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Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2 , TNF , SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1 , MDR1 , ADRA1A and INSIG2 . More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application.

Epigenetic studies of DNA and histone modifications represent a new and important activity in molecular investigations of human disease. Our previous epigenome-wide scan identified numerous DNA methylation differences in post-mortem brain samples from individuals affected with major psychosis. In this article, we present the results of fine mapping DNA methylation differences at the human leukocyte antigen (HLA) complex group 9 gene ( HCG9 ) in bipolar disorder (BPD). Sodium bisulfite conversion coupled with pyrosequencing was used to interrogate 28 CpGs spanning ∼700 bp region of HCG9 in 1402 DNA samples from post-mortem brains, peripheral blood cells and germline (sperm) of bipolar disease patients and controls. The analysis of nearly 40 000 CpGs revealed complex relationships between DNA methylation and age, medication as well as DNA sequence variation (rs1128306). Two brain tissue cohorts exhibited lower DNA methylation in bipolar disease patients compared with controls at an extended HCG9 region ( P =0.026). Logistic regression modeling of BPD as a function of rs1128306 genotype, age and DNA methylation uncovered an independent effect of DNA methylation in white blood cells (odds ratio (OR)=1.08, P =0.0077) and the overall sample (OR=1.24, P =0.0011). Receiver operating characteristic curve A prime statistics estimated a 69–72% probability of correct BPD prediction from a case vs control pool. Finally, sperm DNA demonstrated a significant association ( P =0.018) with BPD at one of the regions demonstrating epigenetic changes in the post-mortem brain and peripheral blood samples. The consistent multi-tissue epigenetic differences at HCG9 argue for a causal association with BPD.

Placebo effect research over the past 15 years has improved our understanding of how placebo treatments reduce patient symptoms. The expectation of symptom improvement is the primary factor underlying the placebo effect. Such expectations are shaped by past experiences, contextual cues and biological traits, which ultimately modulate one’s degree of response to a placebo. The body of evidence that describes the physiology of the placebo effect has been derived from mechanistic studies primarily restricted to the setting of pain. Imaging findings support the role of endogenous opioid and dopaminergic networks in placebo analgesia in both healthy patients as well as patients with painful medical conditions. In patients with psychiatric illnesses such as anxiety disorders or depression, a vast overlap in neurological changes is observed in drug responders and placebo responders supporting the role of serotonergic networks in placebo response. Molecular techniques have been relatively underutilized in understanding the placebo effect until recently. We present an overview of the placebo responder phenotypes and genetic markers that have been associated with the placebo effect in pain, schizophrenia, anxiety disorders and depression.

Background: The ‘obesity paradox’ refers to the fact that obese patients have better outcomes than normal weight patients. This has been observed in multiple cardiovascular conditions, but evidence for obesity paradox in pulmonary hypertension (PH) remains sparse. Methods: We categorized 267 patients from the National Institute of Health-PH registry into five groups based on body mass index (BMI): underweight, normal weight, overweight, obese and morbidly obese. Mortality was compared in BMI groups using the χ 2 statistic. Five-year probability of death using the PH connection (PHC) risk equation was calculated, and the model was compared with BMI groups using Cox proportional hazards regression and Kaplan–Meier (KM) survival curves. Results: Patients had a median age of 39 years (interquartile range 30–50 years), a median BMI of 23.4 kg m − 2 (21.0–26.8 kg m −2 ) and an overall mortality at 5 years of 50.2%. We found a U-shaped relationship between survival and 1-year mortality with the best 1-year survival in overweight patients. KM curves showed the best survival in the overweight, followed by obese and morbidly obese patients, and the worst survival in normal weight and underweight patients (log-rank P =0.0008). In a Cox proportional hazards analysis, increasing BMI was a highly significant predictor of improved survival even after adjustment for the PHC risk equation with a hazard ratio for death of 0.921 per kg m −2 (95% confidence interval: 0.886–0.954) ( P <0.0001). Conclusion: We observed that the best survival was in the overweight patients, making this more of an ‘overweight paradox’ than an ‘obesity paradox’. This has implications for risk stratification and prognosis in group 1 PH patients.

We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 ( MIR137 ) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis across four independently collected samples of patients with schizophrenia ( n =510; F 1,506 =17.7, P =3.1 × 10 −5 ). In an imaging-genetics subsample that included additional matched controls ( n =213), patients with schizophrenia who had the MIR137 risk genotype had reduced white matter integrity ( F 3,209 =13.6, P =3.88 × 10 −8 ) throughout the brain as well as smaller hippocampi and larger lateral ventricles; the brain structure of patients who were carriers of the protective allele was no different from healthy control subjects on these neuroimaging measures. Our findings suggest that MIR137 substantially influences variation in phenotypes that are thought to have an important role in clinical outcome and treatment response. Finally, the possible consequences of genetic risk factors may be distinct in patients with schizophrenia compared with healthy controls.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT) n microsatellite, Val 66 Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val 66 Met polymorphism demonstrated significant overtransmission of the val allele ( χ 2 =7.12, d.f.=1, P =0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT) n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z =2.095, P =0.036). Significant haplotypes involved Val 66 Met and BDNF2 ( P =0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val 66 Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.

Background/Objectives: Oxytocin (OXT) is an evolutionarily ancient neuropeptide with strong links to affiliative and prosocial behaviors, and the management of stress. Increases in OXT also tend to decrease food intake, especially of sweet carbohydrates. The social correlates of low OXT levels mesh with the social deficits and stress proneness identified in interpersonal models of overeating, as well as the increased appetite for highly palatable foods typically seen in chronic overeaters. The objectives of this study were to investigate links between polymorphisms of the oxytocin receptor ( OXTR ) gene and overeating, and to examine OXTR links with relevant endophenotypes of overeating related to reward and stress sensitivity, and to food preferences. Subject/Methods: The sample comprised 460 adults between the ages of 25 and 50 years recruited from the community, and representing a broad range of body weights. Overeating, reward and punishment sensitivity, and food preferences, were quantified as composite variables using well-validated questionnaires. In addition, seven single-nucleotide polymorphisms (rs237878, rs237885, rs2268493, rs2268494, rs2254298, rs53576, rs2268498) of the OXTR gene were genotyped. Results: Analyses identified a four-marker haplotype that was significantly related to food preferences. Individual genotype analyses also found that at least one of the markers was related to each of the phenotypic variables. In addition, an empirically derived structural equation model linking genetic and phenotype variables produced a good fit to the data. Conclusions: The results of this preliminary study have demonstrated that OXTR variation is associated with overeating, and with endophenotypic traits such as sweet and fatty food preferences, and reward and punishment sensitivity. In general, the genetic findings also favor the view that overeating may be associated with relatively low basal OXT levels.

Recent research has suggested that serotonin, in addition to dopamine, may be involved in the development of attention deficit hyperactivity disorder (ADHD). Serotonin regulates dopaminergic neurotransmission in some areas of the brain via several 5-HT receptors including 5-HT1B. Animal studies have suggested the involvement of the 5-HT1B receptors in locomotor behaviour. For these reasons, we hypothesized that the 5-HT1B receptor gene may be a good candidate for genetic studies of ADHD. We tested for linkage disequilibrium between the 5-HT1B G861C polymorphism and ADHD in 115 families using the transmission disequilibrium test (TDT). We found evidence for a trend towards excess transmission of the 861G allele (χ 2 =2.91, P =0.09) that when further analysed for parental allele transmissions exhibited significantly greater paternal transmission of the G allele (χ 2 =4.80, P =0.03) to the affected child. Although preliminary, results from this study provide additional evidence that serotonin genes may be important risk factors for the development of ADHD.

Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (–1251 Hae III), D1P.6 (−800 Hae III), D1.1 (−48 Dde I) and D1.7 (+1403 Bsp 1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children ( P =0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.