TY  - JOUR
AB  - IMPORTANCE: Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as depression. OBJECTIVE: To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian randomization, and evaluate the interplay of the human gut microbiome and metabolome in the development of MDD. DESIGN, SETTING AND PARTICIPANTS: This cohort study used data from participants in the UK Biobank cohort (n = 500 000; aged 37 to 73 years; recruited from 2006 to 2010) whose blood was profiled for metabolomics. Replication was sought in the PREDICT and BBMRI-NL studies. Publicly available summary statistics from a 2019 genome-wide association study of depression were used for the mendelian randomization (individuals with MDD = 59 851; control individuals = 113 154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118 000). To evaluate the interplay of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were obtained from a 2019 study performed in Dutch cohorts. Data were analyzed from March to December 2021. MAIN OUTCOMES AND MEASURES: Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform. RESULTS: The study included 6811 individuals with lifetime MDD compared with 51 446 control individuals and 4370 individuals with recurrent MDD compared with 62 508 control individuals. Individuals with lifetime MDD were younger (median [IQR] age, 56 [49-62] years vs 58 [51-64] years) and more often female (4447 [65%] vs 2364 [35%]) than control individuals. Metabolic signatures of MDD consisted of 124 metabolites spanning the energy and lipid metabolism pathways. Novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (ie, citrate and pyruvate). Citrate was significantly decreased (β [SE], -0.07 [0.02]; FDR = 4 × 10-04) and pyruvate was significantly increased (β [SE], 0.04 [0.02]; FDR = 0.02) in individuals with MDD. Changes observed in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. Mendelian randomization suggested that fatty acids and intermediate and very large density lipoproteins changed in association with the disease process but high-density lipoproteins and the metabolites in the tricarboxylic acid cycle did not. CONCLUSIONS AND RELEVANCE: The study findings showed that energy metabolism was disturbed in individuals with MDD and that the interplay of the gut microbiome and blood metabolome may play a role in lipid metabolism in individuals with MDD.
AU  - Amin, N.*
AU  - Liu, J.*
AU  - Bonnechere, B.*
AU  - MahmoudianDehkordi, S.*
AU  - Arnold, M.
AU  - Batra, R.*
AU  - Chiou, Y.J.*
AU  - Fernandes, M.*
AU  - Ikram, M.A.*
AU  - Kraaij, R.*
AU  - Krumsiek, J.*
AU  - Newby, D.*
AU  - Nho, K.*
AU  - Radjabzadeh, D.*
AU  - Saykin, A.J.*
AU  - Shi, L.*
AU  - Sproviero, W.*
AU  - Winchester, L.*
AU  - Yang, Y.*
AU  - Nevado-Holgado, A.J.*
AU  - Kastenmüller, G.
AU  - Kaddurah-Daouk, R.*
AU  - van Duijn, C.M.*
C1  - 67685
C2  - 53992
CY  - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa
SP  - 597-609
TI  - Interplay of metabolome and gut microbiome in individuals with major depressive disorder vs control individuals.
JO  - JAMA psychiatry
VL  - 80
IS  - 6
PB  - Amer Medical Assoc
PY  - 2023
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - Importance: Intimate partner violence (IPV), including physical, sexual, and emotional violence, constitutes a critical public health problem, particularly in low- and middle-income countries. While climate change could escalate violent events, data quantifying its possible association with IPV are scant. Objective: To evaluate the association of ambient temperature with the prevalence of IPV among partnered women in low- and middle-income countries in South Asia, and to estimate the association of future climate warming with IPV. Design, Setting, and Participants: This cross-sectional study used data from the Demographic and Health Survey and included 194871 ever-partnered women aged 15 to 49 years from 3 South Asian countries (India, Nepal, and Pakistan). The study applied the mixed-effect multivariable logistic regression model to investigate the association of ambient temperature with IPV prevalence. The study further modeled the change in IPV prevalence under various future climate change scenarios. The data included in the analyses were collected from October 1, 2010, to April 30, 2018, and the current analyses were performed from January 2, 2022, to July 11, 2022. Exposure: Annual ambient temperature exposure for each woman, estimated based on an atmospheric reanalysis model of the global climate. Main Outcomes and Measures: The prevalence of IPV and its types (physical, sexual, and emotional violence) were assessed based on self-reported questionnaires from October 1, 2010, to April 30, 2018, and the changes in the prevalence with climate changes were estimated through the 2090s. Results: The study included 194871 ever-partnered women aged 15 to 49 years (mean [SD] age, 35.4 [7.6] years; overall IPV prevalence, 27.0%) from 3 South Asian countries. The prevalence of physical violence was highest (23.0%), followed by emotional (12.5%), and sexual violence (9.5%). The annual temperature ranges were mostly between 20 °C and 30 °C. A significant association was found between high ambient temperature and the prevalence of IPV against women, with each 1 °C increase in the annual mean temperature associated with a mean increase in IPV prevalence of 4.49% (95% CI, 4.20%-4.78%). According to the study's projections under the unlimited emissions scenarios (SSPs [shared socioeconomic pathways], as defined by the Intergovernmental Panel on Climate Change] 5-8.5), IPV prevalence would increase by 21.0% by the end of the 21st century, while it would only moderately increase under increasingly stricter scenarios (SSP2-4.5 [9.8%] and SSP1-2.6 [5.8%]). In addition, the projected increases in the prevalence of physical (28.3%) and sexual (26.1%) violence were greater than that of emotional violence (8.9%). In the 2090s, India was estimated to experience the highest IPV prevalence increase (23.5%) among the 3 countries, compared with Nepal (14.8%) and Pakistan (5.9%). Conclusions and Relevance: This cross-sectional, multicountry study provides ample epidemiological evidence to support that high ambient temperature may be associated with the risk of IPV against women. These findings highlight the vulnerabilities and inequalities of women experiencing IPV in low- and middle-income countries in the context of global climate warming.
AU  - Zhu, Y.*
AU  - He, C.
AU  - Bell, M.*
AU  - Zhang, Y.*
AU  - Fatmi, Z.*
AU  - Zaid, M.*
AU  - Bachwenkizi, J.*
AU  - Liu, C.*
AU  - Zhou, L.*
AU  - Chen, R.*
AU  - Kan, H.*
C1  - 68318
C2  - 54649
CY  - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa
SP  - 952-961
TI  - Association of ambient temperature with the prevalence of intimate partner violence among partnered women in low-and middle-income south Asian countries.
JO  - JAMA psychiatry
VL  - 80
IS  - 9
PB  - Amer Medical Assoc
PY  - 2023
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - This genetic correlation and 2-sample mendelian randomization study uses large-scale genome-wide association data sources to explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms.Importance Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. Objective To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. GWAS Data Sources Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms [eg, insomnia and hypersomnia]) as measured with the Patient Health Questionnaire 9 (up to 117;907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386533 individuals); body mass index (BMI) (up to 322154 individuals); and height (up to 253280 individuals). Design In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant-based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. Results Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)-controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate [SE], 0.035 [0.010]; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. Conclusions and Relevance This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strategy for suicide prevention.Question Do inflammatory pathways share a genetic background with individual depressive symptoms, and do they potentially causally contribute to them? Findings Based on large genome-wide association study data sources, this genetic correlation and 2-sample mendelian randomization study found genetic overlap between a higher C-reactive protein (CRP) level, a broad marker of inflammation, and 9 depressive symptoms; upregulated interleukin-6 signaling, a major stimulator of CRP, emerged as a potential causal risk factor for suicidality. Body mass index, but not interleukin 6 or CRP, was potentially causally associated with 4 other depressive symptoms. Meaning Interleukin 6 overactivity could be associated with suicidality; interleukin-6 blockade may be a novel treatment target that warrants future research.
AU  - Kappelmann, N.*
AU  - Knauer-Arloth, J.
AU  - Georgakis, M.K.*
AU  - Czamara, D.*
AU  - Rost, N.*
AU  - Ligthart, S.*
AU  - Khandaker, G.M.*
AU  - Binder, E.B.*
C1  - 60427
C2  - 49452
CY  - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa
SP  - 161-170
TI  - Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms. A genetic correlation and 2-sample mendelian randomization study.
JO  - JAMA psychiatry
VL  - 78
IS  - 2
PB  - Amer Medical Assoc
PY  - 2021
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - This cohort study aims to detect psychosis subgroups and examine their illness courses over 1.5 years and their polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement.Question Will data-driven clustering using high-dimensional clinical data reveal psychosis subgroups with relevance to prognoses and polygenic risk? Findings In this cohort study including 1223 individuals, in the discovery sample of 765 individuals with predominantly bipolar and schizophrenia diagnoses, 5 subgroups were detected with different clinical signatures, illness trajectories, and genetic scores for educational attainment. Results were validated in a sample of 458 individuals. Meaning New data-driven clustering paired with rigorous validation may offer a means to extend symptom-based psychosis taxonomies toward functional outcomes, genetic markers, and trajectory-based stratifications.Importance Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations. Objective To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement. Design, Setting, and Participants This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019. Main Outcomes and Measures A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables. Results Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R-2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R-2 = 0.28; 95% CI, 0.25-0.32), global functioning (R-2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R-2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial eta(2) = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort. Conclusions and Relevance Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.
AU  - Dwyer, D.B.*
AU  - Kalman, J.L.*
AU  - Budde, M.*
AU  - Kambeitz, J.*
AU  - Ruef, A.*
AU  - Antonucci, L.A.*
AU  - Kambeitz-Ilankovic, L.*
AU  - Hasan, A.*
AU  - Kondofersky, I.
AU  - Anderson-Schmidt, H.*
AU  - Gade, K.*
AU  - Reich-Erkelenz, D.*
AU  - Adorjan, K.*
AU  - Senner, F.*
AU  - Schaupp, S.*
AU  - Andlauer, T.F.M.*
AU  - Comes, A.L.*
AU  - Schulte, E.C.*
AU  - Klöhn-Saghatolislam, F.*
AU  - Gryaznova, A.*
AU  - Hake, M.*
AU  - Bartholdi, K.*
AU  - Flatau-Nagel, L.*
AU  - Reitt, M.*
AU  - Quast, S.*
AU  - Stegmaier, S.*
AU  - Meyers, M.*
AU  - Emons, B.*
AU  - Haußleiter, I.S.*
AU  - Juckel, G.*
AU  - Nieratschker, V.*
AU  - Dannlowski, U.*
AU  - Yoshida, T.*
AU  - Schmauß, M.*
AU  - Zimmermann, J.*
AU  - Reimer, J.*
AU  - Wiltfang, J.*
AU  - Reininghaus, E.*
AU  - Anghelescu, I.G.*
AU  - Arolt, V.*
AU  - Baune, B.T.*
AU  - Konrad, C.*
AU  - Thiel, A.*
AU  - Fallgatter, A.J.*
AU  - Figge, C.*
AU  - von Hagen, M.*
AU  - Koller, M.*
AU  - Lang, F.U.*
AU  - Wigand, M.E.*
AU  - Becker, T.*
AU  - Jäger, M.*
AU  - Dietrich, D.E.*
AU  - Scherk, H.*
AU  - Spitzer, C.*
AU  - Folkerts, H.*
AU  - Witt, S.H.*
AU  - Degenhardt, F.*
AU  - Forstner, A.J.*
AU  - Rietschel, M.*
AU  - Nöthen, M.M.*
AU  - Müller, N.S.
AU  - Papiol, S.*
AU  - Heilbronner, U.*
AU  - Falkai, P.*
AU  - Schulze, T.G.*
AU  - Koutsouleris, N.*
C1  - 58646
C2  - 48193
CY  - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa
SP  - 523-533
TI  - An investigation of psychosis subgroups with prognostic validation and exploration of genetic underpinnings: The PsyCourse study.
JO  - JAMA psychiatry
VL  - 77
IS  - 5
PB  - Amer Medical Assoc
PY  - 2020
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - IMPORTANCE Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers.OBJECTIVE To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood.DESIGN, SETTING, AND PARTICIPANTS To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts.MAIN OUTCOMES AND MEASURES Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire.RESULTS The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%) women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 x 10(-)(08); n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 x 10(-09); n = 11256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 x 10(-)(08); n = 11256; chromosome = 15q261). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 x 10(-03)) and of ARHGEF3 in fibroblasts (effect. -0.48; P = 9.8 x 10(-)(04) ) was associated with major depression.CONCLUSIONS AND RELEVANCE This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects. (C) 2018 American Medical Association. All lights reserved.
AU  - Jovanova, O.S.*
AU  - Nedeljkovic, I.*
AU  - Spieler, D.
AU  - Walker, R.M.*
AU  - Liu, C.*
AU  - Luciano, M.*
AU  - Bressler, J.*
AU  - Brody, J.*
AU  - Drake, A.J.*
AU  - Evans, K.L.*
AU  - Gondalia, R.*
AU  - Kunze, S.
AU  - Kühnel, B.
AU  - Lahti, J.*
AU  - Lemaitre, R.N.*
AU  - Marioni, R.E.*
AU  - Swenson, B.R.*
AU  - Himali, J.J.*
AU  - Wu, H.*
AU  - Li, Y.*
AU  - McRae, A.F.*
AU  - Russ, T.C.*
AU  - Stewart, J.*
AU  - Wang, Z.*
AU  - Zhang, G.*
AU  - Ladwig, K.-H.
AU  - Uitterlinden, A.G.*
AU  - Guo, X.*
AU  - Peters, A.
AU  - Räikkönen, K.*
AU  - Starr, J.M.*
AU  - Waldenberger, M.
AU  - Wray, N.R.*
AU  - Whitsel, E.A.*
AU  - Sotoodehnia, N.*
AU  - Seshadri, S*
AU  - Porteous, D.J.*
AU  - van Meurs, J.B.*
AU  - Mosley, T.H.*
AU  - McIntosh, A.M.*
AU  - Mendelson, M.M.*
AU  - Levy, D.*
AU  - Hou, L.*
AU  - Eriksson, J.G.*
AU  - Fornage, M.*
AU  - Deary, I.J.*
AU  - Baccarelli, A.*
AU  - Tiemeier, H.*
AU  - Amin, N.*
C1  - 54319
C2  - 45503
CY  - 330 N Wabash Ave, Ste 39300, Chicago, Il 60611-5885 Usa
SP  - 949-959
TI  - DNA methylation signatures of depressive symptoms in middle-aged and elderly persons meta-analysis of multiethnic epigenome-wide studies.
JO  - JAMA psychiatry
VL  - 75
IS  - 9
PB  - Amer Medical Assoc
PY  - 2018
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - IMPORTANCE Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. OBJECTIVES To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. DESIGN, SETTING, AND PARTICIPANTS Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. RESULTS Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). CONCLUSIONS AND RELEVANCE Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.
AU  - Reuter, M.S.*
AU  - Tawamie, H.*
AU  - Buchert, R.*
AU  - Gebril, O.H.*
AU  - Froukh, T.*
AU  - Thiel, C.*
AU  - Uebe, S.*
AU  - Ekici, A.B.*
AU  - Krumbiegel, M.*
AU  - Zweier, C.*
AU  - Hoyer, J.*
AU  - Eberlein, K.*
AU  - Bauer, J.*
AU  - Scheller, U.*
AU  - Strom, T.M.
AU  - Hoffjan, S.*
AU  - Abdelraouf, E.R.*
AU  - Meguid, N.A.*
AU  - Abboud, A.*
AU  - Al Khateeb, M.A.*
AU  - Fakher, M.*
AU  - Hamdan, S.*
AU  - Ismael, A.*
AU  - Muhammad, S.*
AU  - Abdallah, E.*
AU  - Sticht, H.*
AU  - Wieczorek, D.*
AU  - Reis, A.*
AU  - Abou Jamra, R.*
C1  - 50763
C2  - 42804
CY  - Chicago
SP  - 293-299
TI  - Diagnostic yield and novel candidate genes by exome sequencing in 152 consanguineous families with neurodevelopmental disorders.
JO  - JAMA psychiatry
VL  - 74
IS  - 3
PB  - Amer Medical Assoc
PY  - 2017
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - CONTEXT Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES Primary data. STUDY SELECTION Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19 505) (P = .01). CONCLUSION These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
AU  - Hartz, S.M.*
AU  - Short, S.E.*
AU  - Saccone, N.L.*
AU  - Culverhouse, R.*
AU  - Chen, L.*
AU  - Schwantes-An, T.H.*
AU  - Coon, H.*
AU  - Han, Y.*
AU  - Stephens, S.H.*
AU  - Sun, J.*
AU  - Chen, X.*
AU  - Ducci, F.*
AU  - Dueker, N.*
AU  - Franceschini, N.*
AU  - Frank, J.*
AU  - Geller, F.*
AU  - Gubjartsson, D.*
AU  - Hansel, N.N.*
AU  - Jiang, C.*
AU  - Keskitalo-Vuokko, K.*
AU  - Liu, Z.*
AU  - Lyytikäinen, L.-P.*
AU  - Michel, M.*
AU  - Rawal, R.
AU  - Rosenberger, A.*
AU  - Scheet, P.*
AU  - Shaffer, J.R.*
AU  - Teumer, A.*
AU  - Thompson, J.R.*
AU  - Vink, J.M.*
AU  - Vogelzangs, N.*
AU  - Wenzlaff, A.S.*
AU  - Wheeler, W.*
AU  - Xiao, X.*
AU  - Yang, B.Z.*
AU  - Aggen, S.H.*
AU  - Balmforth, A.J.*
AU  - Baumeister, S.E.*
AU  - Beaty, T.*
AU  - Bennett, S.*
AU  - Bergen, A.W.*
AU  - Boyd, H.A.*
AU  - Broms, U.*
AU  - Campbell, H.*
AU  - Chatterjee, N.*
AU  - Chen, J.*
AU  - Cheng, Y.C.*
AU  - Cichon, S.*
AU  - Couper, D.*
AU  - Cucca, F.*
AU  - Dick, D.M.*
AU  - Foroud, T.*
AU  - Furberg, H.*
AU  - Giegling, I.*
AU  - Gu, F.*
AU  - Hall, A.S.*
AU  - Hällfors, J.*
AU  - Han, S.*
AU  - Hartmann, A.M.*
AU  - Hayward, C.*
AU  - Heikkilä, K.*
AU  - Hewitt, J.K.*
AU  - Hottenga, J.J.*
AU  - Jensen, M.K.*
AU  - Jousilahti, P.*
AU  - Kaakinen, M.*
AU  - Kittner, S.J.*
AU  - Konte, B.*
AU  - Korhonen, T.*
AU  - Landi, M.T.*
AU  - Laatikainen, T.*
AU  - Leppert, M.*
AU  - Levy, S.M.*
AU  - Mathias, R.A.*
AU  - McNeil, D.W.*
AU  - Medland, S.E.*
AU  - Montgomery, G.W.*
AU  - Muley, T.*
AU  - Murray, T.*
AU  - Nauck, M.*
AU  - North, K.*
AU  - Pergadia, M.*
AU  - Polasek, O.*
AU  - Ramos, E.M.*
AU  - Ripatti, S.*
AU  - Risch, A.*
AU  - Ruczinski, I.*
AU  - Rudan, I.*
AU  - Salomaa, V.*
AU  - Schlessinger, D.*
AU  - Styrkarsdottir, U.*
AU  - Terracciano, A.*
AU  - Uda, M.*
AU  - Willemsen, G.*
AU  - Wu, X.*
AU  - Abecasis, G.*
AU  - Barnes, K.*
AU  - Bickeböller, H.*
AU  - Boerwinkle, E.*
AU  - Boomsma, D.I.*
AU  - Caporaso, N.*
AU  - Duan, J.*
AU  - Edenberg, H.J.*
AU  - Francks, C.*
AU  - Gejman, P.V.*
AU  - Gelernter, J.*
AU  - Grabe, H.J.*
AU  - Hops, H.*
AU  - Jarvelin, M.R.*
AU  - Viikari, J.*
AU  - Kähönen, M.*
AU  - Kendler, K.S.*
AU  - Lehtimäki, T.*
AU  - Levinson, D.F.*
AU  - Marazita, M.L.*
AU  - Marchini, J.*
AU  - Melbye, M.*
AU  - Mitchell, B.D.*
AU  - Murray, J.C.*
AU  - Nöthen, M.M.*
AU  - Penninx, B.W.*
AU  - Raitakari, O.*
AU  - Rietschel, M.*
AU  - Rujescu, D.*
AU  - Samani, N.J.*
AU  - Sanders, A.R.*
AU  - Schwartz, A.G.*
AU  - Shete, S.*
AU  - Shi, J.*
AU  - Spitz, M.*
AU  - Stefansson, K.*
AU  - Swan, G.E.*
AU  - Thorgeirsson, T.*
AU  - Völzke, H.*
AU  - Wei, Q.*
AU  - Wichmann, H.-E.
AU  - Amos, C.I.*
AU  - Breslau, N.*
AU  - Cannon, D.S.*
AU  - Ehringer, M.*
AU  - Grucza, R.*
AU  - Hatsukami, D.*
AU  - Heath, A.*
AU  - Johnson, E.O.*
AU  - Kaprio, J.*
AU  - Madden, P.*
AU  - Martin, N.G.*
AU  - Stevens, V.L.*
AU  - Stitzel, J.A.*
AU  - Weiss, R.B.*
AU  - Kraft, P.*
AU  - Bierut, L.J.*
C1  - 8458
C2  - 30114
SP  - 854-860
TI  - Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.
JO  - JAMA psychiatry
VL  - 69
IS  - 8
PB  - American Medical Assoc.
PY  - 2012
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - CONTEXT: Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder. OBJECTIVE: To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and a follow-up study in a population of German male inpatients with an early age at onset. DESIGN: The GWAS tested 524,396 single-nucleotide polymorphisms (SNPs). All SNPs with P < 10(-4) were subjected to the follow-up study. In addition, nominally significant SNPs from genes that had also shown expression changes in rat brains after long-term alcohol consumption were selected for the follow-up step. SETTING: Five university hospitals in southern and central Germany. PARTICIPANTS: The GWAS included 487 male inpatients with alcohol dependence as defined by the DSM-IV and an age at onset younger than 28 years and 1358 population-based control individuals. The follow-up study included 1024 male inpatients and 996 age-matched male controls. All the participants were of German descent. MAIN OUTCOME MEASURES: Significant association findings in the GWAS and follow-up study with the same alleles. RESULTS: The GWAS produced 121 SNPs with nominal P < 10(-4). These, together with 19 additional SNPs from homologues of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, 2 closely linked intergenic SNPs met genome-wide significance (rs7590720, P = 9.72 x 10(-9); rs1344694, P = 1.69 x 10(-8)). They are located on chromosome region 2q35, which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be associated with alcohol dependence. CONCLUSIONS: This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.
AU  - Treutlein, J.*
AU  - Cichon, S.*
AU  - Ridinger, M.*
AU  - Wodarz, N.*
AU  - Soyka, M.*
AU  - Zill, P.*
AU  - Maier, W.*
AU  - Moessner, R.*
AU  - Gaebel, W.*
AU  - Dahmen, N.*
AU  - Fehr, C.*
AU  - Scherbaum, N.*
AU  - Steffens, M.*
AU  - Ludwig, K.U.*
AU  - Frank, J.*
AU  - Wichmann, H.-E.
AU  - Schreiber, S.*
AU  - Dragano, N.*
AU  - Sommer, W.H.*
AU  - Leonardi-Essmann, F.*
AU  - Lourdusamy, A.*
AU  - Gebicke-Haerter, P.*
AU  - Wienker, T.F.*
AU  - Sullivan, P.F.*
AU  - Nöthen, M.M.*
AU  - Kiefer, F.*
AU  - Spanagel, R.*
AU  - Mann, K.*
AU  - Rietschel, M.*
C1  - 165
C2  - 27135
SP  - 773-784
TI  - Genome-wide association study of alcohol dependence.
JO  - JAMA psychiatry
VL  - 66
IS  - 7
PB  - American Medical Assoc.
PY  - 2009
SN  - 2168-622X
ER  - 

TY  - JOUR
AB  - CONTEXT: Cardiac disease and treatment with an implantable cardioverter-defibrillator (ICD) may be psychologically traumatic. Posttraumatic stress disorder (PTSD) is generally overlooked in cardiac patients, and no study to date (to our knowledge) has evaluated the effect of PTSD symptoms on the prognosis in patients with ICDs. OBJECTIVE: To test whether PTSD symptoms at baseline predict long-term mortality risk in patients with ICDs. DESIGN: Prospective cohort study with a mean follow-up period of 5.1 years, accounting for 743 person-years observed. SETTING: Data were derived from the Living With an Implanted Cardioverter-Defibrillator-Study, which initially included 211 patients with ICDs routinely attending the German Heart Center Munich outpatient clinic. PARTICIPANTS: The Impact of Event Scale-Revised was used in 147 patients (125 men and 22 women) who qualified for the "A" criterion of PTSD (survival of a life-threatening event). Thirty-eight patients scoring in the upper quartile of the scale constituted the PTSD index group. MAIN OUTCOME MEASURES: Mortality risk per 1000 person-years as assessed by Cox proportional hazards regression analysis based on an appropriate model fit (area under the curve, >0.80). RESULTS: Index patients experienced more anxiety and depression, had more cardiac symptoms, but showed no differences in left ventricular ejection fraction status or extent of ICD discharges compared with non-index patients. Forty-five patients (30.6%) died during the follow-up period. The relative mortality risk (multivariate adjusted for age, sex, diabetes mellitus, left ventricular ejection fraction, beta-blocker prescription, prior resuscitation, ICD shocks received, depression, and anxiety) hazard ratio was 3.45 (95% confidence interval, 1.57-7.60; P = .002) for the PTSD group. Compared with 55 fatal events per 1000 person-years in patients without PTSD, the long-term absolute mortality risk accounted for 80 fatal events per 1000 person-years in patients with PTSD. CONCLUSION: The adverse effect of PTSD symptoms on the long-term mortality risk in ICD-treated cardiac event survivors, independent of disease severity, supports the need for routinely applied interdisciplinary psychosocial aftercare.
AU  - Ladwig, K.-H.
AU  - Baumert, J.J.
AU  - Marten-Mittag, B.*
AU  - Kolb, C.*
AU  - Zrenner, B.*
AU  - Schmitt, C.*
C1  - 3272
C2  - 25984
SP  - 1324-1330
TI  - Posttraumatic Stress Symptoms and Predicted Mortality in Patients With Implantable Cardioverter-Defibrillators.
JO  - JAMA psychiatry
VL  - 65
IS  - 11
PB  - American Medical Assoc.
PY  - 2008
SN  - 2168-622X
ER  -