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Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically. [ABSTRACT FROM AUTHOR]

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, Pbonferroni<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder. [ABSTRACT FROM AUTHOR]

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. [ABSTRACT FROM AUTHOR]

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ∼1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing. [ABSTRACT FROM AUTHOR]

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10-10). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10-13. We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations. [ABSTRACT FROM AUTHOR]

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD. In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence. Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N=872 with CD and N=3091 without CD). We find four markers that meet the criteria for genome-wide significance (P<5 × 10−8) with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association. These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder. [ABSTRACT FROM AUTHOR]

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3′-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5–CHRNA3–CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.Molecular Psychiatry (2009) 14, 501–510; doi:10.1038/mp.2008.42; published online 15 April 2008 [ABSTRACT FROM AUTHOR]

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania 18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.Molecular Psychiatry (2009) 14, 376–380; doi:10.1038/mp.2008.144; published online 30 December 2008 [ABSTRACT FROM AUTHOR]

Arterial stiffening is the major cause of increasing systolic blood pressure in arterial hypertension. Increased arterial stiffness is one major mechanism responsible for morbidity and mortality in hypertension. A C825T polymorphism was identified in the gene encoding the G-protein ß3 subunit (GNB3), and an association of the T-allele with hypertension was demonstrated in several studies. In order to identify a pathogenetic link between hypertension and arterial stiffness, we compared two indices of arterial stiffness, pulse wave velocity (PWV) and augmentation index, in young, healthy men with and without the 825T-allele under resting conditions. PWV was determined from pressure tracing over carotid and femoral arteries in 99 subjects (CC: n=43; CT&TT: n=56). Augmentation index was derived in 72 subjects (CC: n=30; CT&TT: n=42) by pulse wave analysis using radial applanation tonometry. Carriers of the 825T-allele exhibited a significantly higher PWV compared to subjects with the CC genotype (6.0±0.1?m/s (TC&TT) vs 5.7±0.1?m/s (CC); P=0.0251). There was also a significant difference (P = 0.0448) in augmentation index between carriers of the T-allele (CT&TT: 3.4±2.9%) and controls with the CC -genotype (-5.0±4.1 %). There was no difference in any other anthropometric (age, height, weight, body mass index) or haemodynamic (heart rate, peripheral and central blood pressure). In summary, the C825T polymorphism is associated with higher arterial stiffness in young, healthy males. Arterial stiffening may pathogenetically contribute to the development of hypertension in carriers of the T-allele.Journal of Human Hypertension (2004) 18, 267-271. doi:10.1038/sj.jhh.1001665 [ABSTRACT FROM AUTHOR]

Pulse wave velocity (PWV) and augmentation index are widely used measures of arterial stiffness. The purpose of this study was to evaluate the role of blood pressure as a determinant of both indices independent of potentially confounding factors including gender, age and cardiovascular disorders. A total of 77 young, healthy subjects were investigated under resting conditions. Augmentation index was derived by pulse wave analysis using carotid applanation tonometry. PWV was determined from pressure tracing over the carotid and femoral artery. The relations between stiffness markers and haemodynamic parameters were analysed by simple (r) and multiple (?) regression analysis. Using simple regression analysis, augmentation index was correlated to age (r=0.292, P=0.0105), diastolic blood pressure (DBP, r=0.483, P<0.0001), mean arterial blood pressure (MAP, r=0.381, P=0.0007), pulse pressure (r=-0.414, P=0.0002) and total peripheral resistance (r=0.266, P=0.0204). After multiple regression analysis, augmentation index remained significantly correlated only to DBP (?=0.347, P=0.0051). Using simple regression analysis, PWV was correlated to age (r=0.304, P=0.0067), systolic blood pressure (r=0.280, P=0.0129). DBP (r=0.455, P<0.0001), MAP (r=0.446, P<0.0001) and heart rate (r=0.348, P=0.0018). After multiple regression analysis, PWV remained correlated only to age (?=0.218, P=0.0422) and DBP (?=0.4105, P=0.0316). In summary, DBP is an important determinant of augmentation index and PWV in young, healthy males. Further studies are needed to characterize the impact of blood pressure on arterial stiffness in other populations including females and older subjects.Journal of Human Hypertension (2003) 17, 153-158. doi:10.1038/sj.jhh.1001526 [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about association between bipolar disorder and Citron on chromosome 12q24.

A correction to the article "Identifying Blood Biomakers for Mood Disorders Using Convergent Functional Genomics" that was published in a previous issue is presented.

A correction to the article "Evidence of Association Between Bipolar Disorder and Citron on Chromosome 12q24" is presented.