Minoretti P, Arra M, Emanuele E, Olivieri V, Aldeghi A, Politi P et al. A W148R depression and suicide attempt phenotypes: results from a large multicenter mutation in the human FOXD4 gene segregating with dilated cardiomyopathy, association study. Drug Alcohol Depend 2013; 133: 459–467. obsessive-compulsive disorder, and suicidality. Int J Mol Med 2007; 19: 369–372. 144 Fernandez-Navarro P, Vaquero-Lorenzo C, Blasco-Fontecilla H, Diaz-Hernandez 169 Sokolowski M, Ben-Efraim YJ, Wasserman J, Wasserman D. Glutamatergic GRIN2B M, Gratacos M, Estivill X et al. Genetic epistasis in female suicide attempters. Prog and polyaminergic ODC1 genes in suicide attempts: associations and gene- 38 – Neuropsychopharmacol Biol Psychiatry 2012; :294 301. environment interactions with childhood/adolescent physical assault. Mol Psy- 145 Rochet T, Tonon MC, Kopp N, Vaudry H, Miachon S. Evaluation of endozepine- chiatry 2013; 18:985–992. like immunoreactivity in the frontal cortex of suicide victims. Neuroreport 1998; 170 Poulter MO, Du L, Zhurov V, Palkovits M, Faludi G, Merali Z et al. Altered orga- 9 – :53 56. nization of GABA(A) receptor mRNA expression in the depressed suicide brain. 146 Giegling I, Moreno-De-Luca D, Rujescu D, Schneider B, Hartmann AM, Schnabel A Front Mol Neurosci 2010; 3:3. et al. Dopa decarboxylase and tyrosine hydroxylase gene variants in suicidal 171 Cheetham SC, Crompton MR, Katona CL, Parker SJ, Horton RW. Brain GABAA/ 147 – behavior. Am J Med Genet B Neuropsychiatr Genet 2008; : 308 315. benzodiazepine binding sites and glutamic acid decarboxylase activity in 147 Roy A, Karoum F, Pollack S. Marked reduction in indexes of dopamine meta- depressed suicide victims. Brain Res 1988; 460: 114–123. bolism among patients with depression who attempt suicide. Arch Gen Psy- 172 Rochet T, Kopp N, Vedrinne J, Deluermoz S, Debilly G, Miachon S. Benzodiaze- 49 – chiatry 1992; : 447 450. pine binding sites and their modulators in hippocampus of violent suicide vic- 148 Lalovic A, Sequeira A, DeGuzman R, Chawky N, Lesage A, Seguin M et al. tims. Biol Psychiatry 1992; 32:922–931. Investigation of completed suicide and genes involved in cholesterol metabo- 173 Bernstein HG, Tausch A, Wagner R, Steiner J, Seeleke P, Walter M et al. Disruption lism. J Affect Disord 2004; 79:25–32. of glutamate-glutamine-GABA cycle significantly impacts on suicidal behaviour: 149 Lalovic A, Merkens L, Russell L, Arsenault-Lapierre G, Nowaczyk MJ, Porter FD survey of the literature and own findings on glutamine synthetase. CNS Neurol et al. Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome Disord Drug Targets 2013; 12: 900–913. carriers. Am J Psychiatry 2004; 161:2123–2126. 174 Jancic D, Seifuddin F, Zandi PP, Potash JB, Willour VL. Association study 150 Ratta-apha W, Hishimoto A, Mouri K, Shiroiwa K, Sasada T, Yoshida M et al. of X chromosome SNPs in attempted suicide. Psychiatry Res 2012; 200: Haplotype analysis of the DISC1 Ser704Cys variant in Japanese suicide com- 1044–1046. pleters. Psychiatry Res 2014; 215: 249–251. 175 Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernst C et al. Astrocytic 151 Monsalve EM, Garcia-Gutierrez MS, Navarrete F, Giner S, Laborda J, Manzanares J. abnormalities and global DNA methylation patterns in depression and suicide. Abnormal expression pattern of Notch receptors, ligands, and downstream Mol Psychiatry advance online publication, 25 March 2014; doi:10.1038/ effectors in the dorsolateral prefrontal cortex and amygdala of suicidal victims. mp.2014.21 (e-pub ahead of print). Mol Neurobiol 2013; 49: 957–965. 176 Jimenez E, Arias B, Mitjans M, Goikolea JM, Roda E, Saiz PA et al. Genetic 152 Murphy TM, Mullins N, Ryan M, Foster T, Kelly C, McClelland R et al. Genetic variability at IMPA2, INPP1 and GSK3beta increases the risk of suicidal behavior variation in DNMT3B and increased global DNA methylation is associated with in bipolar patients. Eur Neuropsychopharmacol 2013; 23:1452–1462. suicide attempts in psychiatric patients. Genes Brain Behav 2013; 12:125–132. 177 Yoon HK, Kim YK. Association between glycogen synthase kinase-3beta gene 153 Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z et al. GABAA receptor promoter hypermethylation in suicide brain: implications for the polymorphisms and major depression and suicidal behavior in a Korean popu- 34 – involvement of epigenetic processes. Biol Psychiatry 2008; 64:645–652. lation. Prog Neuropsychopharmacol Biol Psychiatry 2010; :331 334. 154 Johann M, Putzhammer A, Eichhammer P, Wodarz N. Association of the -141C 178 Pandey GN, Dwivedi Y, Rizavi HS, Teppen T, Gaszner GL, Roberts RC et al. Del variant of the dopamine D2 receptor (DRD2) with positive family history and GSK-3beta gene expression in human postmortem brain: regional distribution, 34 – suicidality in German alcoholics. Am J Med Genet B Neuropsychiatr Genet 2005; effects of age and suicide. Neurochem Res 2009; :274 285. 132B:46–49. 179 Strauss J, McGregor S, Freeman N, Tiwari A, George CJ, Kovacs M et al. Asso- 155 Suda A, Kawanishi C, Kishida I, Sato R, Yamada T, Nakagawa M et al. Dopamine ciation study of early-immediate genes in childhood-onset mood disorders and 197 – D2 receptor gene polymorphisms are associated with suicide attempt in the suicide attempt. Psychiatry Res 2012; :49 54. Japanese population. Neuropsychobiology 2009; 59:130–134. 180 Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD et al. Impaired 156 Bowden C, Cheetham SC, Lowther S, Katona CL, Crompton MR, Horton RW. repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated 23 – Reduced dopamine turnover in the basal ganglia of depressed suicides. Brain with major depression and suicide. J Neurosci 2003; : 8788 8799. Res 1997; 769:135–140. 181 Huang YY, Battistuzzi C, Oquendo MA, Harkavy-Friedman J, Greenhill L, Zalsman 157 Tsai SJ, Wang YC, Hong CJ, Chiu HJ. Association study of oestrogen receptor G et al. Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. alpha gene polymorphism and suicidal behaviours in major depressive disorder. Int J Neuropsychopharmacol 2004; 7: 441–451. Psychiatr Genet 2003; 13:19–22. 182 Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and 158 Giegling I, Chiesa A, Calati R, Hartmann AM, Moller HJ, De Ronchi D et al. Do the postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of estrogen receptors 1 gene variants influence the temperament and character suicide victims. Brain Res 1995; 688: 121–133. inventory scores in suicidal attempters and healthy subjects? Am J Med Genet B 183 Gonzalez-Castro TB, Tovilla-Zarate CA, Juarez-Rojop I, Pool Garcia S, Genis A, Neuropsychiatr Genet 2009; 150B:434–438. Nicolini H et al. Association of 5HTR1A gene variants with suicidal behavior: case- 159 Baca-Garcia E, Diaz-Sastre C, Ceverino A, Perez-Rodriguez MM, Navarro-Jimenez control study and updated meta-analysis. J Psychiatr Res 2013; 47: 1665–1672. R, Lopez-Castroman J et al. Suicide attempts among women during low estra- 184 New AS, Gelernter J, Goodman M, Mitropoulou V, Koenigsberg H, Silverman J diol/low progesterone states. J Psychiatr Res 2010; 44:209–214. et al. Suicide, impulsive aggression, and HTR1B genotype. Biol Psychiatry 2001; 160 Ostlund H, Keller E, Hurd YL. Estrogen receptor gene expression in relation to 50:62–65. neuropsychiatric disorders. Ann NY Acad Sci 2003; 1007:54–63. 185 Rujescu D, Giegling I, Sato T, Moller HJ. Lack of association between serotonin 161 Must A, Koks S, Vasar E, Tasa G, Lang A, Maron E et al. Common variations in 4p 5-HT1B receptor gene polymorphism and suicidal behavior. Am J Med Genet B locus are related to male completed suicide. Neuromolecular Med 2009; 11:13–19. Neuropsychiatr Genet 2003; 116B:69–71. 162 Monteleone P, Bifulco M, Maina G, Tortorella A, Gazzerro P, Proto MC et al. 186 Murphy TM, Ryan M, Foster T, Kelly C, McClelland R, O'Grady J et al. Risk and Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in protective genetic variants in suicidal behaviour: association with SLC1A2, bipolar disorder and major depression. Pharmacol Res 2010; 61:400–404. SLC1A3, 5-HTR1B &NTRK2 polymorphisms. Behav Brain Funct 2011; 7: 22.

Molecular Psychiatry (2015), 56 – 71 © 2015 Macmillan Publishers Limited The neurosystem of suicidal behaviors M Sokolowski et al 69 187 Turecki G, Sequeira A, Gingras Y, Seguin M, Lesage A, Tousignant M et al. Suicide 211 Chojnicka I, Sobczyk-Kopciol A, Fudalej M, Fudalej S, Wojnar M, Waskiewicz A and serotonin: study of variation at seven serotonin receptor genes in suicide et al. No association between MTHFR C677T polymorphism and completed completers. Am J Med Genet B Neuropsychiatr Genet 2003; 118B:36–40. suicide. Gene 2012; 511: 118–121. 188 Huang YY, Grailhe R, Arango V, Hen R, Mann JJ. Relationship of psychopathology 212 Giegling I, Calati R, Porcelli S, Hartmann AM, Moller HJ, De Ronchi D et al. to the human serotonin1B genotype and receptor binding kinetics in post- NCAM1, TACR1 and NOS genes and temperament: a study on suicide attempters mortem brain tissue. Neuropsychopharmacology 1999; 21:238–246. and controls. Neuropsychobiology 2011; 64:32–37. 189 Zhang L, Su TP, Choi K, Maree W, Li CT, Chung MY et al. P11 (S100A10) as a 213 Giegling I, Chiesa A, Mandelli L, Gibiino S, Hartmann AM, Moller HJ et al. Influ- potential biomarker of psychiatric patients at risk of suicide. J Psychiatr Res 2011; ence of neuronal cell adhesion molecule (NCAM1) variants on suicidal behaviour 45:435–441. and correlated traits. Psychiatry Res 2010; 179:222–225. 190 Schild AH, Pietschnig J, Tran US, Voracek M. Genetic association studies between 214 Maheu ME, Davoli MA, Turecki G, Mechawar N. Amygdalar expression of proteins SNPs and suicidal behavior: a meta-analytical field synopsis. Prog Neuropsycho- associated with neuroplasticity in major depression and suicide. J Psychiatr Res pharmacol Biol Psychiatry 2013; 46:36–42. 2013; 47: 384–390. 191 Lowther S, Katona CL, Crompton MR, Horton RW. 5-HT1D and 5-HT1E/1F binding 215 Dwivedi Y, Mondal AC, Rizavi HS, Conley RR. Suicide brain is associated with sites in depressed suicides: increased 5-HT1D binding in globus pallidus but decreased expression of neurotrophins. Biol Psychiatry 2005; 58: 315–324. not cortex. Mol Psychiatry 1997; 2:314–321. 216 Banerjee R, Ghosh AK, Ghosh B, Bhattacharyya S, Mondal AC. Decreased mRNA 192 Gonzalez-Castro TB, Tovilla-Zarate C, Juarez-Rojop I, Pool Garcia S, Velazquez- and protein expression of BDNF, NGF, and their receptors in the hippocampus Sanchez MP, Genis A et al. Association of the 5HTR2A gene with suicidal from suicide: an analysis in human postmortem brain. Clin Med Insights Pathol behavior: case-control study and updated meta-analysis. BMC Psychiatry 2013; 2013; 6:1–11. 13:25. 217 McGregor S, Strauss J, Bulgin N, De Luca V, George CJ, Kovacs M et al. 193 Garbett K, Gal-Chis R, Gaszner G, Lewis DA, Mirnics K. Transcriptome alterations p75(NTR) gene and suicide attempts in young adults with a history of childhood- in the prefrontal cortex of subjects with schizophrenia who committed suicide. onset mood disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: Neuropsychopharmacol Hung 2008; 10:9–14. 696–700. 194 Sequeira A, Morgan L, Walsh DM, Cartagena PM, Choudary P, Li J et al. Gene 218 Cui H, Supriyanto I, Asano M, Ueno Y, Nagasaki Y, Nishiguchi N et al. A common expression changes in the prefrontal cortex, anterior cingulate cortex and polymorphism in the 3'-UTR of the NOS1 gene was associated with completed nucleus accumbens of mood disorders subjects that committed suicide. PLoS suicides in Japanese male population. Prog Neuropsychopharmacol Biol Psy- One 2012; 7: e35367. chiatry 2010; 34:992–996. 195 Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T et al. A population- 219 Rujescu D, Giegling I, Mandelli L, Schneider B, Hartmann AM, Schnabel A et al. specific HTR2B stop codon predisposes to severe impulsivity. Nature 2010; 468: NOS-I and -III gene variants are differentially associated with facets of suicidal 1061–1066. behavior and aggression-related traits. Am J Med Genet B Neuropsychiatr Genet 196 Videtic A, Peternelj TT, Zupanc T, Balazic J, Komel R. Promoter and functional 2008; 147B:42–48. polymorphisms of HTR2C and suicide victims. Genes Brain Behav 2009; 8: 220 Wang AG, Koefoed P, Jacoby AS, Woldbye D, Rasmussen HB, Timm S et al. 541–545. Neuropeptide Y genes and suicidal behaviour among schizophrenic patients. 197 Pandey GN, Dwivedi Y, Ren X, Rizavi HS, Faludi G, Sarosi A et al. Regional Psychiatr Genet 2013; 23:139–140. distribution and relative abundance of serotonin(2c) receptors in human brain: 221 Traskman-Bendz L, Ekman R, Regnell G, Ohman R. HPA-related CSF neuropep- effect of suicide. Neurochem Res 2006; 31:167–176. tides in suicide attempters. Eur Neuropsychopharmacol 1992; 2:99–106. 198 Polsinelli G, Zai CC, Strauss J, Kennedy JL, De Luca V. Association and CpG SNP 222 Widdowson PS, Ordway GA, Halaris AE. Reduced neuropeptide Y concentrations analysis of HTR4 polymorphisms with suicidal behavior in subjects with schi- in suicide brain. J Neurochem 1992; 59:73–80. zophrenia. J Neural Transm 2013; 120:253–258. 223 Caberlotto L, Hurd YL. Neuropeptide Y Y(1) and Y(2) receptor mRNA expression 199 Azenha D, Alves M, Matos R, Santa JF, Silva B, Cordeiro C et al. Male specific in the prefrontal cortex of psychiatric subjects. Relationship of Y(2) subtype to association between the 5-HTR6 gene 267C/T SNP and suicide in the Portuguese suicidal behavior. Neuropsychopharmacology 2001; 25:91–97. population. Neurosci Lett 2009; 466:128–130. 224 Lopez JF, Palkovits M, Arato M, Mansour A, Akil H, Watson SJ. Localization 200 Omrani MD, Bushehri B, Bagheri M, Salari-Lak S, Alipour A, Anoshae MR et al. and quantification of pro-opiomelanocortin mRNA and glucocorticoid Role of IL-10 -1082, IFN-gamma +874, and TNF-alpha -308 genes polymorphisms receptor mRNA in pituitaries of suicide victims. Neuroendocrinology 1992; 56: in suicidal behavior. Arch Suicide Res 2009; 13:330–339. 491–501. 201 Pandey GN, Rizavi HS, Ren X, Fareed J, Hoppensteadt DA, Roberts RC et al. 225 McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M et al. Epige- Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. netic regulation of the glucocorticoid receptor in human brain associates with J Psychiatr Res 2012; 46:57–63. childhood abuse. Nat Neurosci 2009; 12: 342–348. 202 Freemantle E, Mechawar N, Turecki G. Cholesterol and phospholipids in frontal 226 Pandey GN, Rizavi HS, Ren X, Dwivedi Y, Palkovits M. Region-specific alterations cortex and synaptosomes of suicide completers: relationship with endosomal in glucocorticoid receptor expression in the postmortem brain of teenage sui- lipid trafficking genes. J Psychiatr Res 2013; 47:272–279. cide victims. Psychoneuroendocrinology 2013; 38: 2628–2639. 203 Must A, Tasa G, Lang A, Vasar E, Koks S, Maron E et al. Association of limbic 227 Coryell W, Schlesser M. Combined biological tests for suicide prediction. Psy- system-associated membrane protein (LSAMP) to male completed suicide. BMC chiatry Res 2007; 150: 187–191. Med Genet 2008; 9:34. 228 Jokinen J, Nordstrom AL, Nordstrom P. ROC analysis of dexamethasone sup- 204 Perlis RH, Ruderfer D, Hamilton SP, Ernst C. Copy number variation in subjects pression test threshold in suicide prediction after attempted suicide. J Affect with major depressive disorder who attempted suicide. PLoS One 2012; 7: Disord 2008; 106:145–152. e46315. 229 Mann JJ, Currier D, Stanley B, Oquendo MA, Amsel LV, Ellis SP. Can biological 205 Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD. High activity-related tests assist prediction of suicide in mood disorders? Int J Neuropsychopharmacol allele of MAO-A gene associated with depressed suicide in males. Neuroreport 2006; 9:465–474. 2002; 13: 1195–1198. 230 Kohli MA, Salyakina D, Pfennig A, Lucae S, Horstmann S, Menke A et al. Asso- 206 Hung CF, Lung FW, Hung TH, Chong MY, Wu CK, Wen JK et al. Monoamine ciation of genetic variants in the neurotrophic receptor-encoding gene NTRK2 oxidase A gene polymorphism and suicide: an association study and meta-a- and a lifetime history of suicide attempts in depressed patients. Arch Gen Psy- nalysis. J Affect Disord 2012; 136:643–649. chiatry 2010; 67:348–359. 207 Gottfries CG, Oreland L, Wiberg A, Winblad B. Lowered monoamine oxidase 231 Chen GG, Fiori LM, Moquin L, Gratton A, Mamer O, Mechawar N et al. Evidence of activity in brains from alcoholic suicides. J Neurochem 1975; 25: 667–673. altered polyamine concentrations in cerebral cortex of suicide completers. 208 Mann JJ, Stanley M. Postmortem monoamine oxidase enzyme kinetics in the Neuropsychopharmacology 2010; 35: 1477–1484. frontal cortex of suicide victims and controls. Acta Psychiatr Scand 1984; 69: 232 Fiori LM, Gross JA, Turecki G. Effects of histone modifications on increased 135–139. expression of polyamine biosynthetic genes in suicide. Int J Neuropsycho- 209 Brunner HG, Nelen MR, van Zandvoort P, Abeling NG, van Gennip AH, Wolters EC pharmacol 2012; 15: 1161–1166. et al. X-linked borderline mental retardation with prominent behavioral dis- 233 Gross JA, Turecki G. Suicide and the polyamine system. CNS Neurol Disord Drug turbance: phenotype, genetic localization, and evidence for disturbed mono- Targets 2013; 12:980–988. amine metabolism. Am J Hum Genet 1993; 52: 1032–1039. 234 Arias AJ, Chan G, Gelernter J, Farrer L, Kranzler HR. Variation in OPRM1 and risk of 210 Pandey GN, Dwivedi Y, Ren X, Rizavi HS, Roberts RC, Conley RR et al. Altered suicidal behavior in drug-dependent individuals. Am J Addict 2012; 21:5–10. expression and phosphorylation of myristoylated alanine-rich C kinase substrate 235 Hishimoto A, Cui H, Mouri K, Nushida H, Ueno Y, Maeda K et al. A functional (MARCKS) in postmortem brain of suicide victims with or without depression. polymorphism of the micro-opioid receptor gene is associated with completed J Psychiatr Res 2003; 37:421–432. suicides. J Neural Transm 2008; 115:531–536.

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 56 – 71 The neurosystem of suicidal behaviors M Sokolowski et al 70 236 Gross-Isseroff R, Dillon KA, Israeli M, Biegon A. Regionally selective increases in 259 Little KY, McLauglin DP, Ranc J, Gilmore J, Lopez JF, Watson SJ et al. Serotonin mu opioid receptor density in the brains of suicide victims. Brain Res 1990; 530: transporter binding sites and mRNA levels in depressed persons committing 312–316. suicide. Biol Psychiatry 1997; 41: 1156–1164. 237 Deisenhammer EA, Hofer S, Schwitzer O, Defrancesco M, Kemmler G, Wildt L 260 Clayden RC, Zaruk A, Meyre D, Thabane L, Samaan Z. The association of et al. Oxytocin plasma levels in psychiatric patients with and without recent attempted suicide with genetic variants in the SLC6A4 and TPH genes depends suicide attempt. Psychiatry Res 2012; 200:59–62. on the definition of suicidal behavior: a systematic review and meta-analysis. 238 Jokinen J, Chatzittofis A, Hellstrom C, Nordstrom P, Uvnas-Moberg K, Asberg M. Transl Psychiatry 2012; 2: e166. Low CSF oxytocin reflects high intent in suicide attempters. Psychoneur- 261 Sokolowski M, Wasserman J, Wasserman D. Association of polymorphisms in the oendocrinology 2012; 37:482–490. SLIT2 axonal guidance gene with anger in suicide attempters. Mol Psychiatry 239 Dwivedi Y, Rizavi HS, Teppen T, Zhang H, Mondal A, Roberts RC et al. Lower 2010; 15:10–11. phosphoinositide 3-kinase (PI 3-kinase) activity and differential expression levels 262 Fiori LM, Turecki G. Genetic and epigenetic influences on expression of spermine of selective catalytic and regulatory PI 3-kinase subunit isoforms in prefrontal synthase and spermine oxidase in suicide completers. Int J Neuropsycho- cortex and hippocampus of suicide subjects. Neuropsychopharmacology 2008; pharmacol 2010; 13: 725–736. 33: 2324–2340. 263 Olsson A, Regnell G, Traskman-Bendz L, Ekman R, Westrin A. Cerebrospinal 240 Pandey GN, Dwivedi Y, Pandey SC, Teas SS, Conley RR, Roberts RC et al. Low neuropeptide Y and substance P in suicide attempters during long-term anti- phosphoinositide-specific phospholipase C activity and expression of phos- depressant treatment. Eur Neuropsychopharmacol 2004; 14: 479–485. pholipase C beta1 protein in the prefrontal cortex of teenage suicide subjects. 264 Giegling I, Rujescu D, Mandelli L, Schneider B, Hartmann AM, Schnabel A et al. Am J Psychiatry 1999; 156: 1895–1901. Tachykinin receptor 1 variants associated with aggression in suicidal behavior. 241 Feldcamp LA, Souza RP, Romano-Silva M, Kennedy JL, Wong AH. Reduced pre- Am J Med Genet B Neuropsychiatr Genet 2007; 144B:757–761. frontal cortex DARPP-32 mRNA in completed suicide victims with schizophrenia. 265 Burnet PW, Harrison PJ. Substance P (NK1) receptors in the cingulate cortex in Schizophr Res 2008; 103: 192–200. unipolar and bipolar mood disorder and schizophrenia. Biol Psychiatry 2000; 47: 242 Dwivedi Y, Rizavi HS, Shukla PK, Lyons J, Faludi G, Palkovits M et al. Protein 80–83. kinase A in postmortem brain of depressed suicide victims: altered expression of 266 Stockmeier CA, Shi X, Konick L, Overholser JC, Jurjus G, Meltzer HY et al. specific regulatory and catalytic subunits. Biol Psychiatry 2004; 55:234–243. Neurokinin-1 receptors are decreased in major depressive disorder. Neuroreport 243 Pandey GN, Dwivedi Y, Ren X, Rizavi HS, Mondal AC, Shukla PK et al. Brain region 2002; 13: 1223–1227. specific alterations in the protein and mRNA levels of protein kinase A subunits 267 Wasserman D, Geijer T, Sokolowski M, Rozanov V, Wasserman J. Genetic variation in the post-mortem brain of teenage suicide victims. Neuropsychopharmacology in the hypothalamic-pituitary-adrenocortical axis regulatory factor, T-box 19, and 2005; 30: 1548–1556. the angry/hostility personality trait. Genes Brain Behav 2007; 6:321–328. 244 Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Conley RR. Decreased catalytic activity 268 Omrani MD, Bagheri M, Bushehri B, Azizi F, Anoshae MR. The association of TGF- and expression of protein kinase C isozymes in teenage suicide victims: a beta1 codon 10 polymorphism with suicide behavior. Am J Med Genet B Neu- postmortem brain study. Arch Gen Psychiatry 2004; 61:685–693. ropsychiatr Genet 2012; 159B:772–775. 245 Pandey GN, Dwivedi Y, Pandey SC, Conley RR, Roberts RC, Tamminga CA. Protein 269 Kim YK, Lee SW, Kim SH, Shim SH, Han SW, Choi SH et al. Differences in cytokines kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett 1997; between non-suicidal patients and suicidal patients in major depression. Prog 228: 111–114. Neuropsychopharmacol Biol Psychiatry 2008; 32: 356–361. 246 Klempan TA, Ernst C, Deleva V, Labonte B, Turecki G. Characterization of QKI 270 Mahon PB, Stutz AM, Seifuddin F, Huo Y, Goes FS, Jancic D et al. Case-control gene expression, genetics, and epigenetics in suicide victims with major association study of TGOLN2 in attempted suicide. Am J Med Genet B Neuro- depressive disorder. Biol Psychiatry 2009; 66:824–831. psychiatr Genet 2010; 153B:1016–1023. 247 Cui H, Nishiguchi N, Ivleva E, Yanagi M, Fukutake M, Nushida H et al. Association 271 Persson ML, Wasserman D, Geijer T, Jonsson EG, Terenius L. Tyrosine hydroxylase of RGS2 gene polymorphisms with suicide and increased RGS2 immunor- allelic distribution in suicide attempters. Psychiatry Res 1997; 72:73–80. eactivity in the postmortem brain of suicide victims. Neuropsychopharmacology 272 Baumann B, Danos P, Diekmann S, Krell D, Bielau H, Geretsegger C et al. Tyrosine 2008; 33: 1537–1544. hydroxylase immunoreactivity in the locus coeruleus is reduced in depressed 248 Bani-Fatemi A, Goncalves VF, Zai C, de Souza R, Le Foll B, Kennedy JL et al. non-suicidal patients but normal in depressed suicide patients. Eur Arch Psy- Analysis of CpG SNPs in 34 genes: association test with suicide attempt in chiatry Clin Neurosci 1999; 249:212–219. schizophrenia. Schizophr Res 2013; 147: 262–268. 273 Ordway GA, Smith KS, Haycock JW. Elevated tyrosine hydroxylase in the locus 249 Fiori LM, Wanner B, Jomphe V, Croteau J, Vitaro F, Tremblay RE et al. Association coeruleus of suicide victims. J Neurochem 1994; 62:680–685. of polyaminergic loci with anxiety, mood disorders, and attempted suicide. PLoS 274 Biegon A, Fieldust S. Reduced tyrosine hydroxylase immunoreactivity in locus One 2010; 5: e15146. coeruleus of suicide victims. Synapse 1992; 10:79–82. 250 Sequeira A, Gwadry FG, Ffrench-Mullen JM, Canetti L, Gingras Y, Casero RA Jr 275 Gos T, Krell D, Bielau H, Brisch R, Trubner K, Steiner J et al. Tyrosine hydroxylase et al. Implication of SSAT by gene expression and genetic variation in suicide immunoreactivity in the locus coeruleus is elevated in violent suicidal depressive and major depression. Arch Gen Psychiatry 2006; 63:35–48. patients. Eur Arch Psychiatry Clin Neurosci 2008; 258: 513–520. 251 Fiori LM, Mechawar N, Turecki G. Identification and characterization of spermi- 276 Tonelli LH, Stiller J, Rujescu D, Giegling I, Schneider B, Maurer K et al. Elevated dine/spermine N1-acetyltransferase promoter variants in suicide completers. Biol cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psy- Psychiatry 2009; 66: 460–467. chiatr Scand 2008; 117:198–206. 252 Wasserman D, Geijer T, Rozanov V, Wasserman J. Suicide attempt and basic 277 Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M. Suicid- mechanisms in neural conduction: relationships to the SCN8A and ality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan VAMP4 genes. Am J Med Genet B Neuropsychiatr Genet 2005; 133B:116–119. hydroxylase polymorphism. Arch Gen Psychiatry 1994; 51:34–38. 253 Papale LA, Paul KN, Sawyer NT, Manns JR, Tufik S, Escayg A. Dysfunction of the 278 Zill P, Buttner A, Eisenmenger W, Muller J, Moller HJ, Bondy B. Predominant Scn8a voltage-gated sodium channel alters sleep architecture, reduces diurnal expression of tryptophan hydroxylase 1 mRNA in the pituitary: a postmortem corticosterone levels, and enhances spatial memory. J Biol Chem 2010; 285: study in human brain. Neuroscience 2009; 159: 1274–1282. 16553–16561. 279 Boldrini M, Underwood MD, Mann JJ, Arango V. More tryptophan hydroxylase in 254 Sundman-Eriksson I, Allard P. [(3)H]Tiagabine binding to GABA transporter-1 the brainstem dorsal raphe nucleus in depressed suicides. Brain Res 2005; 1041: (GAT-1) in suicidal depression. J Affect Disord 2002; 71:29–33. 19–28. 255 Bowden C, Cheetham SC, Lowther S, Katona CL, Crompton MR, Horton RW. 280 Bonkale WL, Murdock S, Janosky JE, Austin MC. Normal levels of tryptophan Dopamine uptake sites, labelled with [3H]GBR12935, in brain samples from hydroxylase immunoreactivity in the dorsal raphe of depressed suicide victims. J depressed suicides and controls. Eur Neuropsychopharmacol 1997; 7:247–252. Neurochem 2004; 88: 958–964. 256 Ryding E, Ahnlide JA, Lindstrom M, Rosen I, Traskman-Bendz L. Regional brain 281 Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M. Single serotonin and dopamine transporter binding capacity in suicide attempters nucleotide polymorphism and haplotype analysis of a novel tryptophan relate to impulsiveness and mental energy. Psychiatry Res 2006; 148: 195–203. hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 2004; 56: 257 Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of 581–586. life stress on depression: moderation by a polymorphism in the 5-HTT gene. 282 De Luca V, Mueller DJ, Tharmalingam S, King N, Kennedy JL. Analysis of the novel Science 2003; 301:386–389. TPH2 gene in bipolar disorder and suicidality. Mol Psychiatry 2004; 9:896–897. 258 Zalsman G, Frisch A, Bromberg M, Gelernter J, Michaelovsky E, Campino A et al. 283 Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H et al. Family-based association study of serotonin transporter promoter in suicidal Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and adolescents: no association with suicidality but possible role in violence traits. median raphe nuclei: major depression and suicide. Neuropsychopharmacology Am J Med Genet 2001; 105:239–245. 2006; 31: 814–824.

Molecular Psychiatry (2015), 56 – 71 © 2015 Macmillan Publishers Limited The neurosystem of suicidal behaviors M Sokolowski et al 71 284 Isung J, Aeinehband S, Mobarrez F, Martensson B, Nordstrom P, Asberg M et al. 288 Thakker-Varia S, Alder J. Neuropeptides in depression: role of VGF. Behav Brain Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid Res 2009; 197: 262–278. of suicide attempters. Transl Psychiatry 2012; 2: e196. 289 Yanagi M, Shirakawa O, Kitamura N, Okamura K, Sakurai K, Nishiguchi N et al. 285 Isung J, Mobarrez F, Nordstrom P, Asberg M, Jokinen J. Low plasma vascular Association of 14-3-3 epsilon gene haplotype with completed suicide in Japa- endothelial growth factor (VEGF) associated with completed suicide. World J Biol nese. J Hum Genet 2005; 50:210–216. Psychiatry 2012; 13: 468–473. 290 Lett TA, Zai CC, Tiwari AK, Shaikh SA, Likhodi O, Kennedy JL et al. ANK3, CAC- 286 Sequeira A, Kim C, Seguin M, Lesage A, Chawky N, Desautels A et al. NA1C and ZNF804A gene variants in bipolar disorders and psychosis sub- Wolfram syndrome and suicide: evidence for a role of WFS1 in suicidal and phenotype. World J Biol Psychiatry 2011; 12:392–397. impulsive behavior. Am J Med Genet B Neuropsychiatr Genet 2003; 119B: 291 Hess JL, Glatt SJ. How might ZNF804A variants influence risk for schizophrenia 108–113. and bipolar disorder? A literature review, synthesis, and bioinformatic analysis. 287 Zalsman G, Mann MJ, Huang YY, Oquendo MA, Brent DA, Burke AK et al. Wol- Am J Med Genet B Neuropsychiatr Genet 2014; 165:28–40. framin gene H611R polymorphism: no direct association with suicidal behavior 292 Kin T, Ono Y. Idiographica: a general-purpose web application to build but possible link to mood disorders. Prog Neuropsychopharmacol Biol Psychiatry idiograms on-demand for human, mouse and rat. Bioinformatics 2007; 23: 2009; 33: 707–710. 2945–2946.

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