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1.
Genet Res (Camb) ; 97: e13, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26030725

RESUMO

Pharmacogenetic/pharmacogenomic (PGx) testing is currently available for a wide range of health problems including cardiovascular disease, cancer, diabetes, autoimmune disorders, mental health disorders and infectious diseases. PGx contributes important information to the field of precision medicine by clarifying appropriate treatments for specific disease subtypes. Tangible benefits to patients including improved outcomes and reduced total health care costs have been observed. However, PGx-guided therapy faces many barriers to full integration into clinical practice and acceptance by stakeholders, whether practitioner, patient or payer. Each stakeholder has a unique perspective on the role of PGx testing, although all are similarly challenged with demonstrating or appraising its cost-to-benefit value. Coverage by insurers is a critical step in achieving widespread adoption of PGx testing. The acceleration of adoption of precision medicine in general and for PGx testing in particular will be determined by how quickly robust evidence can be accumulated that shows a return on investment for payers in terms of real dollars, for clinicians in terms of patient clinical responses, and for patients in terms of economic, health and quality of life outcomes. Trends in PGx testing utilization and uptake by payers in real-world practice are discussed; the role of pharmacoeconomics in assessing cost-effectiveness is highlighted using a case study in psychiatric care, and several issues that will affect adoption of PGx testing in the United States (US) over the next few years are reviewed.


Assuntos
Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Farmacogenética/métodos , Medicina de Precisão/métodos , Análise Custo-Benefício , Testes Genéticos/economia , Humanos , Avaliação de Resultados em Cuidados de Saúde/economia , Avaliação de Resultados em Cuidados de Saúde/métodos , Administração dos Cuidados ao Paciente/economia , Administração dos Cuidados ao Paciente/métodos , Farmacogenética/economia , Medicina de Precisão/economia
2.
Am J Psychiatry ; 172(1): 82-93, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25158072

RESUMO

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. METHOD: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. RESULTS: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). CONCLUSIONS: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.


Assuntos
Transtorno Obsessivo-Compulsivo/genética , Síndrome de Tourette/genética , Adulto , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/epidemiologia , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/epidemiologia
3.
Am J Manag Care ; 20(5): e146-56, 2014 05.
Artigo em Inglês | MEDLINE | ID: mdl-25326929

RESUMO

OBJECTIVES: Pharmacogenetic testing as a means of guiding treatment decisions is beginning to see wider clinical use in psychiatry. The utility of this genetic information as it pertains to clinical decision making, treatment effectiveness, cost savings, and patient perception has not been fully characterized. STUDY DESIGN: In this retrospective study, we examined health claims data in order to assess medication adherence rates and healthcare costs for psychiatric patients. METHODS: Individuals for whom pharmacogenetic testing was ordered (cases) were contrasted with those who did not undergo such testing (controls). Cases and controls were propensity score matched in order to minimize risk of confounding in this nonrandomized study. An initial analysis of 111 cases and 222 controls examined both adherence and healthcare costs. A replication study of 116 cases and 232 controls examined adherence alone, as cost data was not available for this latter cohort. RESULTS: Overall, individuals with assay-guided treatment were significantly more medication adherent (P = 1.56 3 10­3; Cohen's d = 0.511) than patients with standard treatment and demonstrated a relative cost savings of 9.5% in outpatient costs over a 4-month follow-up period, or $562 in total savings. CONCLUSIONS: The data show the utility of pharmacogenetic testing in everyday psychiatric clinical practice, as it can lead to improved patient adherence and decreased healthcare costs.


Assuntos
Adesão à Medicação/estatística & dados numéricos , Transtornos Mentais/tratamento farmacológico , Farmacogenética , Psicotrópicos/uso terapêutico , Estudos de Casos e Controles , Redução de Custos/métodos , Atenção à Saúde/economia , Atenção à Saúde/estatística & dados numéricos , Feminino , Testes Genéticos , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Masculino , Transtornos Mentais/economia , Transtornos Mentais/genética , Pessoa de Meia-Idade , Farmacogenética/economia , Pontuação de Propensão , Estudos Retrospectivos
4.
J Am Acad Child Adolesc Psychiatry ; 53(8): 910-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25062598

RESUMO

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. METHOD: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. RESULTS: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). CONCLUSION: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.


Assuntos
Variações do Número de Cópias de DNA , Transtorno Obsessivo-Compulsivo/genética , Síndrome de Tourette/genética , Adolescente , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Polimorfismo de Nucleotídeo Único , Síndrome de Tourette/diagnóstico
5.
Nat Genet ; 45(4): 433-9, 439e1-2, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23455636

RESUMO

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.


Assuntos
Biomarcadores/metabolismo , Loci Gênicos/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metanálise como Assunto , Fatores de Risco
6.
Ophthalmology ; 119(9): 1874-85, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22705344

RESUMO

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.


Assuntos
Neovascularização de Coroide/genética , Atrofia Geográfica/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Serina Endopeptidases/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Masculino , Fatores de Risco , Irmãos
7.
J Neurosci ; 31(37): 13246-54, 2011 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-21917807

RESUMO

Stress is a general risk factor for psychopathology, but the mechanisms underlying this relationship remain largely unknown. Animal studies and limited human research suggest that stress can induce anhedonic behavior. Moreover, emerging data indicate that genetic variation within the corticotropin-releasing hormone type 1 receptor gene (CRHR1) at rs12938031 may promote psychopathology, particularly in the context of stress. Using an intermediate phenotypic neurogenetics approach, we assessed how stress and CRHR1 genetic variation (rs12938031) influence reward learning, an important component of anhedonia. Psychiatrically healthy female participants (n = 75) completed a probabilistic reward learning task during stress and no-stress conditions while 128-channel event-related potentials were recorded. Fifty-six participants were also genotyped across CRHR1. Response bias, an individual's ability to modulate behavior as a function of reward, was the primary behavioral variable of interest. The feedback-related positivity (FRP) in response to reward feedback was used as a neural index of reward learning. Relative to the no-stress condition, acute stress was associated with blunted response bias as well as a smaller and delayed FRP (indicative of disrupted reward learning) and reduced anterior cingulate and orbitofrontal cortex activation to reward. Critically, rs12938031 interacted with stress to influence reward learning: both behaviorally and neurally, A homozygotes showed stress-induced reward learning abnormalities. These findings indicate that acute, uncontrollable stressors reduce participants' ability to modulate behavior as a function of reward, and that such effects are modulated by CRHR1 genotype. Homozygosity for the A allele at rs12938031 may increase risk for psychopathology via stress-induced reward learning deficits.


Assuntos
Variação Genética/fisiologia , Aprendizagem/fisiologia , Receptores de Hormônio Liberador da Corticotropina/genética , Recompensa , Estresse Psicológico/psicologia , Adolescente , Adulto , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Potenciais Evocados/genética , Potenciais Evocados/fisiologia , Retroalimentação Psicológica , Feminino , Genótipo , Homozigoto , Humanos , Desempenho Psicomotor/fisiologia , Receptores de Hormônio Liberador da Corticotropina/fisiologia
8.
Hum Mol Genet ; 20(18): 3699-709, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21665990

RESUMO

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.


Assuntos
Colágeno Tipo X/genética , Variação Genética , Estudo de Associação Genômica Ampla , Degeneração Macular/genética , Proteínas de Neoplasias/genética , Proteínas Tirosina Quinases/genética , Fator A de Crescimento do Endotélio Vascular/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genética
9.
Dis Markers ; 30(2-3): 89-99, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21508513

RESUMO

Posttraumatic stress disorder (PTSD) is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1), have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs) in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n=103) who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores de Hormônio Liberador da Corticotropina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adolescente , Criança , Feminino , Seguimentos , Marcadores Genéticos , Haplótipos , Humanos , Funções Verossimilhança , Masculino , Análise de Regressão
10.
Invest Ophthalmol Vis Sci ; 52(7): 4663-70, 2011 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-21447678

RESUMO

PURPOSE: Intermediate and large drusen usually precede advanced age-related macular degeneration (AMD). There is little information about which genes influence drusen accumulation. Discovery of genetic variants associated with drusen may lead to prevention and treatments of AMD in its early stages. METHODS: A total of 3066 subjects were evaluated on the basis of ocular examinations and fundus photography and categorized as control (n = 221), intermediate drusen (n = 814), large drusen (n = 949), or advanced AMD (n = 1082). SNPs in the previously identified CFH, C2, C3, CFB, CFI, APOE, and ARMS2/HTRA1 genes/regions and the novel genes LIPC, CETP, and ABCA1 in the high-density lipoprotein (HDL) cholesterol pathway were genotyped. Associations between stage of AMD and SNPs were assessed using logistic regression. RESULTS: Controlling for age, sex, education, smoking, body mass index, and antioxidant treatment, the number of minor (T) alleles of the genes LIPC and ABCA1 were significantly associated with a reduced risk of intermediate drusen (LIPC [P trend = 0.045], ABCA1 [P = 4.4 × 10(-3)]), large drusen (LIPC [P = 0.041], ABCA1 [P = 7.7 × 10(-4)]), and advanced AMD (LIPC [P = 1.8 × 10(-3)], ABCA1 [P = 3 × 10(-4)]). After further adjustment for known genetic factors, the protective effect of the TT genotype was significant for intermediate drusen (LIPC [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.33-0.94], ABCA1 [OR, 0.48; 95% CI, 0.27-0.85]), large drusen (LIPC [OR, 0.58; 95% CI, 0.34-0.98)], ABCA1 [OR, 0.41; 95% CI, 0.23-0.74)]), and advanced AMD (LIPC [OR, 0.39; 95% CI, 0.21-0.74)], ABCA1 [OR, 0.35; 95% CI, 0.17-0.71)]). CFH, C3, C2, and ARMS2/HTRA1 were associated with large drusen and advanced AMD. CONCLUSIONS: LIPC and ABCA1 are related to intermediate and large drusen, as well as advanced AMD. CFH, C3, C2, and ARMS2/HTRA1 are associated with large drusen and advanced AMD. Genes may have varying effects on different stages of AMD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Variação Genética , Lipase/genética , Degeneração Macular/genética , Drusas do Disco Óptico/genética , Transportador 1 de Cassete de Ligação de ATP , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Degeneração Macular/patologia , Masculino , Drusas do Disco Óptico/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
11.
CNS Neurosci Ther ; 17(3): 141-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20370803

RESUMO

Several studies support a genetic influence on obsessive-compulsive disorder (OCD) etiology. The role of glutamate as an important neurotransmitter affecting OCD pathophysiology has been supported by neuroimaging, animal model, medication, and initial candidate gene studies. Genes involved in glutamatergic pathways, such as the glutamate receptor, ionotropic, kainate 2 (GRIK2), have been associated with OCD in previous studies. This study examines GRIK2 as a candidate gene for OCD susceptibility in a family-based approach. Probands had full DSM-IV diagnostic criteria for OCD. Forty-seven OCD probands and their parents were recruited from tertiary care OCD specialty clinics from France and USA. Genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes were analyzed using Haploview and FBAT software. The polymorphism at rs1556995 (P= 0.0027; permuted P-value = 0.03) was significantly associated with the presence of OCD. Also, the two marker haplotype rs1556995/rs1417182, was significantly associated with OCD (P= 0.0019, permuted P-value = 0.01). This study supports previously reported findings of association between proximal GRIK2 SNPs and OCD in a comprehensive evaluation of the gene. Further study with independent samples and larger sample sizes is required.


Assuntos
Transtorno Obsessivo-Compulsivo/genética , Receptores de Ácido Caínico/genética , Adolescente , Adulto , Criança , DNA/genética , Manual Diagnóstico e Estatístico de Transtornos Mentais , Família , Feminino , França , Marcadores Genéticos , Genótipo , Alemanha , Haplótipos , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/psicologia , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos , Adulto Jovem , Receptor de GluK2 Cainato
12.
Am J Ophthalmol ; 151(2): 345-52.e3, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21122828

RESUMO

PURPOSE: To determine if genetic variants that have been associated with age-related macular degeneration (AMD) have a differential effect on the risk of choroidal neovascularization (CNV) and geographic atrophy. DESIGN: Genetic association study. SETTING: Multicenter study. STUDY POPULATION: Seven hundred forty-nine participants with geographic atrophy and 3209 participants with CNV were derived from 4 AMD studies with similar procedures from Tufts Medical Center, the Age-Related Eye Disease Study, University of Utah, and Hopital Intercommunal de Creteil. PROCEDURES: AMD grade was assigned based on fundus photography and examination using the clinical age-related maculopathy staging system. All samples were genotyped for single nucleotide polymorphisms (SNPs) previously associated with AMD. Allele frequencies were compared between participants with CNV and geographic atrophy using PLINK within each cohort and Mantel-Haenszel meta-analysis was performed to combine odds ratios (OR). MAIN OUTCOME MEASURES: Differences in allele frequencies between participants with geographic atrophy and CNV. RESULTS: The frequency of the T allele of ARMS2/HTRA1 rs10490924 was significantly higher in participants with CNV than in those with geographic atrophy (OR, 1.37; 95% confidence interval, 1.21-1.54; P value = 4.2 × 10(-7)). This result remained statistically significant when excluding individuals who had geographic atrophy in 1 eye and CNV in the contralateral eye (P = 2.2 × 10(-4)). None of the other SNPs showed a significant differential effect for CNV vs geographic atrophy, including CFH, C2/CFB, C3, CFI, LIPC, and TIMP3. CONCLUSIONS: Genetic variation at the ARMS2/HTRA1 locus confers a differential risk for CNV vs geographic atrophy in a well-powered sample.


Assuntos
Neovascularização de Coroide/genética , Predisposição Genética para Doença , Atrofia Geográfica/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Serina Endopeptidases/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Masculino , Fatores de Risco
13.
Am J Med Genet B Neuropsychiatr Genet ; 156B(1): 108-14, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21184590

RESUMO

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that is familial and highly heritable. Although genetic influences are thought to play a significant role in the development of TS, no definite TS susceptibility genes have been identified to date. TS is believed to be genetically related to both obsessive-compulsive disorder (OCD) and grooming disorders (GD) such as trichotillomania (TTM). SAP90/PSD95-associated protein 3 (SAPAP3/DLGAP3) is a post-synaptic scaffolding protein that is highly expressed in glutamatergic synapses in the striatum and has recently been investigated as a candidate gene in both OCD and GD studies. Given the shared familial relationship between TS, OCD and TTM, DLGAP3 was evaluated as a candidate TS susceptibility gene. In a family-based sample of 289 TS trios, 22 common single nucleotide polymorphisms (SNPs) in the DLGAP3 region were analyzed. Nominally significant associations were identified between TS and rs11264126 and two haplotypes containing rs11264126 and rs12141243. Secondary analyses demonstrated that these results cannot be explained by the presence of comorbid OCD or TTM in the sample. Although none of these results remained significant after correction for multiple hypothesis testing, DLGAP3 remains a promising candidate gene for TS.


Assuntos
Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Síndrome de Tourette/genética , Família , Marcadores Genéticos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética
15.
Proc Natl Acad Sci U S A ; 107(16): 7401-6, 2010 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-20385819

RESUMO

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.


Assuntos
Predisposição Genética para Doença , Lipoproteínas HDL/metabolismo , Degeneração Macular/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico , Fator I do Complemento/genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Risco , Inibidor Tecidual de Metaloproteinase-3/fisiologia
16.
Proc Natl Acad Sci U S A ; 107(16): 7395-400, 2010 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-20385826

RESUMO

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.


Assuntos
Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Lipase/genética , Lipase/fisiologia , Degeneração Macular/genética , Alelos , Estudos de Casos e Controles , HDL-Colesterol/metabolismo , Dessaturase de Ácido Graxo Delta-5 , Genótipo , Humanos , Lipídeos/química , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Risco , Inibidor Tecidual de Metaloproteinase-3/antagonistas & inibidores
17.
Eur J Hum Genet ; 18(4): 496-501, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19844262

RESUMO

About 40% of the genetic variance of age-related macular degeneration (AMD) can be explained by a common variation at five common single-nucleotide polymorphisms (SNPs). We evaluated the degree to which these known variants explain the clustering of AMD in a group of densely affected families. We sought to determine whether the actual number of risk alleles at the five variants in densely affected families matched the expected number. Using data from 322 families with AMD, we used a simulation strategy to generate comparison groups of families and determined whether their genetic profile at the known AMD risk loci differed from the observed genetic profile, given the density of disease observed. Overall, the genotypic loads for the five SNPs in the families did not deviate significantly from the genotypic loads predicted by the simulation. However, for a subset of densely affected families, the mean genotypic load in the families was significantly lower than the expected load determined from the simulation. Given that these densely affected families may harbor rare, more penetrant variants for AMD, linkage analyses and resequencing targeting these families may be an effective approach to finding additional implicated genes.


Assuntos
Predisposição Genética para Doença , Testes Genéticos , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único/genética , Simulação por Computador , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
18.
Hum Brain Mapp ; 31(2): 210-21, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19621370

RESUMO

The TREK1 gene has been linked to a depression-resistant phenotype in rodents and antidepressant response in humans, but the neural mechanisms underlying these links are unclear. Because TREK1 is expressed in reward-related basal ganglia regions, it has been hypothesized that TREK1 genetic variation may be associated with anhedonic symptoms of depression. To investigate whether TREK1 genetic variation influences reward processing, we genotyped healthy individuals (n = 31) who completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Three genotypes previously linked to positive antidepressant response were associated with potentiated basal ganglia activity to gains, but did not influence responses to penalties or no change feedback. TREK1 genetic variations did not affect basal ganglia volume, and fMRI group differences were confirmed when accounting for self-report measures of anhedonia. In addition, the total number of "protective" TREK1 alleles was associated with stronger responses to gains in several other reward-related regions, including the dorsal anterior cingulate cortex, orbitofrontal cortex, and mesial prefrontal cortex. In control analyses, associations between basal ganglia responses to gains and functional polymorphisms in the dopamine transporter (DAT1) and catechol-O-methyltransferase (COMT) genes were also explored. Results revealed that TREK1 and DAT/COMT genotypes were independently related to basal ganglia responses to gains. These findings indicate that TREK1 genotypes are associated with individual differences in reward-related brain activity. Future studies in depressed samples should evaluate whether variation in neural responses to rewards may contribute to the association between TREK1 and antidepressant response in humans.


Assuntos
Encéfalo/fisiologia , Polimorfismo de Nucleotídeo Único , Canais de Potássio de Domínios Poros em Tandem/genética , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Recompensa , Gânglios da Base/anatomia & histologia , Gânglios da Base/fisiologia , Encéfalo/anatomia & histologia , Mapeamento Encefálico , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Depressão/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Fenótipo , Análise de Sequência de DNA , Adulto Jovem
19.
Invest Ophthalmol Vis Sci ; 50(5): 2044-53, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19117936

RESUMO

PURPOSE: The joint effects of genetic, ocular, and environmental variables were evaluated and predictive models for prevalence and incidence of AMD were assessed. METHODS: Participants in the multicenter Age-Related Eye Disease Study (AREDS) were included in a prospective evaluation of 1446 individuals, of which 279 progressed to advanced AMD (geographic atrophy or neovascular disease) and 1167 did not progress during 6.3 years of follow-up. For prevalent AMD, 509 advanced cases were compared with 222 controls. Covariates for the incidence analysis included age, sex, education, smoking, body mass index (BMI), baseline AMD grade, and the AREDS vitamin-mineral treatment assignment. DNA specimens were evaluated for six variants in five genes related to AMD. Unconditional logistic regression analyses were performed for prevalent and incident advanced AMD. An algorithm was developed and receiver operating characteristic curves and C statistics were calculated to assess the predictive ability of risk scores to discriminate progressors from nonprogressors. RESULTS: All genetic polymorphisms were independently related to prevalence of advanced AMD, controlling for genetic factors, smoking, BMI, and AREDS treatment. Multivariate odds ratios (ORs) were 3.5 (95% confidence interval [CI], 1.7-7.1) for CFH Y402H; 3.7 (95% CI, 1.6-8.4) for CFH rs1410996; 25.4 (95% CI, 8.6-75.1) for LOC387715 A69S (ARMS2); 0.3 (95% CI, 0.1-0.7) for C2 E318D; 0.3 (95% CI, 0.1-0.5) for CFB; and 3.6 (95% CI, 1.4-9.4) for C3 R102G, comparing the homozygous risk/protective genotypes to the referent genotypes. For incident AMD, all these variants except CFB were significantly related to progression to advanced AMD, after controlling for baseline AMD grade and other factors, with ORs from 1.8 to 4.0 for presence of two risk alleles and 0.4 for the protective allele. An interaction was seen between CFH402H and treatment, after controlling for all genotypes. Smoking was independently related to AMD, with a multiplicative joint effect with genotype on AMD risk. The C statistic for the full model with all variables was 0.831 for progression to advanced AMD. CONCLUSIONS: Factors reflective of nature and nurture are independently related to prevalence and incidence of advanced AMD, with excellent predictive power.


Assuntos
Degeneração Macular/epidemiologia , Degeneração Macular/genética , Modelos Genéticos , Polimorfismo Genético , Idoso , Algoritmos , Complemento C2/genética , Complemento C3/genética , Fator B do Complemento/genética , Fator H do Complemento/genética , Meio Ambiente , Feminino , Genótipo , Humanos , Incidência , Masculino , Epidemiologia Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único , Prevalência , Estudos Prospectivos , Proteínas/genética , Curva ROC , Fatores de Risco , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
20.
Eur J Hum Genet ; 17(1): 100-4, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18685559

RESUMO

A case-control association study for advanced age-related macular degeneration was conducted to explore several regions of interest identified by linkage. This analysis identified a single nucleotide polymorphism just 3' of complement factor I on chromosome 4 showing significant association (P<10(-7)). Sequencing was performed on coding exons in linkage disequilibrium with the detected association. No obvious functional variation was discovered that could be the proximate cause of the association, suggesting a noncoding regulatory mechanism.


Assuntos
Fator I do Complemento/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Cromossomos Humanos Par 4 , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Análise de Sequência de DNA
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