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1.
Mol Psychiatry ; 29(9): 2701-2713, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38548982

RESUMO

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n = 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk.


Assuntos
Bancos de Espécimes Biológicos , Transtorno Bipolar , Comorbidade , Registros Eletrônicos de Saúde , Herança Multifatorial , Fenótipo , Humanos , Transtorno Bipolar/genética , Transtorno Bipolar/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Herança Multifatorial/genética , Estudo de Associação Genômica Ampla/métodos , Predisposição Genética para Doença/genética , Adulto , Idoso de 80 Anos ou mais , Fatores de Risco , Fenômica/métodos
2.
Psychol Med ; 53(15): 7368-7374, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38078748

RESUMO

BACKGROUND: Depression and anxiety are common and highly comorbid, and their comorbidity is associated with poorer outcomes posing clinical and public health concerns. We evaluated the polygenic contribution to comorbid depression and anxiety, and to each in isolation. METHODS: Diagnostic codes were extracted from electronic health records for four biobanks [N = 177 865 including 138 632 European (77.9%), 25 612 African (14.4%), and 13 621 Hispanic (7.7%) ancestry participants]. The outcome was a four-level variable representing the depression/anxiety diagnosis group: neither, depression-only, anxiety-only, and comorbid. Multinomial regression was used to test for association of depression and anxiety polygenic risk scores (PRSs) with the outcome while adjusting for principal components of ancestry. RESULTS: In total, 132 960 patients had neither diagnosis (74.8%), 16 092 depression-only (9.0%), 13 098 anxiety-only (7.4%), and 16 584 comorbid (9.3%). In the European meta-analysis across biobanks, both PRSs were higher in each diagnosis group compared to controls. Notably, depression-PRS (OR 1.20 per s.d. increase in PRS; 95% CI 1.18-1.23) and anxiety-PRS (OR 1.07; 95% CI 1.05-1.09) had the largest effect when the comorbid group was compared with controls. Furthermore, the depression-PRS was significantly higher in the comorbid group than the depression-only group (OR 1.09; 95% CI 1.06-1.12) and the anxiety-only group (OR 1.15; 95% CI 1.11-1.19) and was significantly higher in the depression-only group than the anxiety-only group (OR 1.06; 95% CI 1.02-1.09), showing a genetic risk gradient across the conditions and the comorbidity. CONCLUSIONS: This study suggests that depression and anxiety have partially independent genetic liabilities and the genetic vulnerabilities to depression and anxiety make distinct contributions to comorbid depression and anxiety.


Assuntos
Depressão , Registros Eletrônicos de Saúde , Humanos , Ansiedade/epidemiologia , Ansiedade/genética , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Comorbidade , Depressão/epidemiologia , Depressão/genética , Herança Multifatorial , Fatores de Risco
3.
Nat Hum Behav ; 8(6): 1177-1193, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38632388

RESUMO

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.


Assuntos
Tabagismo , Humanos , Tabagismo/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Estados Unidos/epidemiologia , Masculino , Feminino , Registros Eletrônicos de Saúde
4.
medRxiv ; 2023 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-37034728

RESUMO

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.

5.
J Affect Disord ; 238: 1-7, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29807322

RESUMO

BACKGROUND: Substantial research progress can be achieved if available clinical datasets can be mapped to the National Institute of Mental Health Research-Domain-Criteria (RDoC) constructs. This mapping would allow investigators to both explore more narrowly defined clinical phenotypes and the relationship of these phenotypes to biological markers and clinical outcomes approximating RDoC criteria. METHODS: Using expert review and consensus, we defined four major depression phenotypes based on specific RDoC constructs. Having matched these constructs to individual items from the Hamilton Depression Rating Scale and Quick Inventory of Depressive Symptomatology, we identified subjects meeting criteria for each of these phenotypes from two large clinical trials of patients treated for major depression. In a post hoc analysis, we evaluated the overall treatment response based on the phenotypes: Core Depression (CD), Anxiety (ANX), and Neurovegetative Symptoms of Melancholia (NVSM) and Atypical Depression (NVSAD). RESULTS: The phenotypes were prevalent (range 10.5-52.4%, 50% reduction range 51.9-82.9%) and tracked with overall treatment response. Although the CD phenotype was associated with lower rates of remission in both cohorts, this was mainly driven by baseline symptom severity. However, when controlling for baseline severity, patients with the ANX phenotype had a significantly lower rate of remission. LIMITATIONS: The lack of replication between the studies of the phenotypes' treatment prediction value reflects important variability across studies that may limit generalizability. CONCLUSION: Further work evaluating biological markers associated with these phenotypes is needed for further RDoC concept development.


Assuntos
Transtorno Depressivo Maior/psicologia , Transtornos do Humor/psicologia , Fenótipo , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Pesquisa/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa
6.
Biol Psychiatry ; 61(6): 734-42, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17123473

RESUMO

BACKGROUND: SLC6A4 encodes the serotonin transporter, the protein primarily responsible for the termination of serotonin neurotransmission. Because many antidepressants inhibit the transporter, it has been the focus of intense pharmacogenetic analysis. We sought to replicate our previous findings that SLC6A4 is associated with response to a selective serotonin reuptake inhibitor (SSRI) in a large case-control study. METHODS: Genotypes at the SLC6A4 locus were obtained for 1,914 subjects in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and then tested for association to treatment response of the SSRI citalopram. RESULTS: Nine tagging single nucleotide polymorphisms and two variants previously associated with antidepressant response, including a promoter repeat polymorphism, were genotyped. Single marker and haplotypic analyses failed to detect association with antidepressant response in the largest clinical sample studied to date. CONCLUSIONS: The lack of association between response to an SSRI and variation at the SLC6A4 locus in this large sample, carefully characterized for response to citalopram, strongly suggests that SSRI response in major depression is not determined by DNA variation at this locus. These findings do not replicate findings of a number of studies with considerably smaller sample sizes. Other genetic determinants of SSRI response in depression should be sought.


Assuntos
Citalopram/uso terapêutico , Transtorno Depressivo Maior/genética , Resistência a Medicamentos/genética , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Ligação Genética , Variação Genética , Haplótipos/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética
7.
Leuk Lymphoma ; 48(12): 2412-7, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18067017

RESUMO

Chronic lymphocytic leukemia (CLL) patients with aggressive molecular characteristics such as deletion of 17p13.1 do not respond to conventional treatments and have a shorter survival. Studies suggest that high-dose methylprednisolone (HDMP) has activity in such patients and combining HDMP with rituximab may enhance efficacy. We identified 37 patients with CLL treated with the HDMP-rituximab who had follow-up at Mayo Clinic. Nine of 27 (33%) had deletion of 17p13.1 and six of 27 (22%) had deletion of 11q22.3. After a median of one cycle of HDMP-rituximab, 29 (78%) patients had an objective response according to the National Cancer Institute CLL Working Group Criteria including five of nine patients with deletion of 17p13.1. Eight (22%) patients had a complete clinical response. Although well tolerated, 11 (29%) patients developed infectious complications before completing one month of therapy. Three-year survival was 41% (95% CI: 26 - 66%). HDMP-rituximab is an active regimen in patients with relapsed, refractory, and cytogenetically high-risk CLL. Further evaluation of this regimen in controlled trials appears warranted.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Metilprednisolona/administração & dosagem , Terapia de Salvação , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Deleção Cromossômica , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab
8.
Vasc Endovascular Surg ; 36(1): 41-50, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12704524

RESUMO

Previous results following subfascial endoscopic perforator vein surgery were reported to be worse in post-thrombotic syndrome than in limbs with primary valvular incompetence. This report comprises a larger patient cohort with longer follow-up. The goal of this study was to determine if subfascial endoscopic perforator vein surgery is justified in patients with post-thrombotic venous insufficiency. The clinical data of 91 consecutive patients who underwent subfascial endoscopic perforator vein surgery with or without superficial reflux ablation over a 7-year period from May 1993 to June 2000 were retrospectively analyzed. Fifty-four females and 37 males (median age, 53 years; range, 20-77) underwent 103 subfascial endoscopic perforator vein surgery procedures. Forty-two limbs were classified as C6 (active ulcer), 34 as C5 (healed ulcer), and 24 as C4 (lipodermatosclerosis). Thirty procedures were performed in post-thrombotic limbs. Concomitant superficial reflux ablation was performed in 74 limbs (72%); saphenous vein stripping had been previously performed in 29 (28%). Deep venous incompetence was present in 89% of limbs; 13% had venous outflow obstruction on plethysmography. Cumulative ulcer healing in post-thrombotic limbs was not significantly different from limbs with primary valvular incompetence; 30-, 60-, and 90-day healing rates were 44%, 72%, and 72% vs 39%, 70%, and 87%, respectively (p = 0.35). On univariate analysis, the presence of ulcer greater than 2 cm in diameter was associated with delayed ulcer healing (p = 0.02). Cumulative ulcer recurrence in all limbs was 4%, 20%, and 27% at 1, 3, and 5 years, respectively. Ulcer recurrence in post-thrombotic limbs was higher than in limbs with primary valvular incompetence at 1, 3, and 5 years; 16%, 47%, and 56% vs 0%, 8%, and 15%, respectively (p = 0.001). Recurrent ulcers were small, superficial, and easier to heal. Clinical improvement was significant even in post-thrombotic limbs; median clinical score decreased from 9.5 to 3 (p = 0.001), and median outcome score was +2 (mean 1.9; range, -1 to 3). Median clinical score in patients with primary valvular incompetence improved from 6 to 1.5 (p = 0.0001). Subfascial endoscopic perforator vein surgery with superficial reflux ablation promoted ulcer healing, improved clinical outcome, and resulted in a low long-term ulcer recurrence rate in limbs with primary valvular incompetence. Despite good clinical outcome in post-thrombotic limbs, ulcer recurrence was high. These results imply that the role of subfascial endoscopic perforator vein surgery with superficial reflux ablation in patients with post-thrombotic limbs continues to be controversial.


Assuntos
Ablação por Cateter/efeitos adversos , Fasciotomia , Tábuas de Vida , Doenças Vasculares Periféricas/complicações , Doenças Vasculares Periféricas/cirurgia , Complicações Pós-Operatórias , Úlcera Varicosa/etiologia , Úlcera Varicosa/cirurgia , Insuficiência Venosa/etiologia , Insuficiência Venosa/cirurgia , Trombose Venosa/complicações , Trombose Venosa/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/mortalidade , Estudos Retrospectivos , Fatores de Tempo , Úlcera Varicosa/mortalidade , Insuficiência Venosa/mortalidade , Trombose Venosa/mortalidade
9.
Am J Psychiatry ; 167(5): 565-73, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20194481

RESUMO

OBJECTIVE: Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the mu-opioid receptor gene may influence population variation in response to citalopram treatment. METHOD: A total of 1,953 individuals from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of Non-Hispanic Caucasians, Hispanic Caucasians, and African Americans. Population stratification was corrected using 119 ancestry informative markers and principal components analysis. Markers were tested for association with phenotypes for general and specific citalopram response as well as remission. RESULTS: Association between one SNP and specific citalopram response was observed. After Bonferroni correction, the strongest finding was the association between the rs540825 SNP and specific response. The rs540825 polymorphism is a nonsynonymous SNP in the final exon of the mu-opioid receptor-1X isoform of the OPRM1 gene, resulting in a histidine to glutamine change in the intracellular domain of the receptor. When Hispanic and Non-Hispanic Caucasians were analyzed separately, similar results in the population-corrected analyses were detected. CONCLUSIONS: These results suggest that rates of response to antidepressants and consequent remission from major depressive disorder are influenced by variation in the mu-opioid receptor gene as a result of either an effect on placebo response or true pharmacologic response.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Estudos de Associação Genética , Receptores Opioides mu/genética , Transtorno Depressivo Maior/genética , Genótipo , Haplótipos/genética , Hispânico ou Latino/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , População Branca/genética
10.
Pharmacogenet Genomics ; 19(1): 1-10, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19077664

RESUMO

Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STAR*D sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.


Assuntos
Citalopram/farmacologia , Polimorfismo de Nucleotídeo Único , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/genética , DNA/genética , Depressão/tratamento farmacológico , Depressão/genética , Fluoxetina/farmacologia , Haplótipos , Humanos , Monoaminoxidase/genética , Farmacogenética , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Sitios de Sequências Rotuladas , Triptofano Hidroxilase/genética
11.
PLoS One ; 3(4): e1872, 2008 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-18382661

RESUMO

BACKGROUND: We sought to determine whether clinical response or tolerance to the Selective Serotonin Reuptake Inhibitor (SSRI) citalopram is associated with genetic polymorphisms in potentially relevant pharmacokinetic enzymes. METHODOLOGY: We used a two-stage case-control study design in which we split the sample of 1,953 subjects from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial into a discovery (n = 831) and validation set (n = 1,046). Fifteen polymorphisms from five (CYP2D6, ABCB1, CYP2C19, CYP3A4, and CYP3A5) pharmacokinetic genes were genotyped. We examined the associations between these polymorphisms and citalopram response and tolerance. Significant associations were validated in the second stage for those polymorphism found to be statistically significant in the first stage. CONCLUSIONS: No genetic polymorphism in the pharmacokinetic genes examined was significantly associated with our response or tolerance phenotypes in both stages. For managing pharmacological treatment with citalopram, routine screening of the common pharmacokinetic DNA variants that we examined appears to be of limited clinical utility.


Assuntos
Citalopram/farmacocinética , Sistema Enzimático do Citocromo P-450/genética , Depressão/tratamento farmacológico , Resistência a Medicamentos/genética , Tolerância a Medicamentos/genética , Polimorfismo Genético , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Indução de Remissão
12.
J Clin Microbiol ; 40(2): 495-500, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11825962

RESUMO

A comparison of quantitative results expressed in hepatitis C virus (HCV) international units per milliliter, obtained from the VERSANT HCV RNA 3.0 (bDNA-3.0) assay, the QUANTIPLEX HCV RNA 2.0 (bDNA-2.0) assay, and the COBAS AMPLICOR HCV MONITOR version 2.0 (HCM-2.0) test was performed. A total of 168 patient specimens submitted to the Mayo Clinic Molecular Microbiology Laboratory for HCV quantification or HCV genotyping were studied. Of the specimens tested, 97, 88, and 79% yielded quantitative results within the dynamic range of the bDNA-3.0, bDNA-2.0, and HCM-2.0 assays, respectively. Overall, there was substantial agreement between the results generated by all three assays. A total of 15 out of 29 (52%) of the specimens determined to contain viral loads of <31,746 IU/ml by the bDNA-3.0 assay were categorized as containing viral loads within the range of 31,746 to 500,000 IU/ml by the bDNA-2.0 assay. Although substantial agreement was noted between the results generated by the bDNA-2.0 and bDNA-3.0 assays, a bias toward higher viral titer by the bDNA-2.0 assay was noted (P = 0.001). Likewise, although substantial agreement was noted between the results generated by the HCM-2.0 and bDNA-3.0 assays, a bias toward higher viral titer by the bDNA-3.0 assay was noted (P < or = 0.001). The discrepancy between the HCM-2.0 and bDNA-3.0 results was more pronounced when viral loads were >500,000 IU/ml and resulted in statistically significant differences (P < or = 0.001) in determining whether viral loads were above or below 800,000 IU/ml of HCV RNA, the proposed threshold value for tailoring the duration of combination therapy. The expression of quantitative values in HCV international units per milliliter was a strength of both the bDNA-3.0 and HCM-2.0 assays.


Assuntos
Ensaio de Amplificação de Sinal de DNA Ramificado/métodos , Hepacivirus/isolamento & purificação , Hepatite C/virologia , RNA Viral/sangue , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Humanos , Kit de Reagentes para Diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Carga Viral
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