Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Dysregulated relationship of inflammation and oxidative stress in major depression.

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response.

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic.

NicVAX, a nicotine vaccine (3'AmNic-rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether dosages and frequency of administration are associated with increased Ab response. This randomized, double-blinded, placebo-controlled multicenter clinical trial (N = 301 smokers) tested the results of 200- and 400-µg doses administered four or five times over a period of 6 months, as compared with placebo. 3'AmNic-rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14-6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five-injection, 400-µg dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3'AmNic-rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified.

Genome-wide linkage scan of bipolar disorder in a Colombian population isolate replicates Loci on chromosomes 7p21-22, 1p31, 16p12 and 21q21-22 and identifies a novel locus on chromosome 12q.

BACKGROUND/AIMS: Bipolar disorder (BP) is a severe psychiatric illness, characterised by alternating episodes of depression and mania, which ranks among the top ten causes of morbidity and life-long disability world-wide. We have previously performed a whole-genome linkage scan on 6 pedigrees segregating severe BP from the well-characterised population isolate of Antioquia, Colombia. We recently collected genotypes for the same set of 382 autosomal microsatellite markers in 9 additional Antioquian BP pedigrees. Here, we report the analysis of the combined pedigree set. METHODS: Linkage analysis using both parametric and nonparametric approaches was conducted for 3 different diagnostic models: severe BP only (BPI); mood disorders (BPI, BPII and major depression); and psychosis (operationally defined by the occurrence of at least 1 episode of hallucinations and/or delusions). RESULTS AND CONCLUSION: For BPI only, the most interesting result was obtained for chromosome 7p21.1-p22.2 under a recessive model of inheritance (heterogeneity LOD score = 2.80), a region that had previously been linked to BP in a study on Portuguese Island families. For both BPI and mood disorders, nonparametric analyses identified a locus on chromosome 12ct-q14 (nonparametric linkage = 2.55 and 2.35, respectively). This locus has not previously been reported as a candidate region for BP. Additional candidate regions were found on chromosomes 1p22-31 (mood disorders) and 21q21-22 (BPI), 2 loci that have repeatedly been implicated in BP susceptibility. Linkage analysis of psychosis as a phenotype identified candidate regions on chromosomes 2q24-31 and 16p12-q12. The finding on chromosome 16p is noteworthy because the same locus has been implicated by genome-wide association analyses of BP.

A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees.

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.

Multimodal techniques for smoking cessation: a review of their efficacy and utilisation and clinical practice guidelines.

AIMS: Nicotine addiction is a complex, chronic condition with physiological and psychological/behavioural aspects that make smoking cessation extremely difficult. This paper reviews current recommendations for smoking cessation and the efficacy of pharmacotherapy and behavioural modification techniques, used either alone or in combination, for smoking cessation. RESULTS: Abstinence rates for pharmacotherapies range from approximately 16% to approximately 30% at 1-year follow-up, with efficacy odds ratios (ORs) compared with placebo of approximately 1.7 for nicotine replacement therapy (NRT), approximately 1.9 for bupropion sustained release and approximately 3.0 for varenicline. Behaviour modification therapies have achieved quit rates of between 8% and 43% for up to 1 year, with ORs in comparison to no treatment of between approximately 1.2 and approximately 2.2. No direct comparisons have been made between pharmacotherapy alone and psychological behaviour strategies alone. However, combining physiological approaches with counselling significantly increases the odds of quitting compared with either technique alone. CONCLUSIONS: Applying multimodal techniques for the treatment of nicotine addiction is the recommended approach and has demonstrated the potential to improve rates of permanent abstinence in smokers attempting cessation. While the numbers of patients receiving help and advice regarding smoking cessation is increasing, the multimodal approach appears to be currently underutilised by clinicians and therefore smoking cessation strategies are not being optimised.

Therapeutic drug monitoring of nortriptyline in smoking cessation: a multistudy analysis.

Multiple, controlled clinical trials support the efficacy of nortriptyline as a smoking cessation agent. Although therapeutic plasma nortriptyline concentrations (PNCs) are known for the treatment of depression, little is known about PNCs in smoking cessation treatment. PNCs from three randomized, placebo-controlled smoking cessation trials (N=244) were analyzed both separately and pooled. PNCs normalized for dose and weight were associated with cigarettes per day and race, but not with sex or age. Greater smoking was associated with decreased normalized PNCs. In addition, both Asian and black populations had significantly higher normalized PNCs than the white populations. Weak and inconsistent associations between PNCs and self-reported side effects were observed. PNCs were linearly related to end of treatment and long-term biochemically verified smoking abstinence. Maximum therapeutic effects were observed over a range of plasma concentrations somewhat lower than those found effective for the treatment of depression.

The pharmacogenetics research network: from SNP discovery to clinical drug response.

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

Catecholamine response to methamphetamine is related to glucocorticoid levels but not to pleasurable subjective response.

INTRODUCTION: Corticosteroids may modulate addiction. We previously described subjective, physiological, and endocrine effects of 0.5 mg/kg of intravenous methamphetamine after augmenting cortisol level with hydrocortisone or blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone in a double-blind, balanced crossover study. Although the pharmacologic manipulations produced the expected hormonal changes, pleasurable subjective effects of methamphetamine were unchanged. Metyrapone was followed by frequent premature ventricular complexes (PVCs) in two subjects during methamphetamine administration. In order to better understand these results, we examined changes in two plasma catecholamine metabolites, homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and their relationship to the previously reported hormonal changes and physiological and subjective responses. METHODS: Plasma from 10 methamphetamine subjects from the earlier study was assayed for HVA and MHPG by high performance liquid chromatography. RESULTS: HVA levels were greater after hydrocortisone or metyrapone pretreatment compared to placebo, and MHPG levels were greater after metyrapone pretreatment. Hydrocortisone pretreatment diminished HVA and MHPG increases after methamphetamine (perhaps explaining the lack of expected increase in pleasurable effects), but metyrapone did not. HVA and MHPG concentrations were not correlated with pleasurable drug effects but were inversely related to reports of "Bad Drug Effect." Increases in MHPG and DHEA concentrations were positively correlated. Metyrapone pre-treated subjects with PVCs had lower HVA and MHPG concentrations. CONCLUSION: Raising cortisol concentration and blocking cortisol synthesis did not produce opposite effects, perhaps because of metyrapone's effect on the hypothalamic-pituitary-adrenal axis, its stress-like effects, and its effects on neurosteroids.

Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control.

BACKGROUND: Self injurious behaviour (SIB), the deliberate, repetitive infliction of self harm, is present in a wide variety of neuropsychiatric disorders, including Tourette syndrome (TS). Although SIB occurs in up to 60% of individuals with TS, and can cause significant clinical impairment and distress, little is known about its aetiology. OBJECTIVE: This study examined the relationship between SIB and other behavioural features that commonly co-occur with TS in nearly 300 subjects with TS participating in three genetic studies. SIB, obsessions, compulsions, tic severity, attention deficit hyperactivity disorder related impulsivity, risk taking behaviours, and rages were systematically assessed in all subjects. METHODS: Using logistic regression, a best fit model was determined for both mild to moderate SIB and severe SIB. RESULTS: Mild/moderate SIB in TS was correlated with the presence of obsessive and compulsive symptoms such as the presence of aggressive obsessions or violent or aggressive compulsions, and with the presence of obsessive-compulsive disorder and overall number of obsessions. Severe SIB in TS was correlated with variables related to affect or impulse dysregulation; in particular, with the presence of episodic rages and risk taking behaviours. Both mild/moderate and severe SIB were also correlated with tic severity. CONCLUSIONS: This study suggests that mild/moderate and severe SIB in TS may represent different phenomena, which has implications for clinical management of these symptoms.

Hormonal changes with cholesterol reduction: a double-blind pilot study.

BACKGROUND: The lowering of high serum cholesterol levels may be associated with increased non-cardiac mortality due to behavioral changes, although such endpoints are likely rare. OBJECTIVE: This current study sought to determine if hormonal changes accompany pharmacologically induced decreases in serum cholesterol levels. METHOD: Cholesterol, dopamine, homovanillic acid (HVA), serotonin, 5-HIAA, testosterone, cortisol and pregnenolone were measured at baseline and after 4 weeks of treatment. RESULTS: Subjects' cholesterol levels significantly declined within 4 weeks. Concomitant significant increase in dopamine and HVA were noted. CONCLUSION: Although this study is limited in size, it raises the possibility that cholesterol-lowering drug treatment is associated with hormonal perturbations.

DHEA treatment of Alzheimer's disease: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the efficacy and tolerability of dehydroepiandrosterone (DHEA) vs placebo in AD. METHOD: Fifty-eight subjects with AD were randomized to 6 month's treatment with DHEA (50 mg per os twice a day; n = 28) or placebo (n = 30) in a multi-site, double-blind pilot trial. Primary efficacy measures assessed cognitive functioning (the AD Assessment Scale-Cognitive [ADAS-Cog]) and observer-based ratings of overall changes in severity (the Clinician's Interview-Based Impression of Change with Caregiver Input [CIBIC-Plus]). At baseline, 3 months, and 6 months, the ADAS-Cog was administered, and at 3 and 6 months, the CIBIC-Plus was administered. The 6-month time point was the primary endpoint. RESULTS: Nineteen DHEA-treated subjects and 14 placebo-treated subjects completed the trial. DHEA was relatively well-tolerated. DHEA treatment, relative to placebo, was not associated with improvement in ADAS-Cog scores at month 6 (last observation carried forward; p = 0.10); transient improvement was noted at month 3 (p = 0.014; cutoff for Bonferroni significance = 0.0125). No difference between treatments was seen on the CIBIC-Plus at either the 6-month or the 3-month time points. CONCLUSIONS: DHEA did not significantly improve cognitive performance or overall ratings of change in severity in this small-scale pilot study. A transient effect on cognitive performance may have been seen at month 3, but narrowly missed significance.

Cortisol levels predict cognitive impairment induced by electroconvulsive therapy.

BACKGROUND: Elevated glucocorticoids may increase the vulnerability of the brain to the adverse effects of repeated seizures. This study tested the hypothesis that higher ambient cortisol levels would predict increased cognitive impairment in depressed patients subsequent to receiving electroconvulsive therapy (ECT) for major depression. METHODS: Sixteen subjects provided three samples of saliva the day before receiving unilateral nondominant ECT. Measures of mood, global cognitive functioning, attention, executive function, verbal and visuospatial memory, and visuospatial processing speed were obtained 1 day before the first ECT and 1 day after the sixth ECT treatment. The relationship between basal salivary cortisol obtained before the first ECT treatment and the change score of each cognitive measure after the sixth ECT treatment was examined and tested with Pearson correlation coefficients. RESULTS: Electroconvulsive therapy treatments delivered over 2 weeks resulted in a significant improvement in mood and a decline in most measures of cognitive performance. Elevated basal cortisol was associated with a greater decline in performance of executive function, visuospatial processing speed, and verbal memory. CONCLUSIONS: Although this study is limited by the small number of subjects and the high number of comparisons, all significant correlations were consistent with the hypothesis that elevated cortisol predicts a greater degree of ECT-induced cognitive impairment.

Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population.

We have searched for genes predisposing to bipolar disorder (BP) by studying individuals with the most extreme form of the affected phenotype, BP-I, ascertained from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The results of a previous linkage analysis on two extended CVCR BP-I pedigrees, CR001 and CR004, and of linkage disequilibrium (LD) analyses of a CVCR population sample of BP-I patients implicated a candidate region on 18p11.3. We further investigated this region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism markers for typing in the pedigree and population samples. We report the results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in pedigree CR001. Our results suggest a candidate region containing six genes but also highlight the complexities of LD mapping of common disorders.

Loci geneticos asociados al trastorno bipolar: estudios en poblacion colombiana / Genetic loci associated to bipolar disorder: studies in colombian population

Objetivos: Caracterizar una muestra de familias y tríos de una población colombiana aislada para mapear loci involucrados en la vulnerabilidad al Trastorno Afectivo Bipolar tipo I (TAB- I). Métodos: Se recolectan tríos y genealogías utilizando las entrevistas FIGS-DIGS en miembros de las familias y posibles afectados. El poder para detectar ligamiento (PDL) se estima por simulación. El modelo utilizado asume una frecuencia para el alelo afectado de 0.003, penetrancias de 0.01,0.81 y 0.9 y un marcador de cuatro alelos a 5cM del locus. Resultados: Se identificaron 28 familias con TAB-I, con 3.603 individuos y 160 afectados, y 246 tríos. Asumiendo homogeneidad genética y teniendo en cuenta la evidencia genética del mestizaje, las simulaciones mostraron PDL significativos de 100 por ciento para un LOD-score>3. Estamos examinando el desequilibrio promedio en tríos y tamizando en familias los cromosomas 12,18 y 21. Conclusión: Tenemos un grupo significativo de familias y trios pertenecientes a una población aislada con un poder para detectar ligamiento al Trastorno Afectivo Bipolar. Esto permite realizar estudios de ligamiento buscando genes involucrados en la vulnerabilidad al TAB-I en población Colombiana

Assortative mating in the affective disorders: a systematic review and meta-analysis.

Assortative mating, or the tendency for individuals with similar phenotypes to mate more frequently than expected by chance, has been reported for a variety of complex traits, including many neuropsychiatric disorders. Although assortative mating has been reported in affective disorders, the studies done to date have been inconclusive. This study attempts to assess the degree of assortative mating in individuals with affective disorders using systematic review and meta-analytic techniques. Studies on assortative mating in affective disorders were identified by a computerized literature search and by bibliographic assessment of published studies and reviews. Studies were selected if they had a case-control design and if they reported rates of affective disorders in the spouses of probands and controls. Of the 17 studies reviewed, six were selected for meta-analysis. All studies were blinded. Details of study design, patient characteristics, and rates of affective disorders were assessed by two independent reviewers. Twelve of the 17 studies assessed reported an increase in assortative mating. Results of the meta-analysis supported these findings, and indicated that assortative mating occurs in both bipolar disorder and major depression. Although most studies examined reported an increase in assortative mating among individuals with affective disorders, the degree of assortative mating reported varied widely. Meta-analysis with six controlled studies showed evidence for assortative mating, and suggested that the degree of assortative mating is higher for individuals with bipolar disorder than for those with major depression. These results support the previously reported findings, and may have important implications for genetic studies.

Cultural influences on diagnosis and perception of Tourette syndrome in Costa Rica.

BACKGROUND AND OBJECTIVES: Tourette syndrome (TS) is a neuropsychiatric disorder in which the pattern of symptom presentation can vary greatly between individuals. Although globally described, TS has not been well characterized in many parts of the world. Differences in individual and cultural perceptions of TS may impact its expression and recognition in some countries, confounding the identification of affected individuals. This study examines the phenomenology and presentation of TS in Costa Rica. METHOD: Clinical data on 85 Costa Rican subjects with TS (aged 5-29 years) initially recruited for a genetic study between 1996 and early 2000 were obtained by direct interview and review of medical records. RESULTS: The clinical characteristics of TS were similar to that found elsewhere. The gender ratio was 4.6:1, the mean age of onset was 6.1 years, and 20% of subjects had coprolalia. However, the perceived impact of TS was different. Many subjects denied that their TS caused impairment or distress, even when objective evidence of impairment was available. CONCLUSIONS: TS in Costa Rica is phenomenologically similar to TS seen in other parts of the world, but differs in perceived impairment. In other countries where cultural forces affect disease definition, close scrutiny of symptom expression and possible adjustment of phenotype definition may be important.

Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18.

Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP-I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome-wide analysis are instructive for genome-wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP-I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP-I locus on 18q12.2 is also described.