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  1. Nurnberger JI, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I, et al.
    JAMA Psychiatry, 2014 Jun;71(6):657-64.
    PMID: 24718920 DOI: 10.1001/jamapsychiatry.2014.176
    IMPORTANCE: Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders.

    OBJECTIVE: To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS).

    DATA SOURCES: Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data.

    STUDY SELECTION: The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample.

    DATA EXTRACTION AND SYNTHESIS: We identified 966 genes that contained 2 or more variants associated with BP at P

  2. Milaneschi Y, Lamers F, Peyrot WJ, Baune BT, Breen G, Dehghan A, et al.
    JAMA Psychiatry, 2017 12 01;74(12):1214-1225.
    PMID: 29049554 DOI: 10.1001/jamapsychiatry.2017.3016
    Importance: The association between major depressive disorder (MDD) and obesity may stem from shared immunometabolic mechanisms particularly evident in MDD with atypical features, characterized by increased appetite and/or weight (A/W) during an active episode.

    Objective: To determine whether subgroups of patients with MDD stratified according to the A/W criterion had a different degree of genetic overlap with obesity-related traits (body mass index [BMI] and levels of C-reactive protein [CRP] and leptin).

    Design, Setting, and Patients: This multicenter study assembled genome-wide genotypic and phenotypic measures from 14 data sets of the Psychiatric Genomics Consortium. Data sets were drawn from case-control, cohort, and population-based studies, including 26 628 participants with established psychiatric diagnoses and genome-wide genotype data. Data on BMI were available for 15 237 participants. Data were retrieved and analyzed from September 28, 2015, through May 20, 2017.

    Main Outcomes and Measures: Lifetime DSM-IV MDD was diagnosed using structured diagnostic instruments. Patients with MDD were stratified into subgroups according to change in the DSM-IV A/W symptoms as decreased or increased.

    Results: Data included 11 837 participants with MDD and 14 791 control individuals, for a total of 26 628 participants (59.1% female and 40.9% male). Among participants with MDD, 5347 (45.2%) were classified in the decreased A/W and 1871 (15.8%) in the increased A/W subgroups. Common genetic variants explained approximately 10% of the heritability in the 2 subgroups. The increased A/W subgroup showed a strong and positive genetic correlation (SE) with BMI (0.53 [0.15]; P = 6.3 × 10-4), whereas the decreased A/W subgroup showed an inverse correlation (-0.28 [0.14]; P = .06). Furthermore, the decreased A/W subgroup had a higher polygenic risk for increased BMI (odds ratio [OR], 1.18; 95% CI, 1.12-1.25; P = 1.6 × 10-10) and levels of CRP (OR, 1.08; 95% CI, 1.02-1.13; P = 7.3 × 10-3) and leptin (OR, 1.09; 95% CI, 1.06-1.12; P = 1.7 × 10-3).

    Conclusions and Relevance: The phenotypic associations between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiologic mechanisms in patients with MDD. Development of treatments effectively targeting immunometabolic dysregulations may benefit patients with depression and obesity, both syndromes with important disability.

  3. DeVylder JE, Kelleher I, Lalane M, Oh H, Link BG, Koyanagi A
    JAMA Psychiatry, 2018 Jul 01;75(7):678-686.
    PMID: 29799917 DOI: 10.1001/jamapsychiatry.2018.0577
    Importance: Urban residence is one of the most well-established risk factors for psychotic disorder, but most evidence comes from a small group of high-income countries.
    Objective: To determine whether urban living is associated with greater odds for psychosis in low- and middle-income countries (LMICs).
    Design, Setting, and Participants: This international population-based study used cross-sectional survey data collected as part of the World Health Organization (WHO) World Health Survey from May 2, 2002, through December 31, 2004. Participants included nationally representative general population probability samples of adults (≥18 years) residing in 42 LMICs (N = 215 682). Data were analyzed from November 20 through December 5, 2017.
    Exposures: Urban vs nonurban residence, determined by the WHO based on national data.
    Main Outcomes and Measures: Psychotic experiences, assessed using the WHO Composite International Diagnostic Interview psychosis screen, and self-reported lifetime history of a diagnosis of a psychotic disorder.
    Results: Among the 215 682 participants (50.8% women and 49.2% men; mean [SD] age, 37.9 [15.7] years), urban residence was not associated with psychotic experiences (odds ratio [OR], 0.99; 95% CI, 0.89-1.11) or psychotic disorder (OR, 0.89; 95% CI, 0.76-1.06). Results of all pooled analyses and meta-analyses of within-country effects approached a null effect, with an overall OR of 0.97 (95% CI, 0.87-1.07), OR for low-income countries of 0.98 (95% CI, 0.82-1.15), and OR for middle-income countries of 0.96 (95% CI, 0.84-1.09) for psychotic experiences and an overall OR of 0.92 (95% CI, 0.73-1.16), OR for low-income countries of 0.92 (95% CI, 0.66-1.27), and OR for middle-income countries of 0.92 (95% CI, 0.67-1.27) for psychotic disorder.
    Conclusions and Relevance: Our results provide evidence that urbanicity, a well-established risk factor for psychosis, may not be associated with elevated odds for psychosis in developing countries. This finding may provide better understanding of the mechanisms by which urban living may contribute to psychosis risk in high-income countries, because urban-rural patterns of cannabis use, racial discrimination, and socioeconomic disparities may vary between developing and developed nations.
    Study name: World Health Survey (Malaysia is a study site)
  4. Rajan S, McKee M, Rangarajan S, Bangdiwala S, Rosengren A, Gupta R, et al.
    JAMA Psychiatry, 2020 10 01;77(10):1052-1063.
    PMID: 32520341 DOI: 10.1001/jamapsychiatry.2020.1351
    Importance: Depression is associated with incidence of and premature death from cardiovascular disease (CVD) and cancer in high-income countries, but it is not known whether this is true in low- and middle-income countries and in urban areas, where most people with depression now live.

    Objective: To identify any associations between depressive symptoms and incident CVD and all-cause mortality in countries at different levels of economic development and in urban and rural areas.

    Design, Setting, and Participants: This multicenter, population-based cohort study was conducted between January 2005 and June 2019 (median follow-up, 9.3 years) and included 370 urban and 314 rural communities from 21 economically diverse countries on 5 continents. Eligible participants aged 35 to 70 years were enrolled. Analysis began February 2018 and ended September 2019.

    Exposures: Four or more self-reported depressive symptoms from the Short-Form Composite International Diagnostic Interview.

    Main Outcomes and Measures: Incident CVD, all-cause mortality, and a combined measure of either incident CVD or all-cause mortality.

    Results: Of 145 862 participants, 61 235 (58%) were male and the mean (SD) age was 50.05 (9.7) years. Of those, 15 983 (11%) reported 4 or more depressive symptoms at baseline. Depression was associated with incident CVD (hazard ratio [HR], 1.14; 95% CI, 1.05-1.24), all-cause mortality (HR, 1.17; 95% CI, 1.11-1.25), the combined CVD/mortality outcome (HR, 1.18; 95% CI, 1.11-1.24), myocardial infarction (HR, 1.23; 95% CI, 1.10-1.37), and noncardiovascular death (HR, 1.21; 95% CI, 1.13-1.31) in multivariable models. The risk of the combined outcome increased progressively with number of symptoms, being highest in those with 7 symptoms (HR, 1.24; 95% CI, 1.12-1.37) and lowest with 1 symptom (HR, 1.05; 95% CI, 0.92 -1.19; P for trend 

  5. Lee CH, Ko AM, Yang FM, Hung CC, Warnakulasuriya S, Ibrahim SO, et al.
    JAMA Psychiatry, 2018 03 01;75(3):261-269.
    PMID: 29417149 DOI: 10.1001/jamapsychiatry.2017.4307
    Importance: Betel-quid (BQ) is the fourth most popular psychoactive agent worldwide. An emerging trend across Asia is the addictive consumption of BQ, which is associated with oral cancer and other health consequences.

    Objective: To investigate the validity and pattern of DSM-5-defined BQ use disorder (BUD) and its association with oral potentially malignant disorder (OPMD) among Asian populations.

    Design, Setting, and Participants: In-person interviews were conducted from January 1, 2009, to February 28, 2010, among a random sample of 8922 noninstitutionalized adults from the Asian Betel-quid Consortium study, an Asian representative survey of 6 BQ-endemic populations. Statistical analysis was performed from January 1, 2015, to December 31, 2016.

    Main Outcomes and Measures: Participants were evaluated for BUD using DSM-5 criteria for substance use disorder and for OPMD using a clinical oral examination. Current users of BQ with 0 to 1 symptoms were classified as having no BUD, those with 2 to 3 symptoms as having mild BUD, those with 4 to 5 symptoms as having moderate BUD, and those with 6 or more symptoms as having severe BUD.

    Results: Among the 8922 participants (4564 women and 4358 men; mean [SD] age, 44.2 [0.2] years), DSM-5 symptoms showed sufficient unidimensionality to act as a valid measure for BUD. The 12-month prevalence of DSM-5-defined BUD in the 6 study populations was 18.0% (mild BUD, 3.2%; moderate BUD, 4.3%; and severe BUD, 10.5%). The 12-month proportion of DSM-5-defined BUD among current users of BQ was 86.0% (mild BUD, 15.5%; moderate BUD, 20.6%; and severe BUD, 50.0%). Sex, age, low educational level, smoking, and drinking were significantly associated with BUD. Among individuals who used BQ, family use, high frequency of use, and amount of BQ used were significantly linked to moderate to severe BUD. Compared with individuals who did not use BQ, those who used BQ and had no BUD showed a 22.0-fold (95% CI, 4.3-112.4) risk of OPMD (P 

  6. Giannakopoulou O, Lin K, Meng X, Su MH, Kuo PH, Peterson RE, et al.
    JAMA Psychiatry, 2021 Nov 01;78(11):1258-1269.
    PMID: 34586374 DOI: 10.1001/jamapsychiatry.2021.2099
    IMPORTANCE: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations.

    OBJECTIVE: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression.

    DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021.

    EXPOSURES: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts.

    MAIN OUTCOMES AND MEASURES: Depression status was defined based on health records and self-report questionnaires.

    RESULTS: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent.

    CONCLUSIONS AND RELEVANCE: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

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