Several studies have investigated the potential association between genetic polymorphisms of tryptophan hydroxylase 1 (TPH1) and antidepressant response. However, the results are inconsistent and inconclusive. Our aim was to assess the association of the TPH1 A218C polymorphism (rs1800532) with antidepressant response using ethnicity, antidepressant-specific, and ethnicity-antidepressant interactions in an updated meta-analysis. Data were collected from the related literature published before December 2013 from MEDLINE and EMBASE databases. The meta-analysis was stratified by ethnicity, antidepressants, and ethnicity-antidepressant interaction, and was carried out using a random-effects model as appropriate using the Stata Statistical Package (version 11.0). A total of 12 individual studies and the STAR*D study were identified in the current study, among which six studies and the STAR*D study (White part) reported on the TPH1 A218C polymorphism and antidepressant response in a White population, with 2035 cases, and six studies and the STAR*D study (Asian part) were carried out in an Asian population, with 707 cases. In terms of the classes of antidepressants, eight studies and the STAR*D study explored this relationship using selective serotonin reuptake inhibitors (SSRIs) and four studies used other/mixed antidepressants. We found that the TPH1 A218C genotype was not significantly associated with antidepressant response either in all populations or in White and Asian populations. Moreover, the results did not change according to an ethnicity-antidepressant interaction model either in White populations using SSRIs or other/mixed antidepressants or in Asian populations. The TPH1 A218C polymorphism may not be associated with antidepressant response either in an ethnicity, antidepressant-specific population or in an ethnicity-antidepressant interaction model.

Tourette syndrome (TS) and obsessive-compulsive disorder commonly occur together. Family studies indicate shared genetic risk factors. SLITRK5, one of a family of six SLITRK genes, has been suggested as a possible candidate gene contributing towards obsessive-compulsive disorder on the basis of the mouse knockout model that shows excessive grooming behaviours that are alleviated with fluoxetine. In this study, we tested the SLITRK5 gene as a candidate for TS in a family-based sample with 377 affected children. Using single nucleotide polymorphisms tagging the gene, we did not find any evidence supporting the association of TS and SLITRK5.

Copy number variation (CNV) in 15q11.2, especially between BP1 and BP2, has been reported to be pathogenic and associated with autism spectrum disorder in White populations (Madrigal et al., 2012; Sorte et al., 2013). The segment between BP1 and BP2 contains four evolutionarily conserved genes, TUBGCP5, NIPA1, NIPA2, and CYFIP1, which are widely expressed in the neuronal tissue. Here, we report a microdeletion of chromosome 15q11.2 in a pair of Chinese autistic monozygotic twins. Diagnoses were made on the basis of a clinical evaluation using the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) and Autism Diagnostic Observation Schedule (ADOS). Genomic DNA was extracted from peripheral blood using the QIAamp DNA Blood Mini Kit (Cat# 51104; Qiagen, Hilden, Germany). We screened for the dosage of TUBGCP5, NIPA1, and CYFIP1 by real-time quantitative PCR to identify the copy number changes between BP1 and BP2 in 15q11.2. Whole-genome CNV analysis was then carried out using Agilent SurePrint G3 Human CGH Microarray 1×1 mol/l (Cat# G4824A-021529; Agilent Santa Clara, California, USA) to confirm these changes. Data analysis and CNV identification were carried out on Agilent Genomic Workbench Lite, edition 6.5. All CNVs were checked against the Database of Genomic Variants (http://projects.tcag.ca/variation) to determine whether they have been reported previously in autism spectrum disorder patients. The study was approved by the ethical committee of the Children’s Hospital of Fudan University. The monozygotic twins were found to carry a 434.4 kbp deletion in 15q11.2 (22 756 650–23 191 062), spanning five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML, the former four expressed widely in the neuronal tissue). Besides this, a duplication of 15q11.1-11.2 (20 432 851–22 586 951), often identified in the general population, was also detected. The duplicated region starts with HERC2P3 and ends with REREP3. None of the genes in the duplicated region have been reported to be associated with autism or other neurodevelopmental disorders. The monozygotic twin boys were 3 years old at the time of examination, born by Cesarean section after a natural pregnancy of 31 weeks’ gestation with low birth weight. Their height, weight, and head circumference were in the normal range at the time of examination. Phenotypically and clinically, the Chinese identical twins with autistic disorder bear a close resemblance to previously described patients in the White population. Principal among these are typical autistic features, mental retardation, language and motor delay, seizures, and slightly hypotonic. However, the two patients with the 15q11.2 deletion had no obvious dysmorphic features, no high/narrow forehead, no downturned mouth, no almond-shaped eyes, or small hands and feet. Interestingly, developmental regression characterized by a loss of previously acquired abilities and the appearance of autistic behaviors was observed in the twins (Lainhart et al., 2002; Baird et al., 2008). There was no family history for neurodevelopmental or neuropsychiatric disorders. In conclusion, our study indicates that the 15q11.2 deletion is present in Chinese Han autism patients, with clinical characteristics similar to those reported in patients of American or European descent. The identification of the 15q11.2 deletion provides additional support for the pathogenic nature of this CNV. Importantly, autistic regression observed in these twins with the 15q11.2 deletion had not been reported. Thus, this report may provide new insight into the pathogenesis of the 15q11.2 deletion.

This is a case-control study of the association of NTNG1 subtypes with schizophrenia among a group of individuals from a Caucasian population. Netrins including NTNG1 are known to be axon guidance factors in the developing brain. They could be very important contributors to the genetic risk for psychosis. We examined the hypothesis that NTNG1 allelic variation contributes to the risk for schizophrenia. Our group was able to replicate the findings of Zhu and colleagues among Han Chinese individuals. This is the first finding of this association in a North American population.

Autism is a severe neurodevelopmental disorder. Many susceptible or causative genes have been identified, and most of them are related to synaptogenesis. The THBS1 gene encodes thrombospondin 1, which plays a critical role in synaptogenesis of the central nervous system in the developing brain. However, no study has been carried out revealing that THBS1 is an autism risk gene. We analyzed the whole coding region and the 5'-untranslated region of the THBS1 gene in 313 autistic patients by Sanger sequencing, which was also used to analyze the identified variants in 350 normal controls. Association analysis was carried out using PLINK or R. Haplotype analysis was carried out using Haploview. Functional prediction and conservation analysis of missense variants were carried out using ANNOVAR. Twelve variants, including five common variants and seven rare variants, were identified in the THBS1 coding region and the 5'-untranslated region. Among them, one common variant (c.1567A>G:p.T523A) was significantly associated with autism (P<0.05). Two rare variants (c.2429G>A:p.R810Q, c.3496G>C:p.E1166Q) were absent in the 350 controls and were not reported in the single nucleotide polymorphism database (dbSNP). Combined association analysis of the rare variants (minor allele frequency<0.01) in patients and Asian samples in the 1000 genome project revealed a significant association between these rare variants and autism (P=0.039). Our data revealed that both common and rare variants of the THBS1 gene are associated with risk for autism, suggesting that THBS1 is a novel susceptible gene for autism.

We previously reported that a Kozak sequence variant in the metabotropic glutamate receptor 3 gene (GRM3), rs148754219, is associated with bipolar disorder (BP) and affects gene transcription and translation (Kandaswamy et al., 2013). A marker near GRM3, rs12704290, is one of the top hits and reached genome-wide significance in a recently reported genome-wide association study of schizophrenia (SZ) (Ripke et al., 2014), and markers for GRM3 have also been reported to demonstrate association with alcohol dependence syndrome (ADS) (Levey et al., 2014). In our original sample, considering patients successfully genotyped for rs148754219, 19 out of 1062 BP cases and only four out of 932 controls were heterozygous [odds ratio (OR)=4.2 (1.4–12.3), P=0.005]. We have genotyped this variant in additional controls and cases diagnosed with BP, SZ and ADS with the same ancestry. Patients were assessed by trained clinicians as described previously (Kandaswamy et al., 2013; Way et al., 2014). Allele counts were compared and significance was tested using Fisher’s exact test. Thirteen out of 934 additional BP cases and three out of 377 additional controls were heterozygous [OR=1.8 (0.49–6.2), P=not significant]. Combined with the originally reported results (Kandaswamy et al., 2013), 32 out of 1964 BP cases and seven out of 1309 controls were heterozygous [OR=3.0 (1.3–6.8), P=0.003]. Out of 1235 SZ cases 16 were heterozygous and were compared with the total control sample [OR=2.4 (0.99–5.8), P=0.03]. Out of 1514 ADS cases 18 were heterozygous and one was homozygous for the variant allele [OR=2.5 (1.0–5.9), P=0.03]. If all case cohorts (BP, SZ and ADS) are combined together, there would be one homozygote and 66 heterozygotes out of 4971 cases compared with the seven heterozygotes out of 1309 controls [OR=2.7 (1.2–5.8), P=0.004]. Previous work has supported the view that some genetic risk factors may be common to different psychiatric diagnoses (Lydall et al., 2011; Lee et al., 2013). Although the individual results are of questionable significance, the magnitude and direction of effect are consistent across all the cohorts and thus suggest the possibility that this rare variant may have a direct, functional effect on the risk of developing any of these three disorders. Because of its rarity, large sample sizes would be needed to confirm these results. Doing this would be worthwhile because if this finding is confirmed it could provide molecular insight into a mechanism involving GRM3 leading to increased risk of mental disorders and could provide a basis for further functional and therapeutic studies. Acknowledgements Preparation and analysis of the samples was supported by UK Medical Research Council project grants G9623693N, G0500791, G0701007 and G1000708. NLOB is supported by a PhD studentship funded jointly by a UCL IMPACT award and Equilibrium, the Bipolar Foundation. M.J.W. is supported by a PhD studentship jointly funded by a UCL IMPACT award and The Hobson Charity Limited. R.K. was funded by a UK Government Overseas Research Student award. G.Q. is supported by a PhD studentship jointly funded by a UCL IMPACT award and the Brain Damage Research Trust. A.J. is supported by a PhD studentship jointly funded by a UCL award and the Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH. The UCL clinical and control samples were collected with the support of the Bipolar Organization, the Neuroscience Research Charitable Trust, the Central London NHS Blood Transfusion Service, The Stanley Medical Research Institute, the National Institute for Health Research (NIHR) Mental Health Research Network, the NIHR Primary Care Research Network, Cheshire and Wirral Partnership NHS Foundation Trust, Cumbria Partnership NHS Foundation Trust, Cambridgeshire and Peterborough NHS Foundation Trust, Suffolk Mental Health Partnership NHS Trust, South Essex Partnership University NHS Foundation Trust (in services based in Bedfordshire and Luton), West London Mental Health NHS Trust, Camden and Islington NHS Foundation Trust, East London NHS Foundation Trust, North East London Mental Health NHS Trust, Hertfordshire Partnership NHS Foundation Trust, Berkshire Healthcare NHS Foundation Trust, North Essex Partnership NHS Foundation Trust, Oxfordshire and Buckinghamshire Mental Health NHS Foundation Trust, South Essex Partnership University NHS Foundation Trust, South London and Maudsley NHS Foundation Trust, Oxleas NHS Foundation Trust, Surrey and Borders Partnership NHS Foundation Trust, Kent and Medway NHS and Social Care Partnership Trust, South West London and St George’s Mental Health NHS Trust, Sussex Partnership Trust, South Essex Partnership University NHS Foundation Trust, Cornwall Partnership NHS Trust, Somerset Partnership NHS Foundation Trust, Salisbury NHS Foundation Trust and the Central and North West London NHS Foundation Trust. Conflicts of interest There are no conflicts of interest.

Limprasert, Pornprota; Maisrikhaw, Worathaia; Sripo, Thanyaa; Wirojanan, Juthamasb; Hansakunachai, Tippawanc; Roongpraiwan, Rawiwand; Sombuntham, Tasnawatd; Ruangdaraganon, Nicharad; Guo, Xiuqinge Author Information

One of the major clinical problems faced in treating posttraumatic stress disorder (PTSD) is that no single treatment is effective for every individual. With the efficacy of medications being questioned (Ipser and Stein, 2012) and the suggestion that evidence-based psychotherapies reduce rather than remit PTSD symptoms (Steenkamp and Litz, 2013), finding ways to predict who may positively respond to a particular treatment is imperative to mitigate PTSD’s negative consequences. The dopamine β-hydroxylase (DBH) gene has a functional polymorphism, rs1611115 (known as -1021C->T or C-970T), with higher plasma activity being associated with the CC genotype in Veterans without versus those with PTSD, while the DβH activity was similar among T allele genotype Veterans, with the CC genotype having overall greater activity than the T carrier genotypes (Mustapic et al., 2007). This suggests PTSD attenuates DβH activity in the higher functioning CC genotype but not in the lower functioning T carrier genotypes; possibly representing a compensatory response to prolonged PTSD hyperarousal. Nepicastat is a potent, competitive, and selective DβH inhibitor selected for study because it decreases norepinephrine (NE) more potently and specifically than disulfiram (Stanley et al., 1997). Nepicastat, like disulfiram, should reduce the abnormally high NE activity generally found in PTSD and result in reduced PTSD hyper-arousal symptoms. The purpose of this study was to compare the utility of using genetics versus functional NE biology to predict who may respond to nepicastat. This was a 6-week randomized, double-blind, multi-site, placebo-controlled study involving 22 OEF/OIF Veterans with PTSD, approved by each site’s IRB and R&D Committees. Measures included the Clinician Administered PTSD Scale – D (hyperarousal) subscale (CAPS-D), DBH genotype, and 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) sulfate form representing intra-neuronal noradrenergic metabolism (Filser et al., 1988). All participants who returned for at least one post-randomization visit (12 nepicastat and 10 placebo) were included in the intent-to-treat analysis. The primary efficacy measurement was the change in CAPS-D scores from pre- to post-treatment with the last observation carried forward. Sample consisted of 14 CC and 8 T carriers, was 45.5% White, 54.5% African-American. Alpha was retained at .05. The two treatment groups did not differ for any demographic or psychiatric co-morbid condition, or genotype (all P ≥ .080). Using a pre-post treatment repeated measure ANCOVA, controlling for ethnicity, we identified no direct treatment effect (P = .567) but did find a significant DBH genotype effect (P = .020) with the CC genotype showing greater change than the T carrier genotypes. There was no treatment by genotype interaction (P = .584). In comparison, there were no correlations between the MHPG-sulfate values and CAPS-D scores, whether examined pre-treatment, post-treatment, or for pre-post treatment changes (P > .05). Our findings suggest that a functional genetic marker for DBH may be more useful than using state-dependent measures of noradrenergic activity for predicting an individual's change in PSTD symptomatology. More generally, our results suggest further investigation is warranted to determine if using specific genetic polymorphisms are more useful than functional biologic measures in predicting an individual’s response to other targeted interventions.

Tzang, Ruu-Fen; Hsu, Cheng-Dien; Liou, Ying-Jay; Hong, Chen-Jee; Tsai, Shih-Jen Author Information