Predictors of psychopathology response in atypical anorexia nervosa following inpatient treatment: A propensity score matching study of weight suppression and weight loss speed.

INTRODUCTION: This study examines weight suppression (WS) and weight loss speed (WLS) in atypical anorexia nervosa (AN) and its implications for treatment outcomes, compared to people with AN and bulimia nervosa (BN). METHOD: A mixed cross-sectional and prospective design was employed, assessing WS and WLS in people with atypical AN, AN, and BN. Participants were matched for age, gender, age of onset, and disorder duration. Clinical measurements and eating disorders questionnaire (EDE-Q) scores were employed to evaluate the response to treatment. RESULTS: Individuals with atypical individuals exhibited WS patterns similar to AN, distinct from BN. Rapid WLS predicted clinical responses in atypical AN and BN, underscoring its treatment relevance. Atypical AN showed higher eating psychopathology scores than AN or BN, emphasizing the need for a reframed diagnosis. DISCUSSION: Understanding atypical AN's connection to restrictive behaviors and weight loss informs screening, assessment, and treatment practices. Recognition of atypical AN's severity and adoption of tailored approaches are essential for recovery. This study highlights the significance of WS and WLS in atypical AN treatment outcomes, offering insights into clinical practice and care. The proposal to reframe atypical AN as a restrictive eating disorder emphasizes its clinical relevance. PUBLIC SIGNIFICANCE STATEMENT: The phenomenon of weight suppression, involving the discrepancy between past highest weight and current weight, has garnered attention due to cultural pressures emphasizing fitness and appearance. This study focuses on its implications in atypical anorexia nervosa, aiming to uncover the relationship between WS, its speed, and treatment outcomes. The investigation contributes insights into tailored interventions for atypical anorexia nervosa and enriches the understanding of this complex disorder's dynamics.

A Pilot Interaction Analysis of Gut Microbiota and Peripheral Markers of Aging in Severe Psychiatric Disorders: A Role for Lachnoclostridium?

Excessive predominance of pathological species in the gut microbiota could increase the production of inflammatory mediators at the gut level and, via modification of the gut-blood barrier, at the systemic level. This pro-inflammatory state could, in turn, increase biological aging that is generally proxied by telomere shortening. In this study, we present findings from a secondary interaction analysis of gut microbiota, aging, and inflammatory marker data from a cohort of patients with different diagnoses of severe mental disorders. We analyzed 15 controls, 35 patients with schizophrenia (SCZ), and 31 patients with major depressive disorder (MDD) recruited among those attending a community mental health center (50 males and 31 females, mean and median age 46.8 and 46.3 years, respectively). We performed 16S rRNA sequencing as well as measurement of telomere length via quantitative fluorescence in situ hybridization and high-sensitivity C-reactive protein. We applied statistical modeling with logistic regression to test for interaction between gut microbiota and these markers. Our results showed statistically significant interactions between telomere length and gut microbiota pointing to the genus Lachnostridium, which remained significantly associated with a reduced likelihood of MDD even after adjustment for a series of covariates. Although exploratory, these findings show that specific gut microbiota signatures overexpressing Lachnoclostridium and interacting with biological aging could modulate the liability for MDD.

Preparing for the next pandemic by understanding the impact of COVID-19 mitigation measures on patients with eating Disorders: observations from an inpatient setting.

OBJECTIVE: The COVID-19 pandemic overwhelmed eating disorder (ED) services worldwide. Data suggests a worsening of psychopathology and an increased request for specialised treatments. Still, the studies are mostly based on experimental protocols with underpowered short-term opportunistic experimental designs. Thus, this study aims to assess the clinical and psychological differences between patients admitted to a specialised ED Unit before and after the COVID-19 breakout. METHODS: Consecutive patients admitted from June 2014 to February 2022 in a specialised EDs Unit were enrolled. A total sample of 498 individuals was enrolled in this retrospective study, collecting demographic and psychopathological data at admission. RESULTS: An increase in the admission of patients with anorexia nervosa has been reported, with lower age and higher levels of specific and general psychopathology, especially linked to body uneasiness. CONCLUSIONS: Results are put into the context of the preparation for the next pandemic that may require similar mitigation measures as COVID-19 to ensure the impact on existing and new patients. Covering an extended period with validated tools, our results might help psychiatric services to reassess their treatment pathways after the pandemic, helping clinicians to delineate future treatment interventions.KEYPOINTSAfter the COVID-19 breakdown, there was an increase in the admission of patients with anorexia nervosa to specialised services.More severe psychopathology was not accompanied by lower body mass index.Specialised eating disorders services should face sudden changes in patients' requests for treatment.Understanding the impact of the Covid-19 pandemic and the resulting mitigation measures taken can lead to better preparations for the next pandemic.

Understanding dropout and non-participation in follow-up evaluation for the benefit of patients and research: evidence from a longitudinal observational study on patients with eating disorders.

Treatment outcomes in eating disorders (EDs) are still an open field for clinicians and researchers. Besides difficulties in egosyntonic-linked treatment engagements, dropout is one of the most crucial elements that cause a reduction in the treatment efficacy. Thus, the aim of this study is to evaluate factors that could contribute to high dropout rates and non-participation in follow-up evaluation in patients with ED. This study used a large sample of patients from a specialized ED ward and day hospital (DH). A sample of 428 individuals was recruited for this study. Psychological and demographic data were collected at the time of hospitalization and discharge from the facilities. These data were used to explore a possible link between dropout and follow-up non-participation. Specially, the random forest was used to rank demographic and psychological features in importance and evaluate the top results with regression analyses for statistical significance. A dropout rate of 12.14% during inpatient and DH treatment was found. Anger-hostility and general psychopathology were found to be predictors of dropout during treatment, while the duration of the hospitalization predicted non-participation at the six-month follow-up. Specific psychological features should be considered before and during treatments for patients with EDs to reduce dropout rates. The duration of the hospitalization should also be evaluated as a relevant healthcare element that could affect engagement and, accordingly, outcome.

A systematic review of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients reveals potentially clinically informative panels as well as key challenges in miRNA research.

Breast cancer patients are at a particularly high risk of cardiotoxicity from chemotherapy having a detrimental effect on quality-of-life parameters and increasing the risk of mortality. Prognostic biomarkers would allow the management of therapies to mitigate the risks of cardiotoxicity in vulnerable patients and a key potential candidate for such biomarkers are microRNAs (miRNA). miRNAs are post-transcriptional regulators of gene expression which can also be released into the circulatory system and have been associated with the progression of many chronic diseases including many types of cancer. In this review, the evidence for the potential application of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity (CIC) in breast cancer patientsis evaluated and a simple meta-analysis is performed to confirm the replication status of each reported miRNA. Further selection of miRNAs is performed by reviewing the reported associations of each miRNA with other cardiovascular conditions. Based on this research, the most representative panels targeting specific chemotherapy agents and treatment regimens are suggested, that contain several informative miRNAs, including both general markers of cardiac damage as well as those for the specific cancer treatments.

Exercise and Occupational Stress among Firefighters.

The aim of our study was to evaluate the potential association between physical activity and occupational stress among firefighters. Data were collected from Cypriot firefighters through a web-based battery of internationally validated questionnaires completed anonymously (COPSOQ, DASS). A total of 430 firefighters (response rate 68%) completed the survey (age range: 21-60 years). More than half of the firefighters (54%) reported either no or minimal physical activity. A total of 11% of firefighters reported moderate to extremely severe stress based on the DASS-S scale. Using multivariable-adjusted logistic regression models, we showed that firefighters who exercised had 50% lower risk of occupational stress, and using a categorical model, we found that every hour per week of increased physical activity among firefighters was associated with 16% lower risk of occupational stress after adjusting for age, education, smoking, and body mass index (OR = 1.16; p = 0.05). In addition, our findings suggest an inverse dose-response relationship between physical activity and occupational stress among firefighters. Physical activity appears to be inversely associated with occupational stress and serves as an important mitigating factor of occupational stress in firefighters. Further research is warranted to evaluate the potential effect of exercise interventions on occupational stress, and the overall mental health of firefighters and other occupational groups.

Impulsive behaviors and clinical outcomes following a flexible intensive inpatient treatment for eating disorders: findings from an observational study.

PURPOSE: The aim of the study was to assess the differences between impulsive and non-impulsive patients in response to a multidisciplinary intensive inpatient treatment for eating disorders (EDs). METHODS: 320 patients with EDs were consecutively recruited in an eating disorders unit (EDU). They were assessed by clinical interviews and self-reported questionnaires. The treatment was characterized by a patient-centric approach and included both an intensive and comprehensive standardized multidisciplinary program based on cognitive-behavioral therapy and a flexible and personalized component according to the needs and the history of each patient. RESULTS: Impulsive ED patients showed greater improvement in specific psychopathological areas, in particular: interpersonal sensitivity of Symptom Checklist-90 (SCL-90) (p = 0.007); Eating Disorder Examination Questionnaire (EDE-Q) Global Score (p = 0.009), EDE-Q eating concern (p < 0.001) and EDE-Q shape concern (p = 0.025). The two groups also showed a different pattern on the Body Uneasiness Test, with impulsive patients uniquely showing improvement on Global Severity Index (p = 0.006), body image concern (p = 0.008), compulsive self monitoring (p = 0.002), and weight phobia (p = 0.037). DISCUSSION: Results support the hypothesis that patients with impulsive behaviors might benefit from treatments characterized by a standardized cognitive behavioral therapy implemented by third-wave interventions according to each patient's clinical profile. Personalized treatment approaches could be an answer to the complexity of ED, addressing individual psychopathology. Further studies are needed to confirm these preliminary findings. LEVEL OF EVIDENCE: III, cohort or case-control analytic studies.

Relation between vitamin D and impulse behaviours in patients with eating disorder: a pilot observational study.

OBJECTIVE: There is growing evidence that vitamin D levels have a role not only in bone health and energy metabolism, but also for supporting nervous system and brain functions, including impulsivity. Impulsive behaviours are considered characteristics of great relevance in patients with Eating Disorders (ED) both for the course of the illness and for the treatment. The aim of this study is to examine the relationship between impulsive behaviours and vitamin D in patients with ED. METHOD: 236 patients with a diagnosis of ED, consecutively recruited at an ED ward between 2014 and 2018, were enrolled. Patients were classified as impulsive or non-impulsive based on the presence of clinically relevant impulsive behaviours. RESULTS: Impulsive patients were found to have statistically significant lower levels of vitamin D than non-impulsive (p = .007). A threshold value of 20.4 ng/ml for discriminating impulsive from non-impulsive patients was found. DISCUSSION: This hypothesis generating study partially confirmed a relationship between vitamin D deficiency and impulsive behaviours in ED spectrum mediated by body weight, even if results were not confirmed after corrected by obesity. No definitive conclusion may be taken on whether the effect is reduced due to the loss of power. Future directions are discussed.

Work-Related Psychological Distress and Its Management: The Perspective of Employees in the Financial Industry Compared With Those in Human Services.

OBJECTIVE: Investigate psychological distress and its link to stress management interventions in the financial industry (FI) in comparison to the human services (HS) sector. METHOD: Observational study across participating organizations in FI (66) and HS (81). Web-based version of depression anxiety stress scales (21 questions) and eight questions related to stress prevention interventions adopted by employers. RESULTS: Indicated that FI workers are twice as likely as HS employees to present with stress and depression. Differences emerged on the availability of support at the workplace: FI workers reporting total lack of psychological support, although other forms of wellbeing promotion were more frequent. Close to 60% of individuals in the HS group reported no support (48% in the FI). CONCLUSION: Workers in the FI industry have increased levels of workplace stress that could be possibly attributed to absence of prevention interventions at the workplace.

eHealth Interventions for Anxiety Management Targeting Young Children and Adolescents: Exploratory Review.

BACKGROUND: Advances in technology are progressively more relevant to the clinical practice of psychology and mental health services generally. Studies indicate that technology facilitates the delivery of interventions, such as cognitive behavioral therapy, in the treatment of psychological disorders in adults, such as depression, anxiety, obsessive-compulsive disorder, panic symptoms, and eating disorders. Fewer data exist for computer-based (stand-alone, self-help) and computer-assisted (in combination with face-to-face therapy, or therapist guided) programs for youth. OBJECTIVE: Our objective was to summarize and critically review the literature evaluating the acceptability and efficacy of using technology with treatment and prevention programs for anxiety in young children and adolescents. The aim was to improve the understanding of what would be critical for future development of effective technology-based interventions. METHODS: We conducted an exploratory review of the literature through searches in 3 scientific electronic databases (PsycINFO, ScienceDirect, and PubMed). We used keywords in various combinations: child or children, adolescent, preschool children, anxiety, intervention or treatment or program, smartphone applications or apps, online or Web-based tool, computer-based tool, internet-based tool, serious games, cognitive behavioral therapy or CBT, biofeedback, and mindfulness. For inclusion, articles had to (1) employ a technological therapeutic tool with or without the guidance of a therapist; (2) be specific for treatment or prevention of anxiety disorders in children or adolescents; (3) be published between 2000 and 2018; and (4) be published in English and in scientific peer-reviewed journals. RESULTS: We identified and examined 197 articles deemed to be relevant. Of these, we excluded 164 because they did not satisfy 1 or more of the requirements. The final review comprised 19 programs. Published studies demonstrated promising results in reducing anxiety, especially relative to the application of cognitive behavioral therapy with technology. For those programs demonstrating efficacy, no difference was noted when compared with traditional interventions. Other approaches have been applied to technology-based interventions with inconclusive results. Most programs were developed to be used concurrently with traditional treatments and lacked long-term evaluation. Very little has been done in terms of prevention interventions. CONCLUSIONS: Future development of eHealth programs for anxiety management in children will have to address several unmet needs and overcome key challenges. Although developmental stages may limit the applicability to preschool children, prevention should start in early ages. Self-help formats and personalization are highly relevant for large-scale dissemination. Automated data collection should be built in for program evaluation and effectiveness assessment. And finally, a strategy to stimulate motivation to play and maintain high adherence should be carefully considered.

Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals.

BackgroundDepression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.AimsTo confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.MethodThe sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.ResultsIn the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (ß = 0.12, P = 2.7 × 10-4) and with the Han/Eskin random effects method (P = 1.4 × 10-7) but not with traditional random effects (ß = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (ß = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10-8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTOConclusionsThis meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.

No association between NRG1 and ErbB4 genes and psychopathological symptoms of schizophrenia.

Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5' end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1.

BACKGROUND: Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD). METHODS: Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples. RESULTS: Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling. CONCLUSIONS: The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.

Investigating the genetic variation underlying episodicity in major depressive disorder: suggestive evidence for a bipolar contribution.

BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.

Genome-wide association analysis accounting for environmental factors through propensity-score matching: application to stressful live events in major depressive disorder.

Stressful life events are an established trigger for depression and may contribute to the heterogeneity within genome-wide association analyses. With depression cases showing an excess of exposure to stressful events compared to controls, there is difficulty in distinguishing between "true" cases and a "normal" response to a stressful environment. This potential contamination of cases, and that from genetically at risk controls that have not yet experienced environmental triggers for onset, may reduce the power of studies to detect causal variants. In the RADIANT sample of 3,690 European individuals, we used propensity score matching to pair cases and controls on exposure to stressful life events. In 805 case-control pairs matched on stressful life event, we tested the influence of 457,670 common genetic variants on the propensity to depression under comparable level of adversity with a sign test. While this analysis produced no significant findings after genome-wide correction for multiple testing, we outline a novel methodology and perspective for providing environmental context in genetic studies. We recommend contextualizing depression by incorporating environmental exposure into genome-wide analyses as a complementary approach to testing gene-environment interactions. Possible explanations for negative findings include a lack of statistical power due to small sample size and conditional effects, resulting from the low rate of adequate matching. Our findings underscore the importance of collecting information on environmental risk factors in studies of depression and other complex phenotypes, so that sufficient sample sizes are available to investigate their effect in genome-wide association analysis.

A genomewide association study of smoking relapse in four European population-based samples.

OBJECTIVES: Genomewide association studies (GWAS) have identified clear evidence of genetic markers for nicotine dependence. Other smoking phenotypes have been tested, but the results are less consistent. The tendency to relapse versus the ability to maintain long-term abstinence has received little attention in genetic studies; thus, our aim was to provide a better biological understanding of this phenotype through the identification of genetic loci associated with smoking relapse. METHODS: We carried out a GWAS on data from two European population-based collections, including a total of 835 cases (relapsers) and 990 controls (abstainers). Top-ranked findings from the discovery phase were tested for replication in two additional independent European population-based cohorts. RESULTS: Of the seven top markers from the discovery phase, none were consistently associated with smoking relapse across all samples and none reached genomewide significance. A single-nucleotide polymorphism rs1008509, within the Xylosyltransferase II (XYLT2) gene, was suggestively associated with smoking relapse in the discovery phase (ß=-0.504; P=5.6E-06) and in the first replication sample (ALSPAC) (ß=-0.27; P=0.004; n=1932), but not in the second sample (KORA) (ß=0.19; P=0.138; n=912). We failed to identify an association between loci implicated previously in other smoking phenotypes and smoking relapse. CONCLUSION: Although no genomewide significant findings emerged from this study, we found that loci implicated in other smoking phenotypes were not associated with smoking relapse, which suggests that the neurobiology of smoking relapse and long-term abstinence may be distinct from biological mechanisms implicated in the development of nicotine dependence.

Dissecting the genetic heterogeneity of depression through age at onset.

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.

Genetic variation in GOLM1 and prefrontal cortical volume in Alzheimer's disease.

Replications of the association between APOE-ε4 allele load and regional brain atrophy in Alzheimer's disease (AD) patients hold promise for future studies testing relationships between other disease risk gene variants and brain structure. A polymorphism, rs10868366, in the Golgi phosphoprotein 2 gene, GOLM1, was recently identified as an AD risk factor in a genome-wide association study. In a subset of the same AD cohort, we used voxel-based morphometry to test for association between the disease risk genotype and reduced regional gray matter (GM) volume in AD patients (n = 72). A mean 14% reduction in GM volume was observed in the left frontal gyrus with the higher risk GG genotype. A similar association was observed in an independent, dataset of nondemented subjects (n = 278), although with a smaller effect (1%). This replicated association with GM structural variation suggests that GOLM1 polymorphisms may be related to cognitive phenotypes. The greater effect size in AD patients also suggests that the GG genotype could be a risk factor for the expression of cognitive deficits in AD.

Genomewide association scan of suicidal thoughts and behaviour in major depression.

BACKGROUND: Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT. METHODOLOGY/PRINCIPAL FINDINGS: A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality. CONCLUSIONS/SIGNIFICANCE: This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further.