Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders.

SUMMARY SIRT1 is a NAD+-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.

These results support the internal and external validity of ADHD in adults between 18 and 75 years. ADHD is not merely a child psychiatric disorder that persists into young adulthood, but an important and unique manifestation of psychopathology across the lifespan.

Objective: The purpose of this study was to determine whether a haplotype in the dystrobrevin binding protein 1 (DTNBP1) gene previously associated with schizophrenia not only increases the susceptibility to psychotic illness but also to a more or less clinically specific form of psychotic illness. Method:In the Irish Study of High-Density Schizophrenia Families, subjects with psychotic illness (N=755) were given lifetime ratings of clinical features according to the Operational Criteria Checklist for Psychotic Illness. Exploratory and confirmatory factor analyses were used to extract five factors-hallucinations, delusions, negative, manic, and depressive symptoms-and to create factor-derived scores. The family-based transmission disequilibrium test operationalized in the program TRANSMIT was used to determine whether a high-risk haplotype in the DTNBP1 gene was overtransmitted to subjects in the upper 20th and 40th percentiles for each factor score. These results were compared to baseline overtransmission by examining the empirical distribution of chi-square statistics in groups of 5,000 replicates in which 20% and 40% of ill subjects were randomly selected. This analysis was done for both narrow and broad definitions of psychotic illness.Results: Subjects in the upper 40th percentile for the negative symptom factorin both the narrowly (p=0.004) and broadly (p=0.01) defined illness groupswere more likely to inherit the high-risk haplotype than would be expected by chance. No other significant relationships between clinical features and high-risk haplotype transmission were observed. Conclusions:The etiologically relevant variation in DTNBP1, which is in presumptive linkage disequilibrium with the highrisk haplotype, may predispose individuals to a form of psychotic illness associated with high levels of negative symptoms. This finding supports previous evidence suggesting that genetic factors influence the clinical heterogeneity of schizophrenia.

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