Evening chronotype, disordered eating behavior, and poor dietary habits in bipolar disorder.

OBJECTIVE: Our aim was to evaluate the relationship between evening chronotype, a proxy marker of circadian system dysfunction, and disordered eating behavior and poor dietary habits in individuals with bipolar disorder (BD). METHODS: In this cross-sectional study, we evaluated 783 adults with BD. Chronotype was determined using item 5 from the reduced Morningness-Eveningness Questionnaire. The Eating Disorder Diagnostic Scale (EDDS) and the Rapid Eating Assessment for Participants-Shortened Version (REAP-S) were used to assess disordered eating behavior and dietary habits respectively. General linear models and logistic regression models were utilized to evaluate differences between chronotype groups. RESULTS: Two hundred and eight (27%) BD participants self-identified as having evening chronotypes. Compared to non-evening types, evening types were younger (P < 0.01) and, after controlling for age, had higher mean EDDS composite z-scores (P < 0.01); higher rates of binge-eating (BE) behavior (P = 0.04), bulimia nervosa (P < 0.01), and nocturnal eating binges (P < 0.01); and a higher body mass index (P = 0.04). Compared to non-evening types, evening chronotypes had a lower REAP-S overall score (P < 0.01) and scored lower on the 'healthy foods' and 'avoidance of unhealthy food' factors. Evening types also skipped breakfast more often (P < 0.01), ate less fruit (P = 0.02) and vegetables (P = 0.04), and consumed more fried foods (P < 0.01), unhealthy snacks (P = 0.02), and soft drinks (P = 0.01). CONCLUSIONS: Our findings suggest that the circadian system plays a role in the disordered eating and unhealthy dietary behaviors observed in BD patients. The circadian system may therefore represent a therapeutic target in BD-associated morbidity that warrants further investigation.

Increased cardiovascular mortality in people with schizophrenia: a 24-year national register study.

AimsPeople who have schizophrenia die earlier from somatic diseases than do people in the general population, but information about cardiovascular deaths in people who have schizophrenia is limited. We analysed mortality in all age groups of people with schizophrenia by specific cardiovascular diseases (CVDs), focusing on five CVD diagnoses: coronary heart disease, acute myocardial infarction, cerebrovascular disease, heart failure and cardiac arrhythmias. We also compared hospital admissions for CVDs in people who had schizophrenia with hospital admissions for CVDs in the general population. METHODS: This national register study of 10 631 817 people in Sweden included 46 911 people who were admitted to the hospital for schizophrenia between 1 January 1987 and 31 December 2010. Information from national registers was used to identify people who had schizophrenia and obtain data about mortality, causes of death, medical diagnoses and hospitalisations. RESULTS: CVDs were the leading cause of death in people who had schizophrenia (5245 deaths), and CVDs caused more excess deaths than suicide. The mean age of CVD death was 10 years lower for people who had schizophrenia (70.5 years) than the general population (80.7 years). The mortality rate ratio (MRR) for CVDs in all people who had schizophrenia was 2.80 (95% confidence interval (CI) 2.73-2.88). In people aged 15-59 years who had schizophrenia, the MRR for CVDs was 6.16 (95% CI 5.79-6.54). In all people who had schizophrenia, the MRR for coronary heart disease was 2.83 (95% CI 2.73-2.94); acute myocardial infarction, 2.62 (95% CI 2.49-2.75); cerebrovascular disease, 2.4 (95% CI 2.25-2.55); heart failure, 3.25 (95% CI 2.94-3.6); and cardiac arrhythmias, 2.06 (95% CI 1.75-2.43). Hospital admissions for coronary heart disease were less frequent in people who had schizophrenia than in the general population (admission rate ratio, 0.88 (95% CI 0.83-0.94). In all age groups, survival after hospital admission for CVD was lower in people who had schizophrenia than in the general population. CONCLUSIONS: People who had schizophrenia died 10 years earlier from CVDs than did people in the general population. For all five CVD diagnoses, mortality risk was higher for those with schizophrenia than those in the general population. Survival after hospitalisation for CVDs in people who had schizophrenia was comparable with that of people in the general population who were several decades older.

Spatial variation in the parasite communities and genomic structure of urban rats in New York City.

Brown rats (Rattus norvegicus) are a globally distributed pest. Urban habitats can support large infestations of rats, posing a potential risk to public health from the parasites and pathogens they carry. Despite the potential influence of rodent-borne zoonotic diseases on human health, it is unclear how urban habitats affect the structure and transmission dynamics of ectoparasite and microbial communities (all referred to as "parasites" hereafter) among rat colonies. In this study, we use ecological data on parasites and genomic sequencing of their rat hosts to examine associations between spatial proximity, genetic relatedness and the parasite communities associated with 133 rats at five sites in sections of New York City with persistent rat infestations. We build on previous work showing that rats in New York carry a wide variety of parasites and report that these communities differ significantly among sites, even across small geographical distances. Ectoparasite community similarity was positively associated with geographical proximity; however, there was no general association between distance and microbial communities of rats. Sites with greater overall parasite diversity also had rats with greater infection levels and parasite species richness. Parasite community similarity among sites was not linked to genetic relatedness of rats, suggesting that these communities are not associated with genetic similarity among host individuals or host dispersal among sites. Discriminant analysis identified site-specific associations of several parasite species, suggesting that the presence of some species within parasite communities may allow researchers to determine the sites of origin for newly sampled rats. The results of our study help clarify the roles that colony structure and geographical proximity play in determining the ecology of R. norvegicus as a significant urban reservoir of zoonotic diseases. Our study also highlights the spatial variation present in urban rat parasite communities, indicating that rats across New York City are not reservoirs for a homogenous set of parasites and pathogens. As a result, the epidemiological risks may be similarly heterogeneous for people in urban habitats.

Association of the serotonin transporter-linked polymorphic region genotype with lower bone mineral density.

The serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) S allele is linked to pathogenesis of depression and slower response to selective serotonin reuptake inhibitors (SSRIs); depression and SSRIs are independently associated with bone loss. We aimed to determine whether 5-HTTLPR was associated with bone loss. This cross-sectional study included psychiatric patients with both 5-HTTLPR analysis and bone mineral density (BMD) assessment (hip and spine Z-scores if age <50 years and T-scores if ⩾50 years). BMD association with 5-HTTLPR was evaluated under models with additive allele effects and dominant S allele effects using linear regression models. Patients were stratified by age (<50 and ⩾50 years) and sex. Of 3016 patients with 5-HTTLPR genotyping, 239 had BMD assessments. Among the younger patients, the S allele was associated with lower Z-scores at the hip (P=0.002, dominant S allele effects; P=0.004, additive allele effects) and spine (P=0.0006, dominant S allele effects; P=0.01, additive allele effects). In sex-stratified analyses, the association of the S allele with lower BMD in the younger patients was also significant in the subset of women (P⩽0.003 for both hip and spine BMD under the additive allele effect model). In the small group of men younger than 50 years, the S allele was marginally associated with higher spine BMD (P=0.05). BMD T-scores were not associated with 5-HTTLPR genotypes in patients 50 years or older. The 5-HTTLPR variants may modify serotonin effects on bone with sex-specific effects.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Leveraging electronic health records to study pleiotropic effects on bipolar disorder and medical comorbidities.

Patients with bipolar disorder (BD) have a high prevalence of comorbid medical illness. However, the mechanisms underlying these comorbidities with BD are not well known. Certain genetic variants may have pleiotropic effects, increasing the risk of BD and other medical illnesses simultaneously. In this study, we evaluated the association of BD-susceptibility genetic variants with various medical conditions that tend to co-exist with BD, using electronic health records (EHR) data linked to genome-wide single-nucleotide polymorphism (SNP) data. Data from 7316 Caucasian subjects were used to test the association of 19 EHR-derived phenotypes with 34 SNPs that were previously reported to be associated with BD. After Bonferroni multiple testing correction, P<7.7 × 10(-5) was considered statistically significant. The top association findings suggested that the BD risk alleles at SNP rs4765913 in CACNA1C gene and rs7042161 in SVEP1 may be associated with increased risk of 'cardiac dysrhythmias' (odds ratio (OR)=1.1, P=3.4 × 10(-3)) and 'essential hypertension' (OR=1.1, P=3.5 × 10(-3)), respectively. Although these associations are not statistically significant after multiple testing correction, both genes have been previously implicated with cardiovascular phenotypes. Moreover, we present additional evidence supporting these associations, particularly the association of the SVEP1 SNP with hypertension. This study shows the potential for EHR-based analyses of large cohorts to discover pleiotropic effects contributing to complex psychiatric traits and commonly co-occurring medical conditions.

TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.

Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.

Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders.

The objective of this study was to determine whether proteomic profiling in serum samples can be utilized in identifying and differentiating mood disorders. A consecutive sample of patients with a confirmed diagnosis of unipolar (UP n=52) or bipolar depression (BP-I n=46, BP-II n=49) and controls (n=141) were recruited. A 7.5-ml blood sample was drawn for proteomic multiplex profiling of 320 proteins utilizing the Myriad RBM Discovery Multi-Analyte Profiling platform. After correcting for multiple testing and adjusting for covariates, growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4) and transthyretin (TTR) all showed statistically significant differences among groups. In a series of three post hoc analyses correcting for multiple testing, MMP-7 was significantly different in mood disorder (BP-I+BP-II+UP) vs controls, MMP-7, GDF-15, HPN were significantly different in bipolar cases (BP-I+BP-II) vs controls, and GDF-15, HPX, HPN, RBP-4 and TTR proteins were all significantly different in BP-I vs controls. Good diagnostic accuracy (ROC-AUC⩾0.8) was obtained most notably for GDF-15, RBP-4 and TTR when comparing BP-I vs controls. While based on a small sample not adjusted for medication state, this discovery sample with a conservative method of correction suggests feasibility in using proteomic panels to assist in identifying and distinguishing mood disorders, in particular bipolar I disorder. Replication studies for confirmation, consideration of state vs trait serial assays to delineate proteomic expression of bipolar depression vs previous mania, and utility studies to assess proteomic expression profiling as an advanced decision making tool or companion diagnostic are encouraged.

Preliminary Survey of Ectoparasites and Associated Pathogens from Norway Rats in New York City.

The Norway rat (Rattus norvegicus) is a reservoir of many zoonotic pathogens and lives in close proximity to humans in urban environments. Human infection with rodent-borne disease occurs either directly through contact with a rat or its excreta, or indirectly via arthropod vectors such as fleas and ticks. Here, we report on the diversity and abundance of ectoparasitic arthropod species and associated pathogenic bacteria from 133 Norway rats trapped over a 10-mo period in Manhattan, New York, NY. Norway rats were host to the tropical rat mite [Ornithonyssus bacoti (Hirst)], the spiny rat mite (Laelaps echidnina Berlese), Laelaps nuttalli Hirst, the spined rat louse [Polyplax spinulosa (Burmeister)], and the Oriental rat flea [(Xenopsylla cheopis) (Rothschild)], with an average of 1.7 species per individual. A flea index of 4.1 X. cheopis was determined, whereas previous studies in New York City reported 0.22 fleas per rat. Multiple species of pathogenic Bartonella were identified from Oriental rat fleas that were related to Bartonella tribocorum, Bartonella rochalimae, and Bartonella elizabethae. However, no evidence of Yersinia pestis or Rickettsia spp. infection was detected in fleas. The identification of multiple medically important ectoparasite species in New York City underscores the need for future efforts to fully characterize the diversity and distribution of ectoparasites on Norway rats, and assess the risk to humans of vector-borne disease transmission.

Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects.

Acamprosate has been widely used since the Food and Drug Administration approved the medication for treatment of alcohol use disorders (AUDs) in 2004. Although the detailed molecular mechanism of acamprosate remains unclear, it has been largely known that acamprosate inhibits glutamate action in the brain. However, AUD is a complex and heterogeneous disorder. Thus, biomarkers are required to prescribe this medication to patients who will have the highest likelihood of responding positively. To identify pharmacometabolomic biomarkers of acamprosate response, we utilized serum samples from 120 alcohol-dependent subjects, including 71 responders (maintained continuous abstinence) and 49 non-responders (any alcohol use) during 12 weeks of acamprosate treatment. Notably, baseline serum glutamate levels were significantly higher in responders compared with non-responders. Importantly, serum glutamate levels of responders are normalized after acamprosate treatment, whereas there was no significant glutamate change in non-responders. Subsequent functional studies in animal models revealed that, in the absence of alcohol, acamprosate activates glutamine synthetase, which synthesizes glutamine from glutamate and ammonia. These results suggest that acamprosate reduces serum glutamate levels for those who have elevated baseline serum glutamate levels among responders. Taken together, our findings demonstrate that elevated baseline serum glutamate levels are a potential biomarker associated with positive acamprosate response, which is an important step towards development of a personalized approach to treatment for AUD.

Sex differences in mania phenotype and ethanol consumption in the lateral hypothalamic kindled rat model.

Sex differences have been observed in mania phenotypes in humans. However the mechanisms underlying this difference are poorly understood. Activating the lateral hypothalamus is implicated in manic-like behaviors in rodents. Using newly established lateral hypothalamus kindled (LHK) rat mania model, we investigated sex differences of manic-like behaviors and its correlation with voluntary ethanol intake. We stimulated the lateral hypothalamus bilaterally in the male and female Wistar rats over five consecutive days. We recorded and quantified kindling-induced behaviors for each individual animal. We also assessed ethanol consumption using a two-bottle choice ethanol drinking as well as circadian locomotor activity counts daily throughout the experiment. We found notable sex differences in several aspects of manic-like behaviors during kindling. Males exhibited a significantly increased locomotor activity during the light phase, and reduced rest interval. On the other hand, females displayed significantly higher ethanol consumption and more frequent rearing behavior. However, no sex differences were present in the duration of sexual, feeding or grooming behaviors or in dark-phase activity counts. The excessive alcohol intake in LHK female rats is reminiscent of clinically reported sex differences in bipolar patients while the other phenotypic sex differences such as rearing and locomotor activity are less clearly described in clinical studies. Overall, our results lend further evidence for the validity of the LHK rat as a useful model to study brain region-specific molecular changes during mania and its correlation with alcohol use disorders.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate.

Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P=4.6 × 10(-5)). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P=0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

Risk of myocardial infarction and stroke in bipolar disorder: a systematic review and exploratory meta-analysis.

OBJECTIVE: To review the evidence on and estimate the risk of myocardial infarction and stroke in bipolar disorder. METHOD: A systematic search using MEDLINE, EMBASE, PsycINFO, Web of Science, Scopus, Cochrane Database of Systematic Reviews, and bibliographies (1946 - May, 2013) was conducted. Case-control and cohort studies of bipolar disorder patients age 15 or older with myocardial infarction or stroke as outcomes were included. Two independent reviewers extracted data and assessed quality. Estimates of effect were summarized using random-effects meta-analysis. RESULTS: Five cohort studies including 13 115 911 participants (27 092 bipolar) were included. Due to the use of registers, different statistical methods, and inconsistent adjustment for confounders, there was significant methodological heterogeneity among studies. The exploratory meta-analysis yielded no evidence for a significant increase in the risk of myocardial infarction: [relative risk (RR): 1.09, 95% CI 0.96-1.24, P = 0.20; I(2)  = 6%]. While there was evidence of significant study heterogeneity, the risk of stroke in bipolar disorder was significantly increased (RR 1.74, 95% CI 1.29-2.35; P = 0.0003; I(2)  = 83%). CONCLUSION: There may be a differential risk of myocardial infarction and stroke in patients with bipolar disorder. Confidence in these pooled estimates was limited by the small number of studies, significant heterogeneity and dissimilar methodological features.

More pernicious course of bipolar disorder in the United States than in many European countries: implications for policy and treatment.

BACKGROUND: There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries. METHODS: We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics. RESULTS: Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment. LIMITATIONS: Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation. CONCLUSIONS: The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity.

Effects of racing on reticulocyte concentrations in Greyhounds.

BACKGROUND: Greyhounds have several hematologic variables that are outside of the respective reference intervals of other dog breeds. In addition, increases in HCT, total protein and HGB concentration, and RBC and WBC counts occur immediately after exercise; these values return to resting values within a few hour after racing. OBJECTIVE: This study evaluated the effects of exercise on the concentration of reticulocytes in circulating blood in racing Greyhounds. We hypothesized that reticulocyte numbers are significantly increased immediately after a race, and return to baseline within one to 2 h postrace. METHODS: Fifty actively racing Greyhounds at the Wheeling Island Racetrack and Casino were included in the study. Samples were collected by jugular venipuncture one day prior to racing at the kennel (resting), immediately after racing, and one to 2 h after the race (recovery). Reticulocyte counts were determined with an IDEXX ProCyte Dx Hematology Analyzer (IDEXX Laboratories, Inc., Westbrook, ME, USA). Due to a nonparametric distribution, the results were statistically compared using the Friedman test. RESULTS: Reticulocyte concentrations were significantly different among the 3 sample collection times (P < .0001). There was a significant increase in reticulocyte concentration immediately after racing (P < .001); one to 2 h after racing, the reticulocyte numbers decreased significantly (P < .001) to counts comparable to resting samples. CONCLUSION: The increase in reticulocyte concentration is probably related to splenic contraction secondary to the release of catecholamines, although premature bone marrow release could also account for these changes. Thus, it is important to consider a Greyhound's activity and degree of excitement when interpreting selected hematologic data in a clinical setting.

Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2.

Bipolar disorder (BD) is associated with higher body mass index (BMI) and increased metabolic comorbidity. Considering the associated phenotypic traits in genetic studies of complex diseases, either by adjusting for covariates or by investigating interactions between genetic variants and covariates, may help to uncover the missing heritability. However, obesity-related traits have not been incorporated in prior genome-wide analyses of BD as covariates or potential interacting factors. To investigate the genetic factors underlying BD while considering BMI, we conducted genome-wide analyses using data from the Genetic Association Information Network BD study. We analyzed 729,454 genotyped single-nucleotide polymorphism (SNP) markers on 388 European-American BD cases and 1020 healthy controls with available data for maximum BMI. We performed genome-wide association analyses of the genetic effects while accounting for the effect of maximum BMI, and also evaluated SNP-BMI interactions. A joint test of main and interaction effects demonstrated significant evidence of association at the genome-wide level with rs12772424 in an intron of TCF7L2 (P=2.85E-8). This SNP exhibited interaction effects, indicating that the bipolar susceptibility risk of this SNP is dependent on BMI. TCF7L2 codes for the transcription factor TCF/LF, part of the Wnt canonical pathway, and is one of the strongest genetic risk variants for type 2 diabetes (T2D). This is consistent with BD pathophysiology, as the Wnt pathway has crucial implications in neurodevelopment, neurogenesis and neuroplasticity, and is involved in the mechanisms of action of BD and depression treatments. We hypothesize that genetic risk for BD is BMI dependent, possibly related to common genetic risk with T2D.

Increased parental history of bipolar disorder in the United States: association with early age of onset.

OBJECTIVE: Early-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder. METHOD: Parental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by χ2 and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected. RESULTS: After controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder. CONCLUSION: Parental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.