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1.
Alzheimers Dement ; 19(9): 3894-3901, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37023267

RESUMEN

INTRODUCTION: Angiotensin-converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown. METHODS: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two-sample Mendelian randomization (MR) approach. RESULTS: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04-1.10], P = 5 × 10-07 ) and frontotemporal dementia (1.16 [1.04-1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses. DISCUSSION: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition. HIGHLIGHTS: This study evaluated genetically proxied angiotensin-converting enzyme (ACE) inhibition association with dementias. The results suggest an association between ACE inhibition and Alzheimer's disease. The results suggest an association between ACE inhibition and frontotemporal dementia. Those associations can be interpreted as potentially causal.


Asunto(s)
Enfermedad de Alzheimer , Demencia Vascular , Demencia Frontotemporal , Humanos , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Demencia Frontotemporal/genética , Angiotensinas
2.
Genome Res ; 23(2): 236-47, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23105016

RESUMEN

Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time.


Asunto(s)
Exoma , Mutación , Distrofias Retinianas/genética , Familia , Estudios de Asociación Genética , Genotipo , Humanos , Fenotipo , Análisis de Secuencia de ADN
3.
Bipolar Disord ; 17(6): 598-605, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26291791

RESUMEN

OBJECTIVES: The aim of the present study was to engage a national advocacy group and local stakeholders for guidance in developing a bipolar disorder biobank through a web-based survey and a community advisory board. METHODS: The Depression and Bipolar Support Alliance and the Mayo Clinic Bipolar Biobank conducted a national web-based survey inquiring about interest in participating in a biobank (i.e., giving DNA and clinical information). A community advisory board was convened to guide establishment of the biobank and identify key deliverables from the research project and for the community. RESULTS: Among 385 survey respondents, funding source (87%), professional opinion (76%), mental health consumer opinion (79%), and return of research results (91%) were believed to be important for considering study participation. Significantly more patients were willing to participate in a biobank managed by a university or clinic (78.2%) than one managed by government (63.4%) or industry (58.2%; both p < 0.001). The nine-member community advisory board expressed interest in research to help predict the likelihood of bipolar disorder developing in a child of an affected parent and which medications to avoid. The advisory board endorsed the use of a comprehension questionnaire to evaluate participants' understanding of the study (e.g., longevity of DNA specimens, right to remove samples, accessing medical records) as a means to strengthen the informed consent process. CONCLUSIONS: These national survey and community advisory data support the merit of establishing a biobank to enable studies of disease risk, provided that health records and research results are adequately protected. The goals of earlier diagnosis and individualized treatment of bipolar disorder were endorsed.


Asunto(s)
Bancos de Muestras Biológicas/organización & administración , Trastorno Bipolar , Bases de Datos Genéticas , Consejo Directivo/organización & administración , Sistemas de Registros Médicos Computarizados/organización & administración , Adulto , Actitud , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/genética , Trastorno Bipolar/terapia , Niño , Bases de Datos Factuales , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Proyectos de Investigación , Percepción Social , Estados Unidos
4.
Bipolar Disord ; 17(6): 645-52, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26528762

RESUMEN

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association. METHODS: DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects. RESULTS: Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04). CONCLUSIONS: These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder.


Asunto(s)
Trastorno Bipolar , Factor Neurotrófico Derivado del Encéfalo/genética , Adulto , Edad de Inicio , Alelos , Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo Genético , Estados Unidos
5.
Harv Rev Psychiatry ; 32(4): 150-159, 2024 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-38990903

RESUMEN

ABSTRACT: Clinical neurosciences, and psychiatry specifically, have been challenged by the lack of a comprehensive and practical framework that explains the core mechanistic processes of variable psychiatric presentations. Current conceptualization and classification of psychiatric presentations are primarily centered on a non-biologically based clinical descriptive approach. Despite various attempts, advances in neuroscience research have not led to an improved conceptualization or mechanistic classification of psychiatric disorders. This perspective article proposes a new-work-in-progress-framework for conceptualizing psychiatric presentations based on neural network components (NNC). This framework could guide the development of mechanistic disease classification, improve understanding of underpinning pathology, and provide specific intervention targets. This model also has the potential to dissolve artificial barriers between the fields of psychiatry and neurology.


Asunto(s)
Trastornos Mentales , Neurociencias , Humanos , Trastornos Mentales/clasificación , Redes Neurales de la Computación , Psiquiatría
6.
BMJ Med ; 2(1): e000354, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37564828

RESUMEN

Objective: To examine whether genetically proxied lean mass is associated with risk of Alzheimer's disease. Design: Mendelian randomisation study. Setting: The UK Biobank study and genome wide association study meta-analyses of Alzheimer's disease and cognitive performance. Participants: Summary level genetic data from: 450 243 UK Biobank participants with impedance measures of lean mass and fat mass; an independent sample of 21 982 patients with Alzheimer's disease and 41 944 controls without Alzheimer's disease; a replication sample of 7329 patients with Alzheimer's disease and 252 879 controls; and 269 867 individuals taking part in a genome wide association study of cognitive performance. Main outcome measure: Effect of genetically proxied lean mass on the risk of Alzheimer's disease, and the related phenotype of cognitive performance. Results: An increase in genetically proxied appendicular lean mass of one standard deviation was associated with a 12% reduced risk of Alzheimer's disease (odds ratio 0.88, 95% confidence interval 0.82 to 0.95, P=0.001). This finding was replicated in an independent cohort of patients with Alzheimer's disease (0.91, 0.83 to 0.99, P=0.02) and was consistent in sensitivity analyses that are more robust to the inclusion of pleiotropic variants. Higher genetically proxied appendicular lean mass was also associated with increased cognitive performance (standard deviation increase in cognitive performance for each standard deviation increase in appendicular lean mass 0.09, 95% confidence interval 0.06 to 0.11, P=0.001), and adjusting for potential mediation through genetically proxied cognitive performance did not reduce the association between appendicular lean mass and risk of Alzheimer's disease. Similar results were found for the outcomes of Alzheimer's disease and cognitive performance when the risk factors of genetically proxied trunk lean mass and whole body lean mass were used, respectively, adjusted for genetically proxied fat mass. Conclusions: These findings suggest that lean mass might be a possible modifiable protective factor for Alzheimer's disease. The mechanisms underlying this finding, as well as the clinical and public health implications, warrant further investigation.

7.
Neurology ; 100(18): e1922-e1929, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-36889925

RESUMEN

BACKGROUND AND OBJECTIVES: Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations. METHODS: Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results. RESULTS: Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype (p > 0.05). The genetic proxy of cortical asymmetry in left-handedness was significantly associated with agrammatic PPA (ß = 4.3, p = 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses. DISCUSSION: Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B, TUBB, and MAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.


Asunto(s)
Afasia Progresiva Primaria , Dislexia , Humanos , Afasia Progresiva Primaria/diagnóstico , Estudio de Asociación del Genoma Completo , Encéfalo , Fenotipo
8.
Nat Rev Neurol ; 18(1): 7-24, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34759373

RESUMEN

Endogenous biological clocks, orchestrated by the suprachiasmatic nucleus, time the circadian rhythms that synchronize physiological and behavioural functions in humans. The circadian system influences most physiological processes, including sleep, alertness and cognitive performance. Disruption of circadian homeostasis has deleterious effects on human health. Neurodegenerative disorders involve a wide range of symptoms, many of which exhibit diurnal variations in frequency and intensity. These disorders also disrupt circadian homeostasis, which in turn has negative effects on symptoms and quality of life. Emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders. Therefore, the circadian system has become an attractive target for research and clinical care innovations. Studying circadian disruption in neurodegenerative disorders could expand our understanding of the pathophysiology of neurodegeneration and facilitate the development of novel, circadian-based interventions for these disabling disorders. In this Review, we discuss the alterations to the circadian system that occur in movement (Parkinson disease and Huntington disease) and cognitive (Alzheimer disease and frontotemporal dementia) neurodegenerative disorders and provide directions for future investigations in this field.


Asunto(s)
Ritmo Circadiano , Enfermedades Neurodegenerativas/fisiopatología , Animales , Relojes Circadianos , Humanos , Enfermedades Neurodegenerativas/patología
9.
J Clin Sleep Med ; 18(12): 2751-2761, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-35946418

RESUMEN

STUDY OBJECTIVES: Narcolepsy often begins during adolescence and young adulthood, which are crucial periods for social development. The symptoms of narcolepsy likely impact social interactions, but little research has assessed the effects of narcolepsy on social relationships. The current study investigated the impact of narcolepsy on friendships and romantic and sexual relationships. METHODS: Young adults (18-39 years) with narcolepsy were recruited through national narcolepsy patient organizations. Participants (n = 254) completed an online survey assessing their friendships and romantic and sexual relationships, including communication about their social relationships with medical providers. RESULTS: All participants (mean age = 28.8 years; 87% female, 92% White/Caucasian) reported that narcolepsy made their social life more challenging. They reported receiving more support from significant others, compared to family or friends (P < .05). Most (80%) indicated that narcolepsy currently impacted their sex life. Only a few participants reported that their providers asked about their social and sex lives, though they wanted providers to ask. CONCLUSIONS: Narcolepsy impacts social functioning in young adults. Many individuals with narcolepsy prioritize single, meaningful, romantic relationships as developing and sustaining new relationships may be challenging. In addition, narcolepsy symptoms impact sexual functioning. Though many participants wanted to discuss their social and sex lives with providers, only a few providers ask. Treatment of narcolepsy in young adulthood should include supporting individuals regarding the impact on social, romantic, and sexual health. CITATION: Davidson RD, Biddle K, Nassan M, Scammell TE, Zhou ES. The impact of narcolepsy on social relationships in young adults. J Clin Sleep Med. 2022;18(12):2751-2761.


Asunto(s)
Relaciones Interpersonales , Narcolepsia , Adolescente , Adulto Joven , Femenino , Humanos , Adulto , Masculino , Amigos , Narcolepsia/complicaciones , Encuestas y Cuestionarios
10.
Neuropsychopharmacology ; 47(9): 1672-1679, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35538198

RESUMEN

Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2-1.26, P = 1.37 × 10-61), BP (OR = 1.15, 95% CI = 1.07-1.23, P = 5.11 × 10-5), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07-1.27, P = 2.30 × 10-4), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16-1.54, P = 5.97 × 10-5), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18-1.3, P = 1.47 × 10-18). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB.


Asunto(s)
Trastorno Depresivo Mayor , Trastornos del Inicio y del Mantenimiento del Sueño , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Trastornos del Inicio y del Mantenimiento del Sueño/genética , Ideación Suicida
11.
Brain Behav ; 11(7): e02201, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34056864

RESUMEN

BACKGROUND: Bipolar disorder (BD) and borderline personality disorder (BPD) share overlapping phenomenology and are frequently misdiagnosed. This study investigated the diagnostic accuracy of the Mood Disorder Questionnaire (MDQ) and McLean Screening Instrument for Borderline Personality Disorder (MSI) in a clinical inpatient setting and whether individual screening items could differentiate BD from BPD. METHODS: 757 sequential inpatients admitted to a Mood Disorder Unit completed both the MDQ and MSI. Screen positive for the MDQ was defined as ≥7/13 symptoms endorsed with concurrence and at least moderate impact. Screen positive for the MSI was defined as a score of ≥7. The clinical discharge summary diagnosis completed by a board-certified psychiatrist was used as the reference standard to identify concordance rates of a positive screen with clinical diagnosis. Individual items predicting one disorder and simultaneously predicting absence of other disorder by odds ratio (OR>and <1) were identified. RESULTS: Both screening instruments were more specific than sensitive (MDQ 83.7%/ 67.8%, MSI 73.2% / 63.3%). MDQ individual items (elevated mood, grandiosity, increased energy, pressured speech, decreased need for sleep, hyperactivity) were significant predictors of BD diagnosis and non-predictors of BPD diagnosis. Whereas MSI subitem, self-harm behaviors/suicidal attempts predicted BPD in the absence of BD; distrust and irritability were additional predictors of BPD. CONCLUSION: While this study is limited by the lack of structured diagnostic interview, these data provide differential symptoms to discriminate BD and BPD. Further work with larger datasets and more rigorous bioinformatics machine learning methodology is encouraged to continue to identify distinguishing features of these two disorders to guide diagnostic precision and subsequent treatment recommendations.


Asunto(s)
Trastorno Bipolar , Trastorno de Personalidad Limítrofe , Trastorno Bipolar/diagnóstico , Trastorno de Personalidad Limítrofe/diagnóstico , Humanos , Pacientes Internos , Trastornos del Humor , Autoinforme , Encuestas y Cuestionarios
12.
J Affect Disord ; 267: 96-102, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32063579

RESUMEN

BACKGROUND: The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD. METHODS: Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed. RESULTS: Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2). LIMITATION: Relatively small sample size. CONCLUSION: Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings.


Asunto(s)
Trastorno Bipolar , Factor Neurotrófico Derivado del Encéfalo , Adulto , Alelos , Trastorno Bipolar/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Genotipo , Humanos , Lactante , Metilación , Polimorfismo de Nucleótido Simple , Adulto Joven
13.
Clin Pharmacol Ther ; 108(6): 1233-1242, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32627186

RESUMEN

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED-MSs). To identify genetic polymorphisms that contribute to the variability in AED-MS response, we performed a discovery genome-wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED-MS valproate/divalproex and/or lamotrigine. AED-MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome-wide significant single-nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E-09) and SLC35F3 (rs114872993, P = 3.2E-08) genes. We also identified two genes with statistically significant gene-level associations: ABCC1 (P = 6.7E-07; top SNP rs875740, P = 2.0E-6), and DISP1 (P = 8.9E-07; top SNP rs34701716, P = 8.9E-07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ-aminobutyric acidergic (GABAergic) neurons, which are targets of AED-MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED-MS treatment response, and may facilitate precision medicine in BD.


Asunto(s)
Afecto/efectos de los fármacos , Anticonvulsivantes/uso terapéutico , Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Adulto , Anticonvulsivantes/efectos adversos , Antimaníacos/efectos adversos , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Femenino , Absorción Gastrointestinal , Estudio de Asociación del Genoma Completo , Humanos , Lamotrigina/uso terapéutico , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Oxcarbazepina/uso terapéutico , Farmacogenética , Sitios de Carácter Cuantitativo , Estudios Retrospectivos , Trombospondinas/genética , Trombospondinas/metabolismo , Resultado del Tratamiento , Ácido Valproico/uso terapéutico
14.
Mol Neuropsychiatry ; 3(3): 125-134, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29594131

RESUMEN

Mitochondrial DNA mutations have been reported to be associated with bipolar disorder (BD). In this study, we performed genome-wide analyses to assess mitochondrial single-nucleotide polymorphism (mtSNP) effects on BD risk and early-onset BD (EOBD) among BD patients, focusing on interaction effects between nuclear SNPs (nSNPs) and mtSNPs. Common nSNP and mtSNP data from European American BD cases (n = 1,001) and controls (n = 1,034) from the Genetic Association Information Network BD study were analyzed to assess the joint effect of nSNP and nSNP-mtSNP interaction on the risk of BD and EOBD. The effect of nSNP-mtSNP interactions was also assessed. For BD risk, the strongest evidence of an association was obtained for nSNP rs1880924 in MGAM and mtSNP rs3088309 in CytB (pjoint = 8.2 × 10-8, pint = 1.4 × 10-4). Our results also suggest that the minor allele of the nSNP rs583990 in CTNNA2 increases the risk of EOBD among carriers of the mtSNP rs3088309 minor allele, while the nSNP has no effect among those carrying the mtSNP major allele (OR = 4.53 vs. 1.05, pjoint = 2.1 × 10-7, pint = 1.16 × 10-6). While our results are not statistically significant after multiple testing correction and a large-sample replication is required, our exploratory study demonstrates the potential importance of considering the mitochondrial genome for identifying genetic factors associated with BD.

15.
J Psychiatr Res ; 84: 221-226, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27770741

RESUMEN

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged.


Asunto(s)
Trastorno Bipolar/genética , Trastorno Bipolar/psicología , ADN Mitocondrial , Predisposición Genética a la Enfermedad , Haplotipos , Trastornos Psicóticos/genética , Adolescente , Adulto , Anciano , Trastorno Bipolar/complicaciones , Estudios Transversales , Complejo I de Transporte de Electrón/genética , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , NADH Deshidrogenasa/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Trastornos Psicóticos/complicaciones , Población Blanca/genética , Adulto Joven
16.
J Affect Disord ; 208: 120-129, 2017 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-27769005

RESUMEN

BACKGROUND: Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity. METHODS: We conducted a GWAS of early-onset BD (onset of mania/hypomania ≤19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls. RESULTS: No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E-06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression. LIMITATIONS: The sample sizes of the early-onset BD subgroups were relatively small. CONCLUSIONS: Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model.


Asunto(s)
Trastorno Bipolar/genética , Moléculas de Adhesión Celular/genética , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización Intracelular/genética , Polimorfismo de Nucleótido Simple , Adolescente , Edad de Inicio , Trastorno Bipolar/metabolismo , Estudios de Casos y Controles , Moléculas de Adhesión Celular/metabolismo , Niño , Preescolar , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Genéticos , Neurogénesis/genética , Fenotipo , Receptores de GABA-A/metabolismo , Adulto Joven
17.
J Psychiatr Res ; 95: 208-212, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28886448

RESUMEN

In a prior discovery study, increased levels of serum Growth Differentiation Factor 15 (GDF15), Hepsin (HPN), and Matrix Metalloproteinase-7 (MMP7) were observed in bipolar depressed patients vs controls. This exploratory post-hoc analysis applied a proteomic-informed genomic research strategy to study the potential functional role of these proteins in bipolar disorder (BP). Utilizing the Genotype-Tissue Expression (GTEx) database to identify cis-acting blood expression quantitative trait loci (cis-eQTLs), five eQTL variants from the HPN gene were analyzed for association with BP cases using genotype data of cases from the discovery study (n = 58) versus healthy controls (n = 777). After adjusting for relevant covariates, we analyzed the relationship between these 5 cis-eQTLs and HPN serum level in the BP cases. All 5 cis-eQTL minor alleles were significantly more frequent in BP cases vs controls [(rs62122114, OR = 1.6, p = 0.02), (rs67003112, OR = 1.6, p = 0.02), (rs4997929, OR = 1.7, p = 0.01), (rs12610663, OR = 1.7, p = 0.01), (rs62122148, OR = 1.7, P = 0.01)]. The minor allele (A) in rs62122114 was significantly associated with increased serum HPN level in BP cases (Beta = 0.12, P = 0.049). However, this same minor allele was associated with reduced gene expression in GTEx controls. These exploratory analyses suggest that genetic variation in/near the gene encoding for hepsin protein may influence risk of bipolar disorder. This genetic variation, at least for the rs62122114-A allele, may have functional impact (i.e. differential expression) as evidenced by serum HPN protein expression. Although limited by small sample size, this study highlights the merits of proteomic informed functional genomic studies as a tool to investigate with greater precision the genetic risk of bipolar disorder and secondary relationships to protein expression recognizing, and encouraging in subsequent studies, high likelihood of epigenetic modification of genetic disease risk.


Asunto(s)
Trastorno Bipolar/sangre , Trastorno Bipolar/genética , Proteómica/métodos , Sitios de Carácter Cuantitativo/genética , Serina Endopeptidasas/sangre , Serina Endopeptidasas/genética , Bases de Datos Genéticas , Humanos
18.
J Clin Psychiatry ; 78(9): 1337-1343, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28199072

RESUMEN

OBJECTIVE: In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). METHODS: Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored. RESULTS: GRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons. CONCLUSIONS: These preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.


Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad/genética , Adolescente , Adulto , Edad de Inicio , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Técnicas de Genotipaje , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Adulto Joven
19.
Nat Genet ; 49(2): 238-248, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28067909

RESUMEN

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.


Asunto(s)
Atresia de las Coanas/genética , Proteínas Cromosómicas no Histona/genética , Predisposición Genética a la Enfermedad/genética , Microftalmía/genética , Distrofias Musculares/genética , Mutación/genética , Nariz/anomalías , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Fenotipo
20.
Mayo Clin Proc ; 91(7): 897-907, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27289413

RESUMEN

Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.


Asunto(s)
Antidepresivos de Segunda Generación/farmacocinética , Citocromo P-450 CYP2D6/genética , Inhibidores Enzimáticos del Citocromo P-450/farmacocinética , Trastorno Depresivo Mayor/tratamiento farmacológico , Farmacogenética/normas , Medicina de Precisión/normas , Antidepresivos de Segunda Generación/efectos adversos , Antidepresivos de Segunda Generación/uso terapéutico , Inhibidores Enzimáticos del Citocromo P-450/efectos adversos , Inhibidores Enzimáticos del Citocromo P-450/uso terapéutico , Trastorno Depresivo Mayor/genética , Fluoxetina/efectos adversos , Fluoxetina/farmacocinética , Fluoxetina/uso terapéutico , Humanos , Paroxetina/efectos adversos , Paroxetina/farmacocinética , Paroxetina/uso terapéutico , Farmacogenética/métodos , Guías de Práctica Clínica como Asunto , Medicina de Precisión/métodos , Medicamentos bajo Prescripción/normas , Clorhidrato de Venlafaxina/efectos adversos , Clorhidrato de Venlafaxina/farmacocinética , Clorhidrato de Venlafaxina/uso terapéutico
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