The dynamic interplay between sleep and mood: an intensive longitudinal study of individuals with bipolar disorder.

BACKGROUND: Sleep disturbances are important symptoms to monitor in people with bipolar disorder (BD) but the precise longitudinal relationships between sleep and mood remain unclear. We aimed to examine associations between stable and dynamic aspects of sleep and mood in people with BD, and assess individual differences in the strength of these associations. METHODS: Participants (N = 649) with BD-I (N = 400) and BD-II (N = 249) provided weekly self-reports of insomnia, depression and (hypo)mania symptoms using the True Colours online monitoring tool for 21 months. Dynamic structural equation models were used to examine the interplay between weekly reports of insomnia and mood. The effects of clinical and demographic characteristics on associations were also assessed. RESULTS: Increased variability in insomnia symptoms was associated with increased mood variability. In the sample as a whole, we found strong evidence of bidirectional relationships between insomnia and depressive symptoms but only weak support for bidirectional relationships between insomnia and (hypo)manic symptoms. We found substantial variability between participants in the strength of prospective associations between insomnia and mood, which depended on age, gender, bipolar subtype, and a history of rapid cycling. CONCLUSIONS: Our results highlight the importance of monitoring sleep in people with BD. However, researchers and clinicians investigating the association between sleep and mood should consider subgroup differences in this relationship. Advances in digital technology mean that intensive longitudinal data on sleep and mood are becoming increasingly available. Novel methods to analyse these data present an exciting opportunity for furthering our understanding of BD.

Frontal waves and transmissions for temporal laminates and imperfect chiral interfaces.

The analysis of wave patterns in a structure which possesses periodicity in the spatial and temporal dimensions is presented. The topic of imperfect chiral interfaces is also considered. Although causality is fundamental for physical processes, natural wave phenomena can be observed when a wave is split at a temporal interface. A wave split at a spatial interface is a more common occurrence; however, when the coefficients of the governing equations are time-dependent, the temporal interface becomes important. Here, the associated frontal waves are studied, and regimes are analysed where the growth of the solution in time is found. Imperfect interfaces, across which the displacements are discontinuous, are also considered in the vector case of chiral elastic systems. Analytical study and asymptotic approximations are supplied with illustrative numerical examples. This article is part of the theme issue 'Wave generation and transmission in multi-scale complex media and structured metamaterials (part 1)'.

Development and evaluation of a novel pre-operative surgery school and behavioural change intervention for patients undergoing elective major surgery: Fit-4-Surgery School.

Group pre-operative education has usually been limited to conditioning expectations and providing education. Prehabilitation has highlighted modifiable lifestyle factors that are amenable to change and may improve clinical outcomes. We instituted a pre-operative 'Fit-4-Surgery School' for patients scheduled for major surgery, to educate and promote healthy behaviour. We evaluated patients' views having attended the school, and after surgery we asked how it had changed their behaviour with a lifestyle questionnaire. The school was launched in May 2016 and was attended by 586/1017 (58%) of invited patients. Patients who did not attend: lived further away, median (IQR [range]) 8 (4-19 [0-123]) miles vs. 5 (3-14 [0-172]) miles, p < 0.001; and were more deprived, Index of Multiple Deprivation Rank decile median (IQR [range]), 6 (4-8 [1-10]) vs. 7 (4-9 [1-10]), p = 0.04. Of the 492/586 (84%) participants who completed an evaluation questionnaire, 462 (94%) would recommend the school to a friend having surgery and 296 (60%) planned lifestyle changes. After surgery, 232/586 (40%) completed a behavioural change questionnaire, 106 (46%) of whom reported changing at least one lifestyle factor, most commonly by increasing exercise. The pre-operative school was acceptable to patients.

One-way interfacial waves in a flexural plate with chiral double resonators.

In this paper, we demonstrate a new approach to control flexural elastic waves in a structured chiral plate. The main focus is on creating one-way interfacial wave propagation at a given frequency by employing double resonators in a doubly periodic flexural system. The resonators consist of two beams attached to gyroscopic spinners, which act to couple flexural and rotational deformations, hence inducing chirality in the system. We show that this elastic structure supports one-way flexural waves, localized at an interface separating two sub-domains with gyroscopes spinning in opposite directions, but with otherwise identical properties. We demonstrate that a special feature of double resonators is in the directional control of wave propagation by varying the value of the gyricity, while keeping the frequency of the external time-harmonic excitation fixed. Conversely, for the same value of gyricity, the direction of wave propagation can be reversed by tuning the frequency of the external excitation. This article is part of the theme issue 'Modelling of dynamic phenomena and localization in structured media (part 2)'.

Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder.

Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.

Flexural vibration systems with gyroscopic spinners.

In this paper, we study the spectral properties of a finite system of flexural elements connected by gyroscopic spinners. We determine how the eigenfrequencies and eigenmodes of the system depend on the gyricity of the spinners. In addition, we present a transient numerical simulation that shows how a gyroscopic spinner attached to the end of a hinged beam can be used as a 'stabilizer', reducing the displacements of the beam. We also discuss the dispersive properties of an infinite periodic system of beams with gyroscopic spinners at the junctions. In particular, we investigate how the band-gaps of the structure can be tuned by varying the gyricity of the spinners. This article is part of the theme issue 'Modelling of dynamic phenomena and localization in structured media (part 1)'.

Postpartum psychosis in bipolar disorder: no evidence of association with personality traits, cognitive style or affective temperaments.

BACKGROUND: Bipolar disorder has been associated with several personality traits, cognitive styles and affective temperaments. Women who have bipolar disorder are at increased risk of experiencing postpartum psychosis, however little research has investigated these traits and temperaments in relation to postpartum psychosis. The aim of this study is to establish whether aspects of personality, cognitive style and affective temperament that have been associated with bipolar disorder also confer vulnerability to postpartum psychosis over and above their known association with bipolar disorder. METHODS: Personality traits (neuroticism, extraversion, schizotypy and impulsivity), cognitive styles (low self-esteem and dysfunctional attitudes) and affective temperaments (including cyclothymic and depressive temperaments) were compared between two groups of parous women with DSM-IV bipolar I disorder: i) 284 with a lifetime history of postpartum psychosis within 6 weeks of delivery (PP group), ii) 268 without any history of mood episodes with onset during pregnancy or within 6 months of delivery (no perinatal mood episode, No PME group). RESULTS: After controlling for current mood state, and key demographic, clinical and pregnancy-related variables, there were no statistically significant differences between the PP and No PME groups on any of the personality, cognitive style or affective temperament measures. CONCLUSIONS: Personality traits, cognitive styles and affective temperaments previously shown to be associated with bipolar disorder in general were not specifically associated with the occurrence of postpartum psychosis. These factors may not be relevant for predicting risk of postpartum psychosis in women with bipolar disorder.

Drink wise, age well; reducing alcohol related harm among people over 50: a study protocol.

BACKGROUND: Evidence suggests that the use of alcohol among older adults (defined as those aged 50+) has increased in recent years, with people aged 55-64 now more likely to exceed the recommended weekly guidelines than any other age group. METHODS/ DESIGN: This is a quasi-experimental study with a before-after design. A postal questionnaire will be sent to 76,000 people aged 50 and over registered with a general practice in five different 'demonstration' (intervention) and control areas in the UK. Multiple interventions will then be delivered in demonstration areas across the UK. At the end of the programme, a postal questionnaire will be sent to the same individuals who completed it pre-programme to establish if there has been a reduction in alcohol use, at-risk drinking and alcohol related problems. Qualitative interviews with clients and staff will explore how the interventions were experienced; how they may work to bring about change and to identify areas for practice improvements. DISCUSSION: This study protocol describes a multi-level, multi-intervention prevention-to-treatment programme which aims to reduce alcohol-related harm in people aged 50 and over.

Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

This corrects the article DOI: 10.1038/mp.2015.165.

The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale.

BACKGROUND: Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset. METHOD: Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA. RESULTS: Education, but not ethnicity/race, influenced the reporting of postpartum depression [difference between robust comparative fit indexes (∆*CFI) 0.01), but not between European countries (∆*CFI < 0.01). CONCLUSIONS: Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.

Copy number variation in bipolar disorder.

Large (>100 kb), rare (<1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 × 10(-4)). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4)).

Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Survival impact of the Australian National Bowel Cancer Screening Programme.

BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age-based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50-74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP-detected tumours. METHODS: Data on consecutive patients enrolled into a prospective, comprehensive, multidisciplinary database at six Victorian hospitals were examined. Clinicopathologic and outcome data were compared for NBCSP and symptomatic presentation patients. RESULTS: We identified 3743 patients that presented with colorectal cancer (CRC) at participating hospitals since May 2006. Of 1930 patients aged between 50 and 70 years, 141 (7.3%) had a NBCSP detected cancer, 1441 (74.7%) presented with symptoms and 266 (13.8%) were diagnosed through screening outside of the NBCSP. Based on the American Society of Anaesthesiology score, the NBCSP patients were fitter. They had an earlier stage of diagnosis and were more likely to be female and less likely to have lymphovascular invasion or to present as an emergency. NBCSP detected patients had a lower rate of recurrence (HR 0.17, P = 0.0001) and fewer deaths (HR 0.19, P = 0.005). CONCLUSIONS: Patients with NBCSP-detected CRC have a markedly reduced risk of CRC recurrence and death compared with patients with a symptomatic presentation. The dominant driver of this appears to be earlier stage at diagnosis. Increased promotion of the impact of the NBCSP, including data related to the survival impact, should be undertaken to increase participation rates and achieve further survival gains.

Practices in prescribing protein substitutes for PKU in Europe: No uniformity of approach.

BACKGROUND: There appears little consensus concerning protein requirements in phenylketonuria (PKU). METHODS: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. RESULTS: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). CONCLUSIONS: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.

A pragmatic randomized controlled trial to evaluate the effectiveness of a facilitated exercise intervention as a treatment for postnatal depression: the PAM-PeRS trial.

BACKGROUND: Postnatal depression affects about 10-15% of women in the year after giving birth. Many women and healthcare professionals would like an effective and accessible non-pharmacological treatment for postnatal depression. METHOD: Women who fulfilled the International Classification of Diseases (ICD)-10 criteria for major depression in the first 6 months postnatally were randomized to receive usual care plus a facilitated exercise intervention or usual care only. The intervention involved two face-to-face consultations and two telephone support calls with a physical activity facilitator over 6 months to support participants to engage in regular exercise. The primary outcome was symptoms of depression using the Edinburgh Postnatal Depression Scale (EPDS) at 6 months post-randomization. Secondary outcomes included EPDS score as a binary variable (recovered and improved) at 6 and 12 months post-randomization. RESULTS: A total of 146 women were potentially eligible and 94 were randomized. Of these, 34% reported thoughts of self-harming at baseline. After adjusting for baseline EPDS, analyses revealed a -2.04 mean difference in EPDS score, favouring the exercise group [95% confidence interval (CI) -4.11 to 0.03, p = 0.05]. When also adjusting for pre-specified demographic variables the effect was larger and statistically significant (mean difference = -2.26, 95% CI -4.36 to -0.16, p = 0.03). Based on EPDS score a larger proportion of the intervention group was recovered (46.5% v. 23.8%, p = 0.03) compared with usual care at 6 months follow-up. CONCLUSIONS: This trial shows that an exercise intervention that involved encouragement to exercise and to seek out social support to exercise may be an effective treatment for women with postnatal depression, including those with thoughts of self-harming.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Evidence that duplications of 22q11.2 protect against schizophrenia.

A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.

Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects.

BACKGROUND: Using a monoclonal antibody with greater affinity for IgE than omalizumab, we examined whether more complete suppression of IgE provided greater pharmacodynamic effects, including suppression of skin prick responses to allergen. OBJECTIVE: To explore the pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity humanized monoclonal IgG1κ anti-IgE. METHODS: Preclinical assessments and two randomized, placebo-controlled, double-blind clinical trials were conducted in atopic subjects. The first trial administered single doses of QGE031 (0.1-10 mg/kg) or placebo intravenously, while the second trial administered two to four doses of QGE031 (0.2- 4 mg/kg) or placebo subcutaneously at 2-week intervals. Both trials included an open-label omalizumab arm. RESULTS: Sixty of 73 (82%) and 96 of 110 (87%) subjects completed the intravenous and subcutaneous studies, respectively. Exposure to QGE031 and its half-life depended on the QGE031 dose and serum IgE level. QGE031 had a biexponential pharmacokinetic profile after intravenous administration and a terminal half-life of approximately 20 days. QGE031 demonstrated dose- and time-dependent suppression of free IgE, basophil FcεRI and basophil surface IgE superior in extent (free IgE and surface IgE) and duration to omalizumab. At Day 85, 6 weeks after the last dose, skin prick wheal responses to allergen were suppressed by > 95% and 41% in subjects treated subcutaneously with QGE031 (2 mg/kg) or omalizumab, respectively (P < 0.001). Urticaria was observed in QGE031- and placebo-treated subjects and was accompanied by systemic symptoms in one subject treated with 10 mg/kg intravenous QGE031. There were no serious adverse events. CONCLUSION AND CLINICAL RELEVANCE: These first clinical data for QGE031, a high-affinity IgG1κ anti-IgE, demonstrate that increased suppression of free IgE compared with omalizumab translated to superior pharmacodynamic effects in atopic subjects, including those with high IgE levels. QGE031 may therefore benefit patients unable to receive, or suboptimally treated with, omalizumab.

Association at SYNE1 in both bipolar disorder and recurrent major depression.

Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10⁻7, odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10⁻8, OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.