Objectives: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. Methods: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. Results: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis. Conclusion: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use. Objectives Geneenvironment Gene environment genegene gene geneenvironment (SNVs dopamine2 dopamine 2 dopamine- D2R, DR , D R (D2R) Nmethyldaspartate N methyl d aspartate NMDAR, (NMDAR) CB1R, CBR CB (CB1R) trauma Methods Twentythree Twenty three DRD2 DRD (DRD2 rs1799978 rs rs7131056 rs6275, rs6275 rs6275) GRIN1 GRIN (GRIN1 rs4880213 rs11146020 GRIN2A GRINA A rs1420040 rs11866328 GRIN2B GRINB B rs890 rs2098469 rs7298664, rs7298664 rs7298664) CNR (CNR1 rs806380 rs806379 rs1049353 rs6454674 rs1535255 rs2023239 rs6928499 rs806374 rs7766029 rs806378 rs10485170 rs9450898 14 firstepisode first episode FEPp (FEPp 28 communitybased community based HumanCoreExome24 HumanCoreExome 24 HumanCoreExome-2 BeadChip Genegene software Results Singlelocus Single locus p 005 0 05 0.0 comparisons comparisons) however 0.001. 0001 0.001 . 001 0.001) Moreover bestperforming best performing rs1272007 0.001, Conclusion Tallele T allele (D2R (NMDAR (CB1R (DRD rs179997 rs713105 rs627 (GRIN rs488021 rs1114602 rs142004 rs1186632 rs89 rs209846 rs729866 (CNR rs80638 rs80637 rs104935 rs645467 rs153525 rs202323 rs692849 rs776602 rs1048517 rs945089 HumanCoreExome2 HumanCoreExome- 00 0. 000 0.00 rs127200 rs17999 rs71310 rs62 rs48802 rs111460 rs14200 rs118663 rs8 rs20984 rs72986 rs8063 rs10493 rs64546 rs15352 rs20232 rs69284 rs77660 rs104851 rs94508 rs12720 rs1799 rs7131 rs6 rs4880 rs11146 rs1420 rs11866 rs2098 rs7298 rs806 rs1049 rs6454 rs1535 rs2023 rs6928 rs7766 rs10485 rs9450 rs1272 rs179 rs713 rs488 rs1114 rs142 rs1186 rs209 rs729 rs80 rs104 rs645 rs153 rs202 rs692 rs776 rs1048 rs945 rs127 rs17 rs71 rs48 rs111 rs14 rs118 rs20 rs72 rs10 rs64 rs15 rs69 rs77 rs94 rs12 rs1 rs7 rs4 rs11 rs2 rs9

Resumo Nós investigamos a viabilidade de incluir a pesquisa de anticorpos anti-NMDAR na avaliação de pacientes em primeiro episódio psicótico em um programa de intervenção precoce no Hemisfério Sul. Anticorpos IgG anti-NMDAR foram avaliados por ELISA em 166 pacientes (64,0% homens), 166 controles de base populacional pareados e 76 irmãos (30,3% homens). Foram realizados teste exato de Fisher e ANOVA. Os anticorpos anti-NMDAR positivos foram mais observados no transtorno afetivo bipolar (10,0%) do que na esquizofrenia (2,4%) ou depressão psicótica (3,1%), embora não tenham sido observadas diferenças significativas. Nossos resultados não são conclusivos quanto à inclusão de anticorpos IgG anti-NMDAR no plasma em protocolos de diagnósticos diferenciais para psicose.

Abstract We investigated the feasibility of including plasma anti-NMDAR antibody screening in the assessment of first-episode psychosis patients in an early intervention programme in the Southern hemisphere. Anti-NMDAR IgG antibodies were assessed by ELISA in 166 patients (64.0% men), 166 matched population-based controls and 76 patients’ siblings (30.3% men). Fisher’s exact test and ANOVA were performed. Positive anti-NMDAR antibody patients were more often observed in bipolar disorder (10.0%) than schizophrenia (2.4%) or psychotic depression (3.1%), although no significant differences were observed. Our results are not conclusive regarding the inclusion of plasma anti-NMDAR IgG antibodies in differential diagnostic protocols for psychosis.

Resumo Nós investigamos a viabilidade de incluir a pesquisa de anticorpos anti-NMDAR na avaliação de pacientes em primeiro episódio psicótico em um programa de intervenção precoce no Hemisfério Sul. Anticorpos IgG anti-NMDAR foram avaliados por ELISA em 166 pacientes (64,0% homens), 166 controles de base populacional pareados e 76 irmãos (30,3% homens). Foram realizados teste exato de Fisher e ANOVA. Os anticorpos anti-NMDAR positivos foram mais observados no transtorno afetivo bipolar (10,0%) do que na esquizofrenia (2,4%) ou depressão psicótica (3,1%), embora não tenham sido observadas diferenças significativas. Nossos resultados não são conclusivos quanto à inclusão de anticorpos IgG anti-NMDAR no plasma em protocolos de diagnósticos diferenciais para psicose.

Abstract We investigated the feasibility of including plasma anti-NMDAR antibody screening in the assessment of first-episode psychosis patients in an early intervention programme in the Southern hemisphere. Anti-NMDAR IgG antibodies were assessed by ELISA in 166 patients (64.0% men), 166 matched population-based controls and 76 patients’ siblings (30.3% men). Fisher’s exact test and ANOVA were performed. Positive anti-NMDAR antibody patients were more often observed in bipolar disorder (10.0%) than schizophrenia (2.4%) or psychotic depression (3.1%), although no significant differences were observed. Our results are not conclusive regarding the inclusion of plasma anti-NMDAR IgG antibodies in differential diagnostic protocols for psychosis.